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Long-term function of cryopreserved aortic homografts
Long-term function of cryopreserved aortic homografts A ten-year study Cryopreserved aortic valve homografts have become an accepted aortic valve substitute, but long-term studies with echocardiographic assessment of valve function are largely unavailable. Between 1981 and January 1, 1991, a total of 178 patients aged 9 months to 80 years (median 46 years) underwent implantation of a cryopreserved aortic valve homograft. Serial two-dimensional Doppler echocardiographic studies were obtained in 149 patients. OveraU survival was 91 % at 1 year and 85% at 8 years. Survival of patients undergoing isolated primary infracoronary aortic valve replacement was 99 % at 1 month and 94 % at 8 years. Twelve patients underwent homograft explantation. Freedom from explantation for leaflet degeneration was 95 % at 8 years. Freedom from presumed leaflet failure (valve degeneration at explantation or aortic insufficiency grade 3/4 or more without reoperation on echocardiography) was 94% at 5 years and 85% at 8 years. By multivariable analysis younger recipient age was the only risk factor identified for leaflet failure. Ninety-five percent of patients followed up for 4 or more years were in New York Heart Association class I or II. (J THORAC CARDIOVASC SURG 1993;106:154-66)
James K. Kirklin, MD,a Dennis Smith, MDa (by invitation), William Novick, MDa (by invitation), David C. Naftel, Phl)" (by invitation), John W. Kirklin, MD,a Albert D. Pacifico, MD,a Navin C. Nanda, MD b (by invitation), Frederick R. Helmcke, MDb (by invitation), and Robert C. Bourge, MD C (by invitation), Birmingham, Ala.
Homograft aortic valves have been used in the replacement of diseased human aortic valves since the initial reports ofBarra tt - BoyesI (1964) and Ross2 (1962). Although fresh, antibiotic-sterilized aortic homografts have been used with good results for many years, they have the disadvantage of a finite safe storage time of approximately 1 month.' Techniques of sterilization by irradiation and chemical means used in the 1960s and early 1970s did not provide effective long-term durability.4.5 O'Brien and colleagues developed the techniques From theDivision ofCardiothoracic Surgery, Department ofSurgery; the Division of Cardiology, Department of Medicine," and the Division of Cardiovascular Disease, Department of Medicine," University of Alabama at Birmingham, Birrningharn, Ala. Read at the Seventy-second Annual Meeting ofThe American Association for Thoracic Surgery, Los Angeles, Calif., April 26-29, 1992. Address for reprints: James K. Kirklin, MD, University ofAlabama at Birmingham, Department ofSurgery, Division ofCardiothoracic Surgery, Birmingham, AL 35294-0007. Copyright @ 1993 by Mosby-Year Book, Inc. 0022-5223/93 $1.00+ .10 12/6/46220 1 54
currently used for homograft valve cryopreservation, and in 1987 they" reported excellent intermediate-term function in cryopreserved valves. A program of cryopreservation of homograft aortic valves was initiated at the University of Alabama at Birmingham in 1981. This study analyzes a 10-year experience with cryopreserved aortic valve homografts, including long-term echocardiographic functional evaluation. Patients and methods Between 1981 and January 1991, a total of 178 patients underwent implantation of a cryopreserved aortic valve homograft. The valve wasplaced in the infracoronary position by a freehand implantation technique in 155 patients and was part of a combined aortic valve replacement (AVR) and ascending aortic replacement in 23 patients. Thirteen of these patients duringthis 10-year period underwent homograft reoperation, with 12explanations. The studygroupincluded 124maleand 54 female patients, aged 9 months to 80 years(median age 46 years). During this same IO-year period approximately 1900 AVRs were performed at this institution. Indications. The indications for homograft AVR were
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 1
acquired aortic stenosis in 20 patients, acquired aortic insufficiency (AI) in 16, native or prosthetic valve endocarditis in 41, congenital aortic stenosis in 80, aortic dissection in 9, aortic aneurysm in 3, and bioprosthetic valve degeneration in 9 patients, Demographics. All homograft valves were obtained from the hearts of brain-dead donors under sterile operating conditions, procured at the time of multiorgan donation or tissue donation. Aortic valves were processed only if the heart itself was deemed unsuitable for cardiac transplantation. The donors' ages ranged from 4 to 67 years, with a median age of 34.5 years. Seventyeight percent of allograft donors were less than 50 years of age. Ninety-four percent of valves were from white donors and 6% from black donors. Male donors accounted for 76% of allograft valves. Technique of cryopreservation. The technique of cryopreservation was essentially the technique described by O'Brien and colleagues 7 in Brisbane, Australia. The details of the cryopreservation method have been described elsewhere.f During this IO-yearexperience several changes were made in the initial antibiotic storage protocols before cryopreservation. Between 1981 and 1987, valves were stored in a broad-spectrum antibiotic solution for 48 hours at 4° C. Between 1987 and 1990, initial antibiotic storage was carried out at 37° C for 24 hours. From December of 1990 to the present, an initial 24 hours of antibiotic storage has been carried out at 4° C before cryopreservation. Surgical technique. During this IO-year experience, most of the aortic valve homografts (n = ISS) were implanted in the infracoronary position; two suture lines of continuous 4-0 polypropylene were used and each sinus of Valsalva was scalloped for the freehand implantation. In recent years, some valves have been implanted with the noncoronary sinus aortic wall intact as described by Ross.2 Homograft replacement of the aortic valve and ascending aorta (n = 23) was generally performed by means of the techniques described by Ross,? with reimplantation of the coronary ostia. Tailoring of an enlarged aortic root for purposes of infracoronary homograft implantation was not practiced. Postoperative echocardiographic studies. Postoperative valve function was assessed primarily by echocardiographic studies. A total of 381 postoperative echocardiograms were obtained in 149 patients (84%) during the follow-up period. The last follow-up echocardiogram was obtained 8 to 10 years after homograft AVR in 5 patients, at 5 to 8 years in 34 patients, at 3 to 5 years in 29 patients, at I to 3 years in 50 patients, and within the first year after homograft A VR in 31 patients. In nearly all instances, postoperative studies included two-dimensional color-guided Doppler echocardiography, in which the degree of AI, as well as the peak and mean left ventricular outflow tract gradient, was measured.!" In most instances, the severity was reported on a scale of 0 to 4, with 0 being no insufficiency and grade 4 severe incompetence. Echocardiograms obtained at outside hospitals were frequently reported in terms of mild, moderate, or severe incompetence. For purposes of data analysis, five categories of AI were described. Grade 0 echocardiographic AI was categorized as no AI, grades 0.5 to 1.5 as mild AI, grades 2.0 to 2.5 as moderate AI, grades 3.0 to 3.5 as moderately severe AI, and grade 4 as severe AI. Data acquisition. Basic demographic information for the patient and the allograft donor, surgical details, and all postoperative echocardiograms and catheterizations were analyzed for
Kirklin et af.
I55
all patients undergoing implantation of a cryopreserved aortic valve homograft between 1981 and January I, 1991. Follow-up studies on the entire patient cohort were initiated in April 1991, with questionnaires mailed to all patients and letters mailed to all primary care physicians. Direct patient and physician telephone contact was made whenever sufficient information was not obtained by mail. A concerted effort was made to obtain recent (after July I, 1990) follow-up echocardiographic studies on all patients in whom this was possible. Follow-up was continued through January I, 1992. New York Heart Association (NYHA) functional status, survival status, and history of morbid events (including valve reoperation, thromboembolism, prosthetic endocarditis) were obtained. Overall, follow-up information was obtained on 96% of patients. Maximum follow-up was 9.2 years and mean 48.5 months. Data analysis. Linear regression techniques were used to explore relationships between annular size, homograft size, and annular size predicted by preoperative echocardiogram. Survival and other postoperative events were examined with Kaplan-Meier actuarial analysis and, where appropriate, parametric and hazard function survival analysis. Possible risk factors for early and late death after homograft AVR were examined by multivariable analysis. Specific variables examined included donor variables (age, race, sex, blood type); homograft variables (storage time, valve size); patient demographic variables (age, sex, race, body surface area, blood type); clinical variables (previous aortic operation, NYHA functional classification at the time of operation, emergency operation, preoperative ventilator support, prosthetic or native endocarditis as indication for operation, recipient blood type, and aortic valve lesion); and surgical details (date of operation, surgeon, native anulus size, infracoronary implantation versus ascending aortic replacement, and associated surgical procedures). An estimate of the frequency of primary leaflet failure was examined by considering both explantation information and follow-up echocardiographic data. Patients were considered to have presumed leaflet failure if (I) cusp rupture or valve degeneration was noted at the time of explantation or autopsy or (2) an echocardiogram during follow-up in patients who did not undergo valve explanation indicated aortic regurgitation of grade 3 or higher (moderately severe or severe). Explanted valves were not considered to have leaflet failure if the surgeon observed a normal appearance to the leaflets in the presence of central incompetence or leaflet malalignment or if partial dehiscence of the homograft wall was noted with normalappearing leaflets. Results Survival. Among all patients the actuarial survival was
92% at I month, 91 % at I year, and 85% at 8 years (Fig. I). The hazard function had a rapidly falling early phase of risk during the first month after operation and a low constant hazard extending over the entire period of follow-up. Among patients undergoing AVR and ascending aortic replacement the early mortality was high (Fig. 2). Among the 11 such deaths, all were associated with complex procedures or urgent operations in patients in
I 56
The Journal of Thoracic and Cardiovascular Surgery July 1993
Kirklin et al.
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Years after Homograft AVR Fig. 1. Actuarial (Kaplan-Meier) and parametric survival for all 178 patients receiving cryopreserved aortic homograft implantation at the University of Alabama at Birmingham from 1981 to 1991. Opencirclesindicate individual patient deaths. Vertical bars represent ± 1 standard error. Solid line represents the parametric survival estimate with its 70% confidence limits (dashed lines).
