Ann Thorac Surg 2005;79:1491-1495
© 2005 The Society of Thoracic Surgeons
Original articles: Cardiovascular
Valve-Related Events After Aortic Root Replacement With Cryopreserved Aortic Homografts
Abdullah Kaya, MDa,*,
Marc A. Schepens, MD, PhDa,
Wim J. Morshuis, MD, PhDa,
Robin H. Heijmen, MD, PhDa,
Aart Brutel De La Riviere, MD, PhDb,
Karl M. Dossche, MD, PhDa
a Department of Cardiothoracic Surgery, St. Antonius Hospital Nieuwegein, Nieuwegein, Netherlands
b Department of Cardiothoracic Surgery, University Medical Centre Utrecht, Utrecht, the Netherlands
Accepted for publication November 17, 2004.
* Address reprint requests to Dr Kaya, Department of Cardiothoracic Surgery, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, the Netherlands (E-mail: a_kaya33{at}hotmail.com).
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Abstract
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BACKGROUND: Aortic root replacement with aortic homografts for various pathologic conditions involving the aortic root has yielded good early results. To assess mid-term valve-related events, a follow-up study was conducted.
METHODS: From February 1989 through January 2003, 213 patients with a mean age of 51.3 ± 11.8 years underwent aortic root replacement with a cryopreserved aortic homograft. Bacterial endocarditis (58.7%) was the predominant indication for surgery (native valve endocarditis, n = 73; prosthetic valve endocarditis, n = 52). Of the 197 hospital survivors, 194 were entered in the follow-up study (98.5% complete). Endpoints of the study were death, valve-related death, reoperation for valve failure, endocarditis, thromboembolic events, and anticoagulant-related bleeding events. Follow-up was conducted between February and April 2003.
RESULTS: Overall hospital mortality was 7.5% (n = 16; 70% confidence limits, 5.6% to 9.4%). Mean follow-up was 5.8 years (range, 0.3 to 14.3). In total, 20 late deaths occurred (10.3%); of these, 5 were valve-related. The overall survival at 5 and 10 years is 87.3% ± 2.4% and 70.8% ± 5.3%, respectively. Twenty-one patients (10.8%) required reoperation, either for structural valve deterioration (n = 12), false aneurysm (n = 3), endocarditis of the homograft (n = 3), or for other reason (n = 3). Mortality for reoperation was 28.6% (n = 6). Five-year and 10-year freedom from reoperation is 94.5% ± 1.8% and 76.4% ± 5.3%, respectively. Endocarditis of the homograft was reported in 4 patients (3.2%), of whom 1 patient was treated medically and 3 required reoperation. Thromboembolic events (n = 1) and antioagulant-related bleeding events (n = 0) were rarely seen. A recent echocardiographic study was available in 124 patients (71.3%). Aortic regurgitation grade I to II was reported in 121 patients (97.6%).
CONCLUSIONS: Cryopreserved aortic homografts function well on mid-term evaluation. The incidence of structural valve failure is acceptable. Reoperations for homograft endocarditis carry a high mortality rate.
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Introduction
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Since the publications on the clinical use of homografts for aortic valve replacement, human tissue valves formed their own position in the era of aortic valve substitutes [1, 2]. As with every valve substitute, the homograft aortic valve has its advantages and disadvantages. Restoration of normal flow in the aortic root and coronary orifice resulting in better hydraulic performance, resistance to endocarditis, and rare thromboembolic events without the need for anticoagulation are considered as advantages. Limited donor availability and homograft durability are the serious disadvantages. The long-term performance of homograft aortic valves is profoundly influenced by sterilization and preservation. Early methods like chemical preservation, irradiation [3–5], and freeze drying [6, 7] have shown profound deleterious effect on the long-term function of the aortic homografts. The method of preservation that is currently used in most centers is the technique of homograft valve cryopreservation [8, 9]. It has the advantage of a long shelf half-life time and is readily available for use.
After yielding good early results with cryopreserved aortic homografts used as a freestanding aortic root replacement [10], the present purpose is to assess the mid-term valve-related events in a retrospective follow-up study.