NYHA class IV. Four patients had extensive aortic root endocarditis, 3 had acute ascending aortic dissection, 1 patient underwent replacement of a previous ascending aortic conduit (preoperative NYHA class IV), 2 patients had ascending aortic aneurysms with NYHA class IV symptoms, and I patient had an associated Konno procedure. Among the II early survivors in the group with valve and ascending aortic replacement, there were no late deaths out to 8 years (Fig. '2). Among patients with infracoronary valve implantation, the survival among patients undergoing isolated primary AVR was 99% at I month and 94% at 8 years (Fig. 3). By multivariable analysis of the entire group of 178 patients, advanced preoperative NYHA class (p = 0.06) and the procedure ascending aortic replacement (p = 0.0001) were risk factors for early mortality. No risk factors for late mortality were identified. Correlation between anulus and homograft size. Homograft valve size (measured via graded Hagar dilators as an index of internal valve diameter) ranged from 14 to 30 mm (Table I). The relationship between the intraoperative measurement of anulus size and the internal homograft valve diameter is plotted in Fig. 4. By linear regression analysis, the internal homograft size was generally I to 3 mm smaller than the native anulus. A preoperative echocardiographic anulus estimate could be correlated with the direct intraoperative measurement of anulus size in 43 patients (Fig. 5). In general, the preop-
erative echocardiogram predicted an anulus diameter that was 2 to 3 mm smaller than the directly measured anulus size. Homograft valve reoperations. Thirteen patients underwent homograft valve reoperation, including explanation of 12 homografts (Table II). In 5 cases there was clearly no evidence of degeneration (2 cases of homograft obstruction at the original operation, 2 cases of late subvalvular obstruction unrelated to the homograft valve, and I case of dehiscence of the homograft suture line away from the native aortic wall). Four other patients had a normal appearance of the aortic valve at reoperation and were not believed to have leaflet failure. Three of these 4 valves were known to be incompetent early after the operation, likely related to geometric distortion. Four explanted valves were thought to have leaflet failure, based on cusp tear or extensive valve degeneration noted at reoperation. In 2 of the 4 cases, there was extensive calcification of the homograft leaflets. At 5 years, 92% of patients with infracoronary homograft valveswere free of explantation, with 77% freedom at 8 years (Fig. 6). None of the ascending aortic homografts has been explanted. If only those homograft valves explanted for leaflet failure (degeneration) are considered, there was a 98% freedom from this event at 5 years and 86% freedom at 8 years (Fig. 7). Homograft valve stenosis. Mean systolic transvalvular gradients were available in 112 patients up to 8.7 years after the operation (Fig. 8). Of these, 77% had a mean
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 1
Kirklin et al.
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Years after Homograft AVR Fig. 3. Actuarial (Kaplan-Meier) survival for patients undergoing infracoronary homograft valve implantation. Three subgroups are presented, as indicated. gradient of 10 mm Hg or less and 94% had a gradient of 20 mm Hg or less. Two of 7 patients with a mean gradient greater than 20 mm Hg on the echocardiogram underwent subsequent homograft valve explantation because of degeneration. One patient with a mean postoperative gradient exceeding 20 mm Hg was noted to have an important gradient across the homograft at the initial operation. Homograft valve insufficiency. In addition to identification of AI at the time of homograft explantation (see
again Table II), intermediate-term homograft valve competence was evaluated by echocardiography. The distribution of moderate-to-severe (grade :::::3) AI on the most recent follow-up echocardiogram is indicated in Table III. There was not a clear trend toward increasing AI with larger valve (and therefore anulus) size. However, few patients had a homograft size exceeding 26 mm. To examine the natural progression of homograft insufficiency after infracoronary implantation, we analyzed all subsequent echocardiographic grades of AI in
158
The Journal of Thoracic and Cardiovascular Surgery July 1993
Kirklin et al.
Table I. Correlation between homograft valve size (first column) and the measured anulus size (third column) Valve size (mm)
Mean anulus size (mm)
n
14 15 16 17 18 19 20 21
12 18 18 21
22
27
23 24 25 26
28 22 10 15 2
27
28 29 30 Total
I I
0 I
I
0 I
Table III. Incidence of echocardiographic moderate or severe (3-4/4) AI after operation related to homograft valve size Moderate-to-severe
Mean age (yr)
16.0 16.5
II
19.0 20.3 21.8 22.2 23.8 24.8 26.1 27.5 28.1 28.4 30.2 31.0
30 39 45 49 46 43 48 44 47 43 54 50
31.0
38
Valve size (mm)
0.7
14 15 16 17 18 19 20 21 22 23 24 25 26 27
28 29 30
178
Table II. Reason for explanation (n = 12) or reoperation without explanation (n = 1) among patients undergoing cryopreserved homograft AVR (University of Alabama at Birmingham, 1981 to 1991, n = 178) Reason for explanation (or reoperation] Homograft obstruction (same operation) Subvalvular obstruction AI with leaflet failure Cusp tear Degeneration Degeneration with severe calcification AI without leaflet failure AI with localized valve dehiscence-repaired
n
Homograft size(s)
2'
17,21
2'
14, 18
I I
21 20 25,26
2 4 I
19,19,23,27 22
• All cases had associated complex left ventricular outflow ohstruction.
the cohort of 94 patients who had a postoperative echocardiogram within the first month after operation. Of these, 59% had no AI and 37% mild AI on the initial echocardiogram (Table IV). Among patients whose valve was totally competent initially, approximately 60% had mild incompetence at 5 years and 20% had moderate incompetence (Table V). Among patients with early mild incompetence, progression to moderate incompetence occurred in less than 10% over 3 years (Table VI). Leaflet failure. The freedom from presumed leaflet
Total px
2=
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%
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0 0
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2
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I
0
0
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15
8
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failure (see again Patients and methods for definition) was 94% at 5 years and 85% at 8 years (Fig. 9). Hazard function analysis showed a slowly rising late risk of leaflet failure (Fig. 10). By multivariable analysis, younger recipient age (p = 0.004) was the only risk factor identified for leaflet failure. Thromboembolism and infective endocarditis. There was one identified thromboembolic episode during this study at 6 months. Three episodes of probable endocarditis were identified at 1.2, 31, and 56 months after operation. Each was successfully managed with intravenous antibiotic therapy. Functional status. Among patients with a follow-upof 4 years or more, 97% were in NYHA class I or II (Table VII). Discussion Survival. The low early mortality rate (1%) and excellent long-term survival after isolated infracoronary homograft AVR (see again Fig. 3) attests to the safety of this method of homograft implantation. The low operative mortality in part reflects application of homograft AVR to patients under 55 years of age (note the median age of 44.6 years for the overall group). The high operative mortality among patients undergoing ascending aortic replacement is disappointing. However, ascending aortic
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 1
Kirklin et al.
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Measured Anulus Diameter (mm) Fig. 4. Scattergram and linear regression for the relationshipbetweeninternal homograft valvediameter and native aortic anulus as measured in the operating room. Solid circles represent multiple observations. Dotted lines about the regression line are 70% confidence limits for the mean.
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Pre-op Echo Anulus Diameter (mm) Fig. 5. Scattergram and linear regression for the relationship between preoperativemeasurement of aortic anulus diameter by echocardiogramand the native aortic anulus as measured in the operating room. Solid circles represent multipleobservations. Dotted lines about the regression line are 70% confidence limits for an individualprediction. replacement with a homograft was largely restricted in this experience to an extremely high-risk patient subset, namely, those with extensive aortic root endocarditis, complex aortic root disease, or complex acute dissection of the ascending aorta. In both types of homograft AVR, there was a virtual absence of late valve-related mortality, which, as also reported by others.l-" is a particular advantage of the homograft aortic valve. Anulus diameter and selection of homograft size. In
this experience, the internal homograft size selected by the surgeon was generally 1 to 3 mm smaller than the intraoperatively measured diameter of the aortic anulus. This is consistent with the prior recommendations of Barratt-Boyes" in selecting homograft sizes. Clearly, as seen in Table I, there is some leeway in selecting a homograft size for a given anulus that will produce a good long-term result. Because of the frequently limited supply of aortic valve homografts available at any institution, it
I 60
The Journal of Thoracic and Cardiovascular Surgery July 1993
Kirklin et at.
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Years after Homograft AVR Fig. 6. Actuarial freedom from valve reoperation for patients undergoing ascending aortic replacement (upper dashed line) and infracoronary aortic valve replacement (circles).
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Fig. 7. Actuarial freedom from homograft explantation for leaflet failure (n would be extremely useful to have a reliable preoperative method of determining anulus size so that the patient could be advised as to the availability of an appropriatesized homograft before the operation. Unfortunately, our regression analysis of preoperative echocardiographically determined anulus size showed considerable variability in relation to the intraoperative anulus measurement. In occasional patients, the echocardiographic prediction was 4 mm more or less than the measured anulus size. For the most part, however, the echocardiographically pre-
= 4).
dieted anulus size was 2 to 3 mm less than the actual measurement. On the basis of this experience, if an allograft needed to be selected before the operation, a homograft size equivalent to or I mm less than the predicted left ventricular outflow tract dimension by echocardiography would seem reasonable. Homograft reoperations. We believe infracoronary homograft implantation is a safe and reproducible operation with appropriate experience. The two intraoperative valve removals for "obstruction" were in patients with
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 1
Kirklin et al.
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Fig. 8. Scattergram of the last available mean systolic valve gradient in each patient assessed by postoperative Doppler echocardiography. Along the horizontal axis is years after AVR. Triangles representpatients who subsequentlyrequired explantation for valvedegeneration. Diamond represents one patient who was observed to have a high gradient in the operating room after implantation. congenital left ventricular outflow obstruction with accompanying aortic stenosis. Only four patients required reoperation for geometric malalignment of the leaflets, and one of those four had a markedly enlarged aortic anulus (31 mm), a known risk factor for early homograft incompetence.' The rare occurrence of partial dehiscence of the homograft away from the aortic wall underscores the importance of secure placement of both homograft suture lines and the prevention of early homograft infection. The absence of any reoperation among patients with insertion of a cylinder allograft containing a valve and ascending aorta is interesting, but the experience is too small to draw secure inferences. McGiffin and O'Brien l l have recommended implantation of a short homograft tube with coronary reirnplantation ("mini-root" replacement), particularly in the presence of a dilated aortic root, as a means of providing improved late homograft valve competence. Homograft valve stenosis. A recognized virtue of homograft aortic valves has been the virtual absence of important valvular gradients in the late postoperative period.' This experience confirms the absence of important gradients in nearly all valves, unless there is associated degeneration, underlying left ventricular outflow tract obstruction, or an important gradient noted at the time of original implantation. Leaflet failure. A controversial aspect of aortic valve homografts relates to the durability of cryopreserved homograft valves in comparison with fresh allografts,
Table IV. Grade of echocardiographic AI early after operation among patients with a Doppler echocardiographic study within the first month after operation (n = 94) Patients with postop. echo during first month AI grade
n
%
None Mild Moderate Moderately severe Severe
55 35 4
59 37 4
Total
94
0 0 100
treated with antibiotics and implanted within about 30 days. In 1987 O'Brien and colleagues? reported the first intermediate-term follow-up of cryopreserved valves and compared the late results to their experience with fresh antibiotic-treated homografts. They noted an 89% freedom from reoperation for degeneration at 10 years for fresh allografts versus 100% for cryopreserved valves. However, they examined only reoperations for degeneration and did not examine the occurrence of late important AI without reoperation. This is probably an underestimate of the phenomenon, because some patients may have moderately severe homograft incompetence that is clinically well tolerated, and therefore they may not undergo reoperation. By including the echocardiograph-
The Journal of Thoracic and Cardiovascular Surgery July 1993
I 6 2 Kirklin et al.
Table V. Follow-up echocardiographic assessment of AI in the 55 patients in whom echocardiographic studies were available in the first month after operation and which showed no AI (see again Table IV) Time after homograft AVR First month
5 Years
3 Years
1 Year
Grade
n
%
n
% of 13
n
% of25
n
% of 15
o
55
100
4 8
31 62 8
12 12
48 48 4
3 9 3 0 0
20 60 20
100
15
100
I 2
I
4
13
100
55
Total
I
0 0
0 0
3
100
25
Table VI. Same depiction as in Table V for the 35 patients in whom Doppler echocardiographic studies were available in the first month after operation and which showed grade 1 AI Time after homograft AVR First month
Al grade
o I 2 3
1 Year
2 4 2
44
22
I
I
II
0 0
100
18
22
9
100
35
Follow-up
n
%
n
%
3
44 12 2 0
76 21 3 0
58
100
IV
38 6
Total
58
100
II
I I I
100
5 19 66 10
I
28 67 6
35
Preop.
II III
5 12
% of9
Table VII. Status of patients who have been followed up for at least 4 years NYHA
n
n
0
Total
% of 18
%
4
Functional status at last follow-up for patients 4 or more years after homograft
AVR
ic "event" of moderately severe or severe AI as an indicator of leaflet failure in addition to proved cases at reoperation, the number of leaflet failure "events" is doubled in the presently reported experience (from four to eight). We believe that this more accurately reflects the future behavior of allograft valves with respect to eventual degeneration and need for replacement. Barratt-Boyes and colleagues ' examined the freedom from reoperation or important clinical AI with fresh aortic valve allografts in a "low-risk" group of patients with aortic anulus size less than 30 mm, patient age greater than IS years, and donor age less than 50 years. Although clinical assessment
5 Years
3 Years n
n
100
% of3
33 33 33
0 0 3
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of important AI is likely not as sensitive as Doppler echocardiography, their reported actuarial freedom from important incompetence of 'approximately 80% at 10 years is similar to our analysis for presumed leaflet failure with cryopreservation techniques. In a more recent analysis, O'Brien and colleagues'? noted a 78% freedom from moderate or severe incompetence at 14 years by clinical and echocardiographic assessment in patients with cryopreserved valves, which was not significantly different from the 50% freedom from moderate or severe AI at 14 years with antibiotic-preserved valves (p = 0.27). The still unresolved issue is the hazard function for leaflet failure in the cryopreserved valves after 10 years; that is, whether the late hazard for degeneration will continue to increase very gradually (as suggested in this study [see again Fig. 10] and in studies from O'Brien's group'<) or whether it will reflect the abrupt increase in the rate of degeneration after about 8 to 10 years that appears to characterize fresh homograft valves.l-? Continued follow-up and analysis of our cohort of patients over the next 5 to 10 years should resolve this question. Clearly, the technique of cryopreservation is critically important in maintaining a supply of homograft valves that could theoretically be used at any time in the future. O'Brien has suggested that fibroblast viability in the
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 1
Kirklin et al.
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Years after Homograft AVR Fig. 10. Hazard function for presumed leaflet failure. The depiction is as in Fig. 3. matrix of cryopreserved valves may promote long-term durability, and he has demonstrated by chromosome studies viable cells of donor origin in one homograft explanted at 9 years.? It is possible that subtle differences in cryopreservation techniques may affect long-term valve durability. O'Brien has emphasized the potentially deleterious effects of prolonged leaflet exposure to some antibiotic preparations (O'Brien, personal communication, 1980). In this study, the valve was treated with antibiotics for 48 hours before cryopreservation during the first 6 years of the study. Only more recently has the antibiotic
exposure time been reduced to 24 hours before cryopreservation. Furthermore, viability testing was not performed on these allografts. To date, however, there is no clear evidence that fibroblast viability enhances valve durability. Freedom from valve-related morbidity. A hallmark of nearly all late follow-up studies of either fresh or cryopreserved homograft aortic valves has been the very low incidence of late valve-related morbidity resulting from thromboembolism or prosthetic valve endocarditis.v 6 Selection of valve substitute in younger patients.
16 4
The Journal of Thoracic and Cardiovascular Surgery July 1993
Kirklin et al.
Although O'Brien6 and Barratt-Boyes! and their associates, as well as we, have demonstrated an increased risk of homograft valve degeneration in younger patients, late homograft valve durability in such patients appears to be considerably better than the published durability of porcine heterografts for comparable ages. In a multivariable analysis of risk factors for late homograft valve incompetence among patients receiving antibiotic-preserved homografts (not cryopreserved), Barratt-Boyes identified recipient age less than 15 years as a risk factor. For patients older than 15 years of age, there was an 80% freedom from important AI (and therefore presumed tissue failure) at 10 years.' O'Brien and colleagues'? reported a 65% freedom from reoperation for structural deterioration at 12 years for patients under 40 years of age with antibiotic-preserved homograft valves. Such age-related analyses for cryopreserved valves are not currently available. In our own experience with cryopreserved homograft valves, the mean age ofpatients with presumed leaflet failure was 33.6 years compared with 45.1 years for patients without leaflet failure. Thus, among patients aged 20 to 50 years in this experience, the 8-year freedom from presumed leaflet failure was approximately 75% after 8 years. Despite the increased rate of aortic homograft valve failure among younger patients, the valve durability in such patients is probably better than that of porcine bioprosthetic valves. The reported rate of porcine heterograft degeneration progressively increases for each decade of age less than 50 years, with a 40% to 60% prevalence of valve failure by 10 years for patients under 40 years of age. 13- 16 Thus, among patients less than about 50 years of age in whom long-term anticoagulation is undesirable, the cryopreserved aortic valve homograft remains the valve substitute of choice. In this study we would make the following inferences: 1. Isolated primary A VR with an aortic valve homograft is a safe operation, with an expected hospital mortality of 1% and an anticipated 80% probability of survival without reoperation for leaflet failure after 10 years. 2. Cryopreserved homograft valves that are perfectly competent early after operation frequently are observed to have mild asymptomatic insufficiency in the ensuing 5 years. 3. Experience with homograft replacement of the aortic valve with a cylinder of valve and ascending aortic homograft is insufficient to determine whether this would provide greater freedom from late AI. 4. This analysis suggests that cryopreserved homograft aortic valves are similar in long-term performance
to fresh aortic homografts for the first 8 to 10 years and that they remain the valve substitute of choice among younger patients who require A VR. REFERENCES I. Barratt-Boyes BG. Homograft aortic valve replacementin
aortic incompetence and stenosis. Thorax 1964;19:131. 2. Ross DN. Homograft replacement of the aortic valve. Lancet 1962;2:487. 3. Barratt-Boyes BG, Roche AHG, Subramanyan R, Pemberton JR, Whitlock RML. Long-term followupofpatients with the antibiotic-sterilized aortic homograft valveinserted freehand in the aortic position. Circulation 1987;75:76877. 4. Barratt-Boyes BG. A method for preparing and insertinga homograft aortic valve. Br J Surg 1965;52:847. 5. Pacifico AD, Karp RB, Kirklin JW. Homografts for replacement of the aortic valve. Circulation 1972;45, 46(Suppl):36-143. 6. O'Brien MF, Stafford EG, Gardner MAH, Pohlner PG, McGiffin DC, Kirklin JW. A comparison of aortic valve replacement with viable cryopreserved and fresh allograft valves with a note on chromosomal studies. J THORAC CARDIOVASC SURG 1987;94:812-23. 7. O'Brien MF, Stafford G, Gardner M, et al. The viablecryopreserved allograft aortic valve. J Cardiac Surg 1987;2 (Suppl 1):153-67. 8. Kirklin JK, Diethelm AG, Kirklin JW. Procurement, cryopreservation and transplantation of aortic valve homografts. In: Fawcett KJ, Barr AR, eds. Tissue Banking. Arlington, Virginia:American Association of Blood Banks, 1987. 9. Ross D. Aortic root replacement with a cardiac allograft: the infected aortic root. In: Yankah AC, Hertzer R, Miller DC, et ai, eds. Cardiac Valve Allografts 1962-1987. New York: Springer, 1988:167. 10. Fan PH, Kapur KK, Nanda NC. Color-guided Doppler echocardiographicassessmentof aortic valvestenosis. J Am Coli Cardiol 1988;12:441-9. II. McGiffin DC, O'Brien MF. A technique for aortic root replacement by an aortic allograft. Ann Thorac Surg 1989; 47:625-7. 12. O'Brien MF, McGiffin DC, Stafford EG, et al. Allograft aortic valve replacement: long-term comparative clinical analysis of the viable cryopreserved and antibiotic 4 0 C stored valves. J Cardiac Surg 1991 ;6(Suppl):534-43. 13. Jamieson WRE, Rosado LJ, Munro AI, et al. CarpentierEdwards standard porcine bioprosthesis: primary tissue failure (structural valve deteioration) by age groups. Ann Thorac Surg 1988;46: 155-62. 14. Jones EL, Weintraub WS, Craver JM, et al. Ten-year experience with the porcine bioprosthetic valve: interrelationshipof valvesurvivaland patient survivalin 1,050valve replacements. Ann Thorac Surg 1990;49:370-84. 15. Burdon TA, Miller DC, Oyer PE, et al. Durability of porcine valves at fifteenyears in a representative North Amer-
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 1
ican patient population. J THORAC CARDIOVASC SURG 1992;I03:238-51. 16. Gallucci Y, Mazzucco A, Bortolotti U, Milano A, Guerra F, Thiene G. The standard Hancock porcine bioprosthesis: overall experience at the University of Padova. J Cardiac Surg I988;3(Suppl):337-45.
Discussion Dr. Charles Yankah (Berlin. Germany). In our institution in Berlin we procure our homograft valves from our heart transplantation program. Ninety percent of these valves are cryopreserved within 4 yours after explantation of the heart. About 6% of the valves are preserved within 4 to 12 hours and the others after 18 hours. On the basis of this procurement technique and knowledge of viability of allografts, we give our homograft valves a viability score of 2, I, or 0, corresponding to the terms allovital, viable, and nonviable. Our preservation technique consists of controlled cooling in I% dimethyl sulfoxide and 20% human albumin (1 0 C per minute) and storage at -80 0 C. The range of preservation times is between I day and 15 months. Histologic examination of a valve that we explanted 3 years after insertion demonstrated the efficacy of our preservation technique. We routinely implant ABO-compatible homografts without immunosuppressive drugs, using only aspirin for 3 months. A valve explanted 3 years after implantation shows endothelial cell lining, macrophages, and maintenance of fibroblasts. I have several questions for Dr. Kirklin: Which type of homograft do you use according to our described criteria? Are they allovital, viable, or nonviable? Do you observe ABO compatibility during implantation with the aim of maintaining the cellular components of the homograft for the long term? Histologic study shows that, although there is an ongoing immunologicprocess, the integrity of the homograft valve is maintained. A nonviable homograft is also acceptable, but the rate of degeneration will be higher than that of allovital valves. Which of these valve groups do you prefer for which patient group on the basis of the degeneration rate? In other words, which allograft type would you use for a young patient? Which of the homograft valves would you use for a patient group with endocarditis? This is a provocative question. At such an operation one cannot be very selective. In our institution we prefer prosthetic valve implantation for endocarditis without ring abscess because recurrence is not at all prevalent in those patients. What is your opinion on that? Sir Brian Barratt-Boyes (Auckland. New Zealand). Dr. Kirklin, I suspect the reason for your inability to find risk factors for degeneration other than young age was that your donor valves all came from donors younger than 50 or 55 years. We found age to be a highly significant risk factor, valves from older donors being subject to faster degeneration. Another reason may be that you used root replacement in larger roots. Perhaps you could tell us whether that was the case. What was the mode of tissue failure in these valves? I suspect that the mode of tissue failure in your viable cryopreserved valvesis different from that ofthe nonviable valves because cusp rupture is more prevalent in the nonviable valves and thickening, retraction, and perhaps calcification are more common in viable valves. The material you presented, from our group is a nonviable valve series.
Kirklin et al.
16 5
Five of your 12 reoperations were for obstruction-an unusually high incidence. Do you think this indicates a technical problem, or have you any other explanation? There is no question in my mind that the major factor affecting the time-related curves that you have presented are technical factors at the time of implantation. In other words, even a slight technical error in freehand placement of a homograft valve, so that it is not geometrically perfect, increases the stress on the leaflets, whether the valve is viable or nonviable, so that failure is more rapid. The only way to assess this factor in a realistic way, and separate it from changes caused by rejection, is to compare freehand, nonstented homograft replacement with aortic allograft root replacement, in which the device is inserted as a unit and the failure mode introduced by technical error is absent. Has regurgitation developed in any of your survivors of the root replacement technique? Dr. Alain F. Carpentier (Paris. France). This is the first study I know of in which the importance of echocardiography in the follow-up of homograft valves is stressed. Cryopreservation was thought to be a breakthrough in homograft valve durability. This study, however, shows that, in addition to a 6% rate of early reoperation caused by technical problems (the price to pay for using a free graft), there is a continuous attrition rate shown not only by late reoperations, the incidence of which has been low in this experience and in this time frame, but mainly by the progressive worsening of AI, as seen by echocardiography; in 5 years, the AI grade increased three times, from 0.5 at 1 month to 1.5 at 5 years. This shows that cryopreservation, although representing an improvement, does not provide the stable result that was expected in the long term. This second generation of homografts should be compared with the second generation of bioprostheses, particularly the new pericardiaI bioprostheses. In a series of 48 such valves reviewed by echocardiography within almost the same time frame, at 3 and 7 years, the stability of the results was superior to that achieved by the first generation of bioprostheses. This improved stability is confirmed by the 0% actuarial rate of reoperation at 9 years in a series of 124 consecutive AYRs in which this pericardial bioprosthesis was used in patients 35 years of age or older. I have three questions for Dr. Kirklin. Can the 5% to 6% incidence of early reoperation be reduced with experience, as suggested by Sir Brian Barratt-Boyes, or is it an unreducible figure linked to the free graft concept itself with its associated risk of dissection of the valve from the anulus? Second, have you seen a difference in the attrition rate according to patient age? Although most of your patients were older than 35 years, there were some younger patients and one of them had a valve degeneration. Does attrition represent a higher risk than in the adult population? Finally, in the three valves you removed for valve degenera tion or calcification, was there any implantation anomaly that could have contributed to early degeneration, since there is a well-known relationship between hemodynamics and degeneration? Dr. J. K. Kirklin. Thank you very much. In response to Dr. Yankah's question about viability testing, I should state that in general in the United States (and also in our own cryopreserved valves) there is no specific viability testing, so it is not possible for me to discuss specificsof our valve viability. We do of course follow the same general guidelines in this country set forth by Mark O'Brien for the cryopreservation technique. Generally there is a 24-hour period of antibiotic storage before cryopreser-
1 6 6 Kirklin et at.
vation at 4 0 C. I assume, on the basis of other information, that these are viable valves. ABO compatibility had no influence on degeneration in our analysis. Regarding endocarditis: on the basis of evidence from both Greenland Hospital and Brisbane, we believe strongly that the homograft valve is the valve substitute of choice in the presence of active infection. I have no opinion regarding the categories of viability testing in the selection of a valve for endocarditis, except that homografts per se are probably an advantage. Sir Brian Barratt-Boyes raised a number of provocative questions. In the earlier experience our donor age limit was 60 years, and more recently it has been restricted to less than 55 years. Essentially all of our valves are from brain-dead, heartbeating transplant donors in whom the hearts are not deemed suitable for transplantation. Regarding larger aortic root sizes, we generally used an aortic valve homograft if the anulus of the native valve was 30 mm or less so long as we had a 26 mm homograft available. If it was larger than 30 mm, we generally used either root replacement or, more commonly, a prosthetic valve. There was no attempt to tailor the aortic root to allow implantation of the homograft. Within that spectrum, larger anulus size was not a risk factor for incompetence. Degeneration of the valves occurred in two specific time periods. In one valve, the cusp rupture occurred within the first year, and there could be some argument that this was not a true leaflet failure. Perhaps this was caused by a small leaflet tear at the time of implantation that set the stage for early incompetence. All we can say is that the surgeon observed a tear of the leaflet at the time of reoperation. Two of the other three degenerated valves were calcified at the time of explantation. We could not identify any factors at the original operation which would have predicted that. I should note also that the experience in Brisbane suggests that the mode of degeneration with the cryopreserved valve may be different from that of the nonviable fresh homo-
The Journal of Thoracic and Cardiovascular Surgery July 1993
grafts, in that there is intense calcification of the leaflets, not so dissimilar in severe cases from a degenerated porcine heterograft valve. Regarding left ventricular outflow obstruction, the vast majority of these cases occurred early after operation and were related to complex operations for congenital disease in which there was multilevel obstruction in the left ventricular outflow tract. In the last 5 years the incidence of early reoperation for incompetence or obstruction is essentially zero. Regarding the comment from Dr. Carpentier about progression of AI, it is important to realize that there is some progression of AI in these valves. It may well relate to subtle geometric abnormalities at the time of implantation. In our small group of 13 patients who are surviving long term after aortic root and ascending aortic replacement, there have been no explantation of those valves for AI. Thus there continues to be some uncertainty about whether a tube would potentially be better than a freehand implantation. In response to Dr. Carpentier's comments about the immutable tendency for progressive insufficiency, I am not convinced that will occur. Recall that of those patients with zero AI after operation, 60% of them did have AI by 5 years, but it was usually very mild. I think it is really unknown whether we can expect this to progress and eventually lead to valve removal. Finally, age versus degeneration: our median age for patients undergoing valve removal for probable tissue failure was about 38 years versus about 46 years for those not undergoing reoperation. Degeneration is slightly more likely to occur in younger patients, but further studies will be required to characterize that relationship. I am excited by the preliminary data about the new series of heterograft valves, but it is important to remember that for them to be compared with the homograft valve for younger patients, they must be analyzed for the rate of degeneration among patients in their 20s, 30s, and 40s, which are the critical groups for application of aortic valve homografts.
James K. Kirklin, MD,a Dennis Smith, MDa (by invitation), William Novick, MDa (by invitation), David C. Naftel, Phl)" (by invitation), John W. Kirklin, MD,a Albert D. Pacifico, MD,a Navin C. Nanda, MD b (by invitation), Frederick R. Helmcke, MDb (by invitation), and Robert C. Bourge, MD C (by invitation), Birmingham, Ala.
Homograft aortic valves have been used in the replacement of diseased human aortic valves since the initial reports ofBarra tt - BoyesI (1964) and Ross2 (1962). Although fresh, antibiotic-sterilized aortic homografts have been used with good results for many years, they have the disadvantage of a finite safe storage time of approximately 1 month.' Techniques of sterilization by irradiation and chemical means used in the 1960s and early 1970s did not provide effective long-term durability.4.5 O'Brien and colleagues developed the techniques From theDivision ofCardiothoracic Surgery, Department ofSurgery; the Division of Cardiology, Department of Medicine," and the Division of Cardiovascular Disease, Department of Medicine," University of Alabama at Birmingham, Birrningharn, Ala. Read at the Seventy-second Annual Meeting ofThe American Association for Thoracic Surgery, Los Angeles, Calif., April 26-29, 1992. Address for reprints: James K. Kirklin, MD, University ofAlabama at Birmingham, Department ofSurgery, Division ofCardiothoracic Surgery, Birmingham, AL 35294-0007. Copyright @ 1993 by Mosby-Year Book, Inc. 0022-5223/93 $1.00+ .10 12/6/46220 1 54
currently used for homograft valve cryopreservation, and in 1987 they" reported excellent intermediate-term function in cryopreserved valves. A program of cryopreservation of homograft aortic valves was initiated at the University of Alabama at Birmingham in 1981. This study analyzes a 10-year experience with cryopreserved aortic valve homografts, including long-term echocardiographic functional evaluation. Patients and methods Between 1981 and January 1991, a total of 178 patients underwent implantation of a cryopreserved aortic valve homograft. The valve wasplaced in the infracoronary position by a freehand implantation technique in 155 patients and was part of a combined aortic valve replacement (AVR) and ascending aortic replacement in 23 patients. Thirteen of these patients duringthis 10-year period underwent homograft reoperation, with 12explanations. The studygroupincluded 124maleand 54 female patients, aged 9 months to 80 years(median age 46 years). During this same IO-year period approximately 1900 AVRs were performed at this institution. Indications. The indications for homograft AVR were
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 1
acquired aortic stenosis in 20 patients, acquired aortic insufficiency (AI) in 16, native or prosthetic valve endocarditis in 41, congenital aortic stenosis in 80, aortic dissection in 9, aortic aneurysm in 3, and bioprosthetic valve degeneration in 9 patients, Demographics. All homograft valves were obtained from the hearts of brain-dead donors under sterile operating conditions, procured at the time of multiorgan donation or tissue donation. Aortic valves were processed only if the heart itself was deemed unsuitable for cardiac transplantation. The donors' ages ranged from 4 to 67 years, with a median age of 34.5 years. Seventyeight percent of allograft donors were less than 50 years of age. Ninety-four percent of valves were from white donors and 6% from black donors. Male donors accounted for 76% of allograft valves. Technique of cryopreservation. The technique of cryopreservation was essentially the technique described by O'Brien and colleagues 7 in Brisbane, Australia. The details of the cryopreservation method have been described elsewhere.f During this IO-yearexperience several changes were made in the initial antibiotic storage protocols before cryopreservation. Between 1981 and 1987, valves were stored in a broad-spectrum antibiotic solution for 48 hours at 4° C. Between 1987 and 1990, initial antibiotic storage was carried out at 37° C for 24 hours. From December of 1990 to the present, an initial 24 hours of antibiotic storage has been carried out at 4° C before cryopreservation. Surgical technique. During this IO-year experience, most of the aortic valve homografts (n = ISS) were implanted in the infracoronary position; two suture lines of continuous 4-0 polypropylene were used and each sinus of Valsalva was scalloped for the freehand implantation. In recent years, some valves have been implanted with the noncoronary sinus aortic wall intact as described by Ross.2 Homograft replacement of the aortic valve and ascending aorta (n = 23) was generally performed by means of the techniques described by Ross,? with reimplantation of the coronary ostia. Tailoring of an enlarged aortic root for purposes of infracoronary homograft implantation was not practiced. Postoperative echocardiographic studies. Postoperative valve function was assessed primarily by echocardiographic studies. A total of 381 postoperative echocardiograms were obtained in 149 patients (84%) during the follow-up period. The last follow-up echocardiogram was obtained 8 to 10 years after homograft AVR in 5 patients, at 5 to 8 years in 34 patients, at 3 to 5 years in 29 patients, at I to 3 years in 50 patients, and within the first year after homograft A VR in 31 patients. In nearly all instances, postoperative studies included two-dimensional color-guided Doppler echocardiography, in which the degree of AI, as well as the peak and mean left ventricular outflow tract gradient, was measured.!" In most instances, the severity was reported on a scale of 0 to 4, with 0 being no insufficiency and grade 4 severe incompetence. Echocardiograms obtained at outside hospitals were frequently reported in terms of mild, moderate, or severe incompetence. For purposes of data analysis, five categories of AI were described. Grade 0 echocardiographic AI was categorized as no AI, grades 0.5 to 1.5 as mild AI, grades 2.0 to 2.5 as moderate AI, grades 3.0 to 3.5 as moderately severe AI, and grade 4 as severe AI. Data acquisition. Basic demographic information for the patient and the allograft donor, surgical details, and all postoperative echocardiograms and catheterizations were analyzed for
Kirklin et af.
I55
all patients undergoing implantation of a cryopreserved aortic valve homograft between 1981 and January I, 1991. Follow-up studies on the entire patient cohort were initiated in April 1991, with questionnaires mailed to all patients and letters mailed to all primary care physicians. Direct patient and physician telephone contact was made whenever sufficient information was not obtained by mail. A concerted effort was made to obtain recent (after July I, 1990) follow-up echocardiographic studies on all patients in whom this was possible. Follow-up was continued through January I, 1992. New York Heart Association (NYHA) functional status, survival status, and history of morbid events (including valve reoperation, thromboembolism, prosthetic endocarditis) were obtained. Overall, follow-up information was obtained on 96% of patients. Maximum follow-up was 9.2 years and mean 48.5 months. Data analysis. Linear regression techniques were used to explore relationships between annular size, homograft size, and annular size predicted by preoperative echocardiogram. Survival and other postoperative events were examined with Kaplan-Meier actuarial analysis and, where appropriate, parametric and hazard function survival analysis. Possible risk factors for early and late death after homograft AVR were examined by multivariable analysis. Specific variables examined included donor variables (age, race, sex, blood type); homograft variables (storage time, valve size); patient demographic variables (age, sex, race, body surface area, blood type); clinical variables (previous aortic operation, NYHA functional classification at the time of operation, emergency operation, preoperative ventilator support, prosthetic or native endocarditis as indication for operation, recipient blood type, and aortic valve lesion); and surgical details (date of operation, surgeon, native anulus size, infracoronary implantation versus ascending aortic replacement, and associated surgical procedures). An estimate of the frequency of primary leaflet failure was examined by considering both explantation information and follow-up echocardiographic data. Patients were considered to have presumed leaflet failure if (I) cusp rupture or valve degeneration was noted at the time of explantation or autopsy or (2) an echocardiogram during follow-up in patients who did not undergo valve explanation indicated aortic regurgitation of grade 3 or higher (moderately severe or severe). Explanted valves were not considered to have leaflet failure if the surgeon observed a normal appearance to the leaflets in the presence of central incompetence or leaflet malalignment or if partial dehiscence of the homograft wall was noted with normalappearing leaflets. Results Survival. Among all patients the actuarial survival was
92% at I month, 91 % at I year, and 85% at 8 years (Fig. I). The hazard function had a rapidly falling early phase of risk during the first month after operation and a low constant hazard extending over the entire period of follow-up. Among patients undergoing AVR and ascending aortic replacement the early mortality was high (Fig. 2). Among the 11 such deaths, all were associated with complex procedures or urgent operations in patients in
I 56
The Journal of Thoracic and Cardiovascular Surgery July 1993
Kirklin et al.
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NYHA class IV. Four patients had extensive aortic root endocarditis, 3 had acute ascending aortic dissection, 1 patient underwent replacement of a previous ascending aortic conduit (preoperative NYHA class IV), 2 patients had ascending aortic aneurysms with NYHA class IV symptoms, and I patient had an associated Konno procedure. Among the II early survivors in the group with valve and ascending aortic replacement, there were no late deaths out to 8 years (Fig. '2). Among patients with infracoronary valve implantation, the survival among patients undergoing isolated primary AVR was 99% at I month and 94% at 8 years (Fig. 3). By multivariable analysis of the entire group of 178 patients, advanced preoperative NYHA class (p = 0.06) and the procedure ascending aortic replacement (p = 0.0001) were risk factors for early mortality. No risk factors for late mortality were identified. Correlation between anulus and homograft size. Homograft valve size (measured via graded Hagar dilators as an index of internal valve diameter) ranged from 14 to 30 mm (Table I). The relationship between the intraoperative measurement of anulus size and the internal homograft valve diameter is plotted in Fig. 4. By linear regression analysis, the internal homograft size was generally I to 3 mm smaller than the native anulus. A preoperative echocardiographic anulus estimate could be correlated with the direct intraoperative measurement of anulus size in 43 patients (Fig. 5). In general, the preop-
erative echocardiogram predicted an anulus diameter that was 2 to 3 mm smaller than the directly measured anulus size. Homograft valve reoperations. Thirteen patients underwent homograft valve reoperation, including explanation of 12 homografts (Table II). In 5 cases there was clearly no evidence of degeneration (2 cases of homograft obstruction at the original operation, 2 cases of late subvalvular obstruction unrelated to the homograft valve, and I case of dehiscence of the homograft suture line away from the native aortic wall). Four other patients had a normal appearance of the aortic valve at reoperation and were not believed to have leaflet failure. Three of these 4 valves were known to be incompetent early after the operation, likely related to geometric distortion. Four explanted valves were thought to have leaflet failure, based on cusp tear or extensive valve degeneration noted at reoperation. In 2 of the 4 cases, there was extensive calcification of the homograft leaflets. At 5 years, 92% of patients with infracoronary homograft valveswere free of explantation, with 77% freedom at 8 years (Fig. 6). None of the ascending aortic homografts has been explanted. If only those homograft valves explanted for leaflet failure (degeneration) are considered, there was a 98% freedom from this event at 5 years and 86% freedom at 8 years (Fig. 7). Homograft valve stenosis. Mean systolic transvalvular gradients were available in 112 patients up to 8.7 years after the operation (Fig. 8). Of these, 77% had a mean
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 1
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Cryopreserved Aortic Homografts UAB; 1981 -1991; Infracoronary AVR
30 20 10 0
0
2
3
4
567
8
9
10
Years after Homograft AVR Fig. 3. Actuarial (Kaplan-Meier) survival for patients undergoing infracoronary homograft valve implantation. Three subgroups are presented, as indicated. gradient of 10 mm Hg or less and 94% had a gradient of 20 mm Hg or less. Two of 7 patients with a mean gradient greater than 20 mm Hg on the echocardiogram underwent subsequent homograft valve explantation because of degeneration. One patient with a mean postoperative gradient exceeding 20 mm Hg was noted to have an important gradient across the homograft at the initial operation. Homograft valve insufficiency. In addition to identification of AI at the time of homograft explantation (see
again Table II), intermediate-term homograft valve competence was evaluated by echocardiography. The distribution of moderate-to-severe (grade :::::3) AI on the most recent follow-up echocardiogram is indicated in Table III. There was not a clear trend toward increasing AI with larger valve (and therefore anulus) size. However, few patients had a homograft size exceeding 26 mm. To examine the natural progression of homograft insufficiency after infracoronary implantation, we analyzed all subsequent echocardiographic grades of AI in
158
The Journal of Thoracic and Cardiovascular Surgery July 1993
Kirklin et al.
Table I. Correlation between homograft valve size (first column) and the measured anulus size (third column) Valve size (mm)
Mean anulus size (mm)
n
14 15 16 17 18 19 20 21
12 18 18 21
22
27
23 24 25 26
28 22 10 15 2
27
28 29 30 Total
I I
0 I
I
0 I
Table III. Incidence of echocardiographic moderate or severe (3-4/4) AI after operation related to homograft valve size Moderate-to-severe
Mean age (yr)
16.0 16.5
II
19.0 20.3 21.8 22.2 23.8 24.8 26.1 27.5 28.1 28.4 30.2 31.0
30 39 45 49 46 43 48 44 47 43 54 50
31.0
38
Valve size (mm)
0.7
14 15 16 17 18 19 20 21 22 23 24 25 26 27
28 29 30
178
Table II. Reason for explanation (n = 12) or reoperation without explanation (n = 1) among patients undergoing cryopreserved homograft AVR (University of Alabama at Birmingham, 1981 to 1991, n = 178) Reason for explanation (or reoperation] Homograft obstruction (same operation) Subvalvular obstruction AI with leaflet failure Cusp tear Degeneration Degeneration with severe calcification AI without leaflet failure AI with localized valve dehiscence-repaired
n
Homograft size(s)
2'
17,21
2'
14, 18
I I
21 20 25,26
2 4 I
19,19,23,27 22
• All cases had associated complex left ventricular outflow ohstruction.
the cohort of 94 patients who had a postoperative echocardiogram within the first month after operation. Of these, 59% had no AI and 37% mild AI on the initial echocardiogram (Table IV). Among patients whose valve was totally competent initially, approximately 60% had mild incompetence at 5 years and 20% had moderate incompetence (Table V). Among patients with early mild incompetence, progression to moderate incompetence occurred in less than 10% over 3 years (Table VI). Leaflet failure. The freedom from presumed leaflet
Total px
2=
AI on last echo or at explant No.
%
0 0
0 0
0 I
0 8
2
II
I
0
6 19 7 7 0 10 7 50 0
I
0
0
178
15
8
n I I
0 I
12 18 18 21 27
28 22 10 15 2 I
4 2 2 0 I I I
0
0.8.
failure (see again Patients and methods for definition) was 94% at 5 years and 85% at 8 years (Fig. 9). Hazard function analysis showed a slowly rising late risk of leaflet failure (Fig. 10). By multivariable analysis, younger recipient age (p = 0.004) was the only risk factor identified for leaflet failure. Thromboembolism and infective endocarditis. There was one identified thromboembolic episode during this study at 6 months. Three episodes of probable endocarditis were identified at 1.2, 31, and 56 months after operation. Each was successfully managed with intravenous antibiotic therapy. Functional status. Among patients with a follow-upof 4 years or more, 97% were in NYHA class I or II (Table VII). Discussion Survival. The low early mortality rate (1%) and excellent long-term survival after isolated infracoronary homograft AVR (see again Fig. 3) attests to the safety of this method of homograft implantation. The low operative mortality in part reflects application of homograft AVR to patients under 55 years of age (note the median age of 44.6 years for the overall group). The high operative mortality among patients undergoing ascending aortic replacement is disappointing. However, ascending aortic
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 1
Kirklin et al.
E E
l!l
32
Anulus Diameter (mm)
30
Measured
>
IV
16 17 19
21
26
27
>
22
~
20
............
.'
".
.... "
.
o
0
~::
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•• . 0• 0•• •
n =127 R2 =87%
0
+'
o
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Cl
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0
.". .... 0'-
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21 22 24
23 25
24
./
Homograft Size
17 19
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\1'1 Ql
159
18
::I: 16 14
J.c:....~-e_~--'--~_--'---~_-'----~----'_~--.l._~...J....~_...I-~--'
14
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18
20
22
24
26
32
28
Measured Anulus Diameter (mm) Fig. 4. Scattergram and linear regression for the relationshipbetweeninternal homograft valvediameter and native aortic anulus as measured in the operating room. Solid circles represent multiple observations. Dotted lines about the regression line are 70% confidence limits for the mean.
-E
-
32
E
30
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28
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Cryopreserved Aortic Homografts UAB; 1981 -1991
E 26
o o
IV
Ci
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:; 22
c:
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p<.0001
18
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18.2
21
= =
n 43 R2 69%
'"
14.0 16.1
17 19
20
20.3 22.4 24.6
23 25
27 26
28
32
Pre-op Echo Anulus Diameter (mm) Fig. 5. Scattergram and linear regression for the relationship between preoperativemeasurement of aortic anulus diameter by echocardiogramand the native aortic anulus as measured in the operating room. Solid circles represent multipleobservations. Dotted lines about the regression line are 70% confidence limits for an individualprediction. replacement with a homograft was largely restricted in this experience to an extremely high-risk patient subset, namely, those with extensive aortic root endocarditis, complex aortic root disease, or complex acute dissection of the ascending aorta. In both types of homograft AVR, there was a virtual absence of late valve-related mortality, which, as also reported by others.l-" is a particular advantage of the homograft aortic valve. Anulus diameter and selection of homograft size. In
this experience, the internal homograft size selected by the surgeon was generally 1 to 3 mm smaller than the intraoperatively measured diameter of the aortic anulus. This is consistent with the prior recommendations of Barratt-Boyes" in selecting homograft sizes. Clearly, as seen in Table I, there is some leeway in selecting a homograft size for a given anulus that will produce a good long-term result. Because of the frequently limited supply of aortic valve homografts available at any institution, it
I 60
The Journal of Thoracic and Cardiovascular Surgery July 1993
Kirklin et at.
c
100
0
90
.,tj
...
I'll QI
80
QI
70
...0
60
C. 0
a:: E
E
(8)
Cryopreserved Aortic Homografts UAB; 1981-1991; n=178
50
% Freedom from Reoperation
0
40
Years
Infracor.
...
Asc. Ao. Rep!.
30
1/12 1
98% 96% 92% 77%
100%
"'C
QI QI.
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20
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e,
10 0
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2
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100% 100% 100%
8
9
10
Years after Homograft AVR Fig. 6. Actuarial freedom from valve reoperation for patients undergoing ascending aortic replacement (upper dashed line) and infracoronary aortic valve replacement (circles).
-
~ 90
~80 70
E o
50
...
QI QI LL.
-
-
-
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UAB; 1981 -1991; n = 178
...o - 60 -C
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Homograft Explants for Leaflet Failure (n = 4)
~ 30 QI
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1/12 1
5
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QI
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Years after Homograft AVR
Fig. 7. Actuarial freedom from homograft explantation for leaflet failure (n would be extremely useful to have a reliable preoperative method of determining anulus size so that the patient could be advised as to the availability of an appropriatesized homograft before the operation. Unfortunately, our regression analysis of preoperative echocardiographically determined anulus size showed considerable variability in relation to the intraoperative anulus measurement. In occasional patients, the echocardiographic prediction was 4 mm more or less than the measured anulus size. For the most part, however, the echocardiographically pre-
= 4).
dieted anulus size was 2 to 3 mm less than the actual measurement. On the basis of this experience, if an allograft needed to be selected before the operation, a homograft size equivalent to or I mm less than the predicted left ventricular outflow tract dimension by echocardiography would seem reasonable. Homograft reoperations. We believe infracoronary homograft implantation is a safe and reproducible operation with appropriate experience. The two intraoperative valve removals for "obstruction" were in patients with
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 1
Kirklin et al.
I6I
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~
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Patients Studied n % 77% 86 19 17% 4% S 2 2% 112 100%
0
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Years from Homograft AVR to Last Echo
Fig. 8. Scattergram of the last available mean systolic valve gradient in each patient assessed by postoperative Doppler echocardiography. Along the horizontal axis is years after AVR. Triangles representpatients who subsequentlyrequired explantation for valvedegeneration. Diamond represents one patient who was observed to have a high gradient in the operating room after implantation. congenital left ventricular outflow obstruction with accompanying aortic stenosis. Only four patients required reoperation for geometric malalignment of the leaflets, and one of those four had a markedly enlarged aortic anulus (31 mm), a known risk factor for early homograft incompetence.' The rare occurrence of partial dehiscence of the homograft away from the aortic wall underscores the importance of secure placement of both homograft suture lines and the prevention of early homograft infection. The absence of any reoperation among patients with insertion of a cylinder allograft containing a valve and ascending aorta is interesting, but the experience is too small to draw secure inferences. McGiffin and O'Brien l l have recommended implantation of a short homograft tube with coronary reirnplantation ("mini-root" replacement), particularly in the presence of a dilated aortic root, as a means of providing improved late homograft valve competence. Homograft valve stenosis. A recognized virtue of homograft aortic valves has been the virtual absence of important valvular gradients in the late postoperative period.' This experience confirms the absence of important gradients in nearly all valves, unless there is associated degeneration, underlying left ventricular outflow tract obstruction, or an important gradient noted at the time of original implantation. Leaflet failure. A controversial aspect of aortic valve homografts relates to the durability of cryopreserved homograft valves in comparison with fresh allografts,
Table IV. Grade of echocardiographic AI early after operation among patients with a Doppler echocardiographic study within the first month after operation (n = 94) Patients with postop. echo during first month AI grade
n
%
None Mild Moderate Moderately severe Severe
55 35 4
59 37 4
Total
94
0 0 100
treated with antibiotics and implanted within about 30 days. In 1987 O'Brien and colleagues? reported the first intermediate-term follow-up of cryopreserved valves and compared the late results to their experience with fresh antibiotic-treated homografts. They noted an 89% freedom from reoperation for degeneration at 10 years for fresh allografts versus 100% for cryopreserved valves. However, they examined only reoperations for degeneration and did not examine the occurrence of late important AI without reoperation. This is probably an underestimate of the phenomenon, because some patients may have moderately severe homograft incompetence that is clinically well tolerated, and therefore they may not undergo reoperation. By including the echocardiograph-
The Journal of Thoracic and Cardiovascular Surgery July 1993
I 6 2 Kirklin et al.
Table V. Follow-up echocardiographic assessment of AI in the 55 patients in whom echocardiographic studies were available in the first month after operation and which showed no AI (see again Table IV) Time after homograft AVR First month
5 Years
3 Years
1 Year
Grade
n
%
n
% of 13
n
% of25
n
% of 15
o
55
100
4 8
31 62 8
12 12
48 48 4
3 9 3 0 0
20 60 20
100
15
100
I 2
I
4
13
100
55
Total
I
0 0
0 0
3
100
25
Table VI. Same depiction as in Table V for the 35 patients in whom Doppler echocardiographic studies were available in the first month after operation and which showed grade 1 AI Time after homograft AVR First month
Al grade
o I 2 3
1 Year
2 4 2
44
22
I
I
II
0 0
100
18
22
9
100
35
Follow-up
n
%
n
%
3
44 12 2 0
76 21 3 0
58
100
IV
38 6
Total
58
100
II
I I I
100
5 19 66 10
I
28 67 6
35
Preop.
II III
5 12
% of9
Table VII. Status of patients who have been followed up for at least 4 years NYHA
n
n
0
Total
% of 18
%
4
Functional status at last follow-up for patients 4 or more years after homograft
AVR
ic "event" of moderately severe or severe AI as an indicator of leaflet failure in addition to proved cases at reoperation, the number of leaflet failure "events" is doubled in the presently reported experience (from four to eight). We believe that this more accurately reflects the future behavior of allograft valves with respect to eventual degeneration and need for replacement. Barratt-Boyes and colleagues ' examined the freedom from reoperation or important clinical AI with fresh aortic valve allografts in a "low-risk" group of patients with aortic anulus size less than 30 mm, patient age greater than IS years, and donor age less than 50 years. Although clinical assessment
5 Years
3 Years n
n
100
% of3
33 33 33
0 0 3
100
of important AI is likely not as sensitive as Doppler echocardiography, their reported actuarial freedom from important incompetence of 'approximately 80% at 10 years is similar to our analysis for presumed leaflet failure with cryopreservation techniques. In a more recent analysis, O'Brien and colleagues'? noted a 78% freedom from moderate or severe incompetence at 14 years by clinical and echocardiographic assessment in patients with cryopreserved valves, which was not significantly different from the 50% freedom from moderate or severe AI at 14 years with antibiotic-preserved valves (p = 0.27). The still unresolved issue is the hazard function for leaflet failure in the cryopreserved valves after 10 years; that is, whether the late hazard for degeneration will continue to increase very gradually (as suggested in this study [see again Fig. 10] and in studies from O'Brien's group'<) or whether it will reflect the abrupt increase in the rate of degeneration after about 8 to 10 years that appears to characterize fresh homograft valves.l-? Continued follow-up and analysis of our cohort of patients over the next 5 to 10 years should resolve this question. Clearly, the technique of cryopreservation is critically important in maintaining a supply of homograft valves that could theoretically be used at any time in the future. O'Brien has suggested that fibroblast viability in the
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 1
Kirklin et al.
16 3
100
...
Ql
::J
80
...
70
III
LL.
Ql ~ III Ql ..J
E
(45) - - -
(88)
90
_
Cryopreserved Aortic Homoqrafts UAB;1981-1991;n=178 Presumed Leaflet Failure
60
(9)
Freedom from presumed leaflet failure. (Grade> 3AR
50
&lor explantation for leaflet
...0
40
Years
E
30
1/12
100%
1
99.8%
5 8
94%
0
"'C Ql Ql
...
LL.
20 10 0
0
3
2
failure)
85%
456
7
8
9
10
Years after Homograft AVR Fig. 9. Actuarial and parametric freedom from presumed leaflet failure. The parametric depiction is as in Fig. 4. Thisincludes patientswithAI byechograde 3or 4 (n = 4), patientsundergoing explantationforleafletfailure (n = 4), or leaflet degeneration found at autopsy (n = 0). AR, Aortic regurgitation (insufficiency). 0.050 ~
.J::: ....
0.045
c::
0.040
:!:
0.035
...
0.030
Cryopreserved Aortic Homografts UAB; 1981-1991; n=178 Presumed Leaflet Failure
0
•
III
QI
::::l
';0 u.
0.025
....
0.020
~ III
0.015
QI
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Years
0.010 0.005 0.000
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t
t - i - -
a
2
-
J
~
-
-
-
3
T
4
0.03 0.4
2.1 3.3
- - - - i -5
- - - - ---
- - ---I
6
7
8
9
10
Years after Homograft AVR Fig. 10. Hazard function for presumed leaflet failure. The depiction is as in Fig. 3. matrix of cryopreserved valves may promote long-term durability, and he has demonstrated by chromosome studies viable cells of donor origin in one homograft explanted at 9 years.? It is possible that subtle differences in cryopreservation techniques may affect long-term valve durability. O'Brien has emphasized the potentially deleterious effects of prolonged leaflet exposure to some antibiotic preparations (O'Brien, personal communication, 1980). In this study, the valve was treated with antibiotics for 48 hours before cryopreservation during the first 6 years of the study. Only more recently has the antibiotic
exposure time been reduced to 24 hours before cryopreservation. Furthermore, viability testing was not performed on these allografts. To date, however, there is no clear evidence that fibroblast viability enhances valve durability. Freedom from valve-related morbidity. A hallmark of nearly all late follow-up studies of either fresh or cryopreserved homograft aortic valves has been the very low incidence of late valve-related morbidity resulting from thromboembolism or prosthetic valve endocarditis.v 6 Selection of valve substitute in younger patients.
16 4
The Journal of Thoracic and Cardiovascular Surgery July 1993
Kirklin et al.
Although O'Brien6 and Barratt-Boyes! and their associates, as well as we, have demonstrated an increased risk of homograft valve degeneration in younger patients, late homograft valve durability in such patients appears to be considerably better than the published durability of porcine heterografts for comparable ages. In a multivariable analysis of risk factors for late homograft valve incompetence among patients receiving antibiotic-preserved homografts (not cryopreserved), Barratt-Boyes identified recipient age less than 15 years as a risk factor. For patients older than 15 years of age, there was an 80% freedom from important AI (and therefore presumed tissue failure) at 10 years.' O'Brien and colleagues'? reported a 65% freedom from reoperation for structural deterioration at 12 years for patients under 40 years of age with antibiotic-preserved homograft valves. Such age-related analyses for cryopreserved valves are not currently available. In our own experience with cryopreserved homograft valves, the mean age ofpatients with presumed leaflet failure was 33.6 years compared with 45.1 years for patients without leaflet failure. Thus, among patients aged 20 to 50 years in this experience, the 8-year freedom from presumed leaflet failure was approximately 75% after 8 years. Despite the increased rate of aortic homograft valve failure among younger patients, the valve durability in such patients is probably better than that of porcine bioprosthetic valves. The reported rate of porcine heterograft degeneration progressively increases for each decade of age less than 50 years, with a 40% to 60% prevalence of valve failure by 10 years for patients under 40 years of age. 13- 16 Thus, among patients less than about 50 years of age in whom long-term anticoagulation is undesirable, the cryopreserved aortic valve homograft remains the valve substitute of choice. In this study we would make the following inferences: 1. Isolated primary A VR with an aortic valve homograft is a safe operation, with an expected hospital mortality of 1% and an anticipated 80% probability of survival without reoperation for leaflet failure after 10 years. 2. Cryopreserved homograft valves that are perfectly competent early after operation frequently are observed to have mild asymptomatic insufficiency in the ensuing 5 years. 3. Experience with homograft replacement of the aortic valve with a cylinder of valve and ascending aortic homograft is insufficient to determine whether this would provide greater freedom from late AI. 4. This analysis suggests that cryopreserved homograft aortic valves are similar in long-term performance
to fresh aortic homografts for the first 8 to 10 years and that they remain the valve substitute of choice among younger patients who require A VR. REFERENCES I. Barratt-Boyes BG. Homograft aortic valve replacementin
aortic incompetence and stenosis. Thorax 1964;19:131. 2. Ross DN. Homograft replacement of the aortic valve. Lancet 1962;2:487. 3. Barratt-Boyes BG, Roche AHG, Subramanyan R, Pemberton JR, Whitlock RML. Long-term followupofpatients with the antibiotic-sterilized aortic homograft valveinserted freehand in the aortic position. Circulation 1987;75:76877. 4. Barratt-Boyes BG. A method for preparing and insertinga homograft aortic valve. Br J Surg 1965;52:847. 5. Pacifico AD, Karp RB, Kirklin JW. Homografts for replacement of the aortic valve. Circulation 1972;45, 46(Suppl):36-143. 6. O'Brien MF, Stafford EG, Gardner MAH, Pohlner PG, McGiffin DC, Kirklin JW. A comparison of aortic valve replacement with viable cryopreserved and fresh allograft valves with a note on chromosomal studies. J THORAC CARDIOVASC SURG 1987;94:812-23. 7. O'Brien MF, Stafford G, Gardner M, et al. The viablecryopreserved allograft aortic valve. J Cardiac Surg 1987;2 (Suppl 1):153-67. 8. Kirklin JK, Diethelm AG, Kirklin JW. Procurement, cryopreservation and transplantation of aortic valve homografts. In: Fawcett KJ, Barr AR, eds. Tissue Banking. Arlington, Virginia:American Association of Blood Banks, 1987. 9. Ross D. Aortic root replacement with a cardiac allograft: the infected aortic root. In: Yankah AC, Hertzer R, Miller DC, et ai, eds. Cardiac Valve Allografts 1962-1987. New York: Springer, 1988:167. 10. Fan PH, Kapur KK, Nanda NC. Color-guided Doppler echocardiographicassessmentof aortic valvestenosis. J Am Coli Cardiol 1988;12:441-9. II. McGiffin DC, O'Brien MF. A technique for aortic root replacement by an aortic allograft. Ann Thorac Surg 1989; 47:625-7. 12. O'Brien MF, McGiffin DC, Stafford EG, et al. Allograft aortic valve replacement: long-term comparative clinical analysis of the viable cryopreserved and antibiotic 4 0 C stored valves. J Cardiac Surg 1991 ;6(Suppl):534-43. 13. Jamieson WRE, Rosado LJ, Munro AI, et al. CarpentierEdwards standard porcine bioprosthesis: primary tissue failure (structural valve deteioration) by age groups. Ann Thorac Surg 1988;46: 155-62. 14. Jones EL, Weintraub WS, Craver JM, et al. Ten-year experience with the porcine bioprosthetic valve: interrelationshipof valvesurvivaland patient survivalin 1,050valve replacements. Ann Thorac Surg 1990;49:370-84. 15. Burdon TA, Miller DC, Oyer PE, et al. Durability of porcine valves at fifteenyears in a representative North Amer-
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 1
ican patient population. J THORAC CARDIOVASC SURG 1992;I03:238-51. 16. Gallucci Y, Mazzucco A, Bortolotti U, Milano A, Guerra F, Thiene G. The standard Hancock porcine bioprosthesis: overall experience at the University of Padova. J Cardiac Surg I988;3(Suppl):337-45.
Discussion Dr. Charles Yankah (Berlin. Germany). In our institution in Berlin we procure our homograft valves from our heart transplantation program. Ninety percent of these valves are cryopreserved within 4 yours after explantation of the heart. About 6% of the valves are preserved within 4 to 12 hours and the others after 18 hours. On the basis of this procurement technique and knowledge of viability of allografts, we give our homograft valves a viability score of 2, I, or 0, corresponding to the terms allovital, viable, and nonviable. Our preservation technique consists of controlled cooling in I% dimethyl sulfoxide and 20% human albumin (1 0 C per minute) and storage at -80 0 C. The range of preservation times is between I day and 15 months. Histologic examination of a valve that we explanted 3 years after insertion demonstrated the efficacy of our preservation technique. We routinely implant ABO-compatible homografts without immunosuppressive drugs, using only aspirin for 3 months. A valve explanted 3 years after implantation shows endothelial cell lining, macrophages, and maintenance of fibroblasts. I have several questions for Dr. Kirklin: Which type of homograft do you use according to our described criteria? Are they allovital, viable, or nonviable? Do you observe ABO compatibility during implantation with the aim of maintaining the cellular components of the homograft for the long term? Histologic study shows that, although there is an ongoing immunologicprocess, the integrity of the homograft valve is maintained. A nonviable homograft is also acceptable, but the rate of degeneration will be higher than that of allovital valves. Which of these valve groups do you prefer for which patient group on the basis of the degeneration rate? In other words, which allograft type would you use for a young patient? Which of the homograft valves would you use for a patient group with endocarditis? This is a provocative question. At such an operation one cannot be very selective. In our institution we prefer prosthetic valve implantation for endocarditis without ring abscess because recurrence is not at all prevalent in those patients. What is your opinion on that? Sir Brian Barratt-Boyes (Auckland. New Zealand). Dr. Kirklin, I suspect the reason for your inability to find risk factors for degeneration other than young age was that your donor valves all came from donors younger than 50 or 55 years. We found age to be a highly significant risk factor, valves from older donors being subject to faster degeneration. Another reason may be that you used root replacement in larger roots. Perhaps you could tell us whether that was the case. What was the mode of tissue failure in these valves? I suspect that the mode of tissue failure in your viable cryopreserved valvesis different from that ofthe nonviable valves because cusp rupture is more prevalent in the nonviable valves and thickening, retraction, and perhaps calcification are more common in viable valves. The material you presented, from our group is a nonviable valve series.
Kirklin et al.
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Five of your 12 reoperations were for obstruction-an unusually high incidence. Do you think this indicates a technical problem, or have you any other explanation? There is no question in my mind that the major factor affecting the time-related curves that you have presented are technical factors at the time of implantation. In other words, even a slight technical error in freehand placement of a homograft valve, so that it is not geometrically perfect, increases the stress on the leaflets, whether the valve is viable or nonviable, so that failure is more rapid. The only way to assess this factor in a realistic way, and separate it from changes caused by rejection, is to compare freehand, nonstented homograft replacement with aortic allograft root replacement, in which the device is inserted as a unit and the failure mode introduced by technical error is absent. Has regurgitation developed in any of your survivors of the root replacement technique? Dr. Alain F. Carpentier (Paris. France). This is the first study I know of in which the importance of echocardiography in the follow-up of homograft valves is stressed. Cryopreservation was thought to be a breakthrough in homograft valve durability. This study, however, shows that, in addition to a 6% rate of early reoperation caused by technical problems (the price to pay for using a free graft), there is a continuous attrition rate shown not only by late reoperations, the incidence of which has been low in this experience and in this time frame, but mainly by the progressive worsening of AI, as seen by echocardiography; in 5 years, the AI grade increased three times, from 0.5 at 1 month to 1.5 at 5 years. This shows that cryopreservation, although representing an improvement, does not provide the stable result that was expected in the long term. This second generation of homografts should be compared with the second generation of bioprostheses, particularly the new pericardiaI bioprostheses. In a series of 48 such valves reviewed by echocardiography within almost the same time frame, at 3 and 7 years, the stability of the results was superior to that achieved by the first generation of bioprostheses. This improved stability is confirmed by the 0% actuarial rate of reoperation at 9 years in a series of 124 consecutive AYRs in which this pericardial bioprosthesis was used in patients 35 years of age or older. I have three questions for Dr. Kirklin. Can the 5% to 6% incidence of early reoperation be reduced with experience, as suggested by Sir Brian Barratt-Boyes, or is it an unreducible figure linked to the free graft concept itself with its associated risk of dissection of the valve from the anulus? Second, have you seen a difference in the attrition rate according to patient age? Although most of your patients were older than 35 years, there were some younger patients and one of them had a valve degeneration. Does attrition represent a higher risk than in the adult population? Finally, in the three valves you removed for valve degenera tion or calcification, was there any implantation anomaly that could have contributed to early degeneration, since there is a well-known relationship between hemodynamics and degeneration? Dr. J. K. Kirklin. Thank you very much. In response to Dr. Yankah's question about viability testing, I should state that in general in the United States (and also in our own cryopreserved valves) there is no specific viability testing, so it is not possible for me to discuss specificsof our valve viability. We do of course follow the same general guidelines in this country set forth by Mark O'Brien for the cryopreservation technique. Generally there is a 24-hour period of antibiotic storage before cryopreser-
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vation at 4 0 C. I assume, on the basis of other information, that these are viable valves. ABO compatibility had no influence on degeneration in our analysis. Regarding endocarditis: on the basis of evidence from both Greenland Hospital and Brisbane, we believe strongly that the homograft valve is the valve substitute of choice in the presence of active infection. I have no opinion regarding the categories of viability testing in the selection of a valve for endocarditis, except that homografts per se are probably an advantage. Sir Brian Barratt-Boyes raised a number of provocative questions. In the earlier experience our donor age limit was 60 years, and more recently it has been restricted to less than 55 years. Essentially all of our valves are from brain-dead, heartbeating transplant donors in whom the hearts are not deemed suitable for transplantation. Regarding larger aortic root sizes, we generally used an aortic valve homograft if the anulus of the native valve was 30 mm or less so long as we had a 26 mm homograft available. If it was larger than 30 mm, we generally used either root replacement or, more commonly, a prosthetic valve. There was no attempt to tailor the aortic root to allow implantation of the homograft. Within that spectrum, larger anulus size was not a risk factor for incompetence. Degeneration of the valves occurred in two specific time periods. In one valve, the cusp rupture occurred within the first year, and there could be some argument that this was not a true leaflet failure. Perhaps this was caused by a small leaflet tear at the time of implantation that set the stage for early incompetence. All we can say is that the surgeon observed a tear of the leaflet at the time of reoperation. Two of the other three degenerated valves were calcified at the time of explantation. We could not identify any factors at the original operation which would have predicted that. I should note also that the experience in Brisbane suggests that the mode of degeneration with the cryopreserved valve may be different from that of the nonviable fresh homo-
The Journal of Thoracic and Cardiovascular Surgery July 1993
grafts, in that there is intense calcification of the leaflets, not so dissimilar in severe cases from a degenerated porcine heterograft valve. Regarding left ventricular outflow obstruction, the vast majority of these cases occurred early after operation and were related to complex operations for congenital disease in which there was multilevel obstruction in the left ventricular outflow tract. In the last 5 years the incidence of early reoperation for incompetence or obstruction is essentially zero. Regarding the comment from Dr. Carpentier about progression of AI, it is important to realize that there is some progression of AI in these valves. It may well relate to subtle geometric abnormalities at the time of implantation. In our small group of 13 patients who are surviving long term after aortic root and ascending aortic replacement, there have been no explantation of those valves for AI. Thus there continues to be some uncertainty about whether a tube would potentially be better than a freehand implantation. In response to Dr. Carpentier's comments about the immutable tendency for progressive insufficiency, I am not convinced that will occur. Recall that of those patients with zero AI after operation, 60% of them did have AI by 5 years, but it was usually very mild. I think it is really unknown whether we can expect this to progress and eventually lead to valve removal. Finally, age versus degeneration: our median age for patients undergoing valve removal for probable tissue failure was about 38 years versus about 46 years for those not undergoing reoperation. Degeneration is slightly more likely to occur in younger patients, but further studies will be required to characterize that relationship. I am excited by the preliminary data about the new series of heterograft valves, but it is important to remember that for them to be compared with the homograft valve for younger patients, they must be analyzed for the rate of degeneration among patients in their 20s, 30s, and 40s, which are the critical groups for application of aortic valve homografts.