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Material and Methods
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Patients
From February 1989 through January 2003, 213 patients with a mean age of 51.3 ± 11.8 years (range, 14 to 79) underwent aortic root replacement (ARR) with a cryopreserved aortic homograft. There were 159 (74.6%) male and 54 (25.4%) female patients. The indication for operation was aortic regurgitation in 172 patients of which 125 cases were due to endocarditis (73 native valve endocarditis versus 52 prosthetic valve endocarditis), aortic stenosis in 27 patients, and mixed lesions in 14 patients. Pertinent patient data are given in Table 1.
Homograft Data
Aortic homograft valves were harvested under sterile conditions from cardiac transplant recipients, beating-heart or nonbeating-heart donors, with a maximum age of 60 years. Dissection of the heart was generally performed within 24 hours after circulatory arrest. After dissection, the valves were decontaminated by incubation in medium with an antibiotic mixture for 5 hours at 37°C. Thereafter, valves were cryopreserved in medium containing 10% dimethylsulfoxide (DMSO) frozen at a controlled rate of –1°C/min up to –100°C and stored on the vapor of liquid nitrogen (–150° to –196°C). All tissues were cryopreserved within 50 hours after circulatory arrest of the donor. All donors were seronegative for human immunodeficiency virus, hepatitis B surface and core antigen, cytomegalovirus or Treponema pallidum. For implantation, ABO compatibility or HLA type matching was not required. In elective operations, mismatch in age of more than 10 years between the donor valve and recipient was avoided; in urgent operations, this was possible only occasionally. All homografts were provided by Bio Implant Services Foundation (BIS [Leiden, Netherlands]). The homograft characteristics are displayed in Table 2. Details on the operative technique were described before [10].
Follow-Up
Recent information (less than 6 months) about the status of all hospital survivors is collected from the referring cardiologist, by visit at our cardiology department, or by their general physician. April 30, 2003, was the closing date for follow-up and included physical examination, echocardiography, and chest radiography. Endpoints of the study were death, valve-related death, reoperation for valve failure, endocarditis of the homograft, thromboembolic events, and anticoagulant-related bleeding. These endpoints were defined according to the guidelines reported by Edmunds and associates [11]. Valve function was determined by echocardiographic Doppler study including color-flow mapping, as much as available, otherwise by auscultation. Homograft regurgitation was graded on a scale of 0 to 4 on echocardiography, with 0 as no regurgitation, 1 as trivial regurgitation, 2 as mild regurgitation, 3 as moderate regurgitation, and 4 as severe regurgitation.
Data Analysis
Retrospective review was done on the data of all consecutive patients who underwent homograft ARR. Quantitative data are presented as mean ± standard deviation. Univariate comparisons between groups were calculated by the unpaired test, Fisher's exact test, 
2 test, or the one-way or two-way analysis of variance as appropriate. All probabilities are two-tailed. Kaplan-Meier survival curves were used for analysis of survival times, and the Tarone or Breslow test for comparisons between survival curves. Precision was indicated by 70% confidence limits (CL).
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Results
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Patient Survival
Hospital mortality rate was 7.5% (n = 16; 70% CL, 5.6% to 9.4%). There were 197 hospital survivors, of whom 194 were entered in the follow-up study (98.5% complete). Mean and median follow-up times were 5.8 years and 5.4 years, respectively (range, 0.3 to 14.3 years). Total follow-up was 1,118 patient-years. Three patients were lost to follow-up—2 patients emigrated and 1 patient moved to an unknown address. During follow-up 20 patients (10.3%) died. Five of these late deaths were valve related. Three patients had endocarditis of the homograft, 1 had structural valve deterioration, and 1 patient had a false aneurysm. All valve-related late deaths were reoperated on. Of the other 15 nonvalve-related late deaths, 4 patients died of cardiac failure (heart failure and 1 myocardial ischemia 79 months postoperatively) and 11 patients died of noncardiac causes. This is summarized in Table 3. The overall survival at 5 and 10 years is 87.3% ± 2.4% and 70.8% ± 5.3%, respectively. Survival at 5 and 10 years for the endocarditis group was 82.7% ± 3.6% and 57.1% ± 9.9%, respectively, and 91.3% ± 3.7% and 84.3% ± 5.9% for the nonendocarditis group. This is presented in Figure 1.
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Fig 1. Survival curve after homograft aortic root replacement. Open circles = nonendocarditis group; solid circles = overall group; triangles = native valve endocarditis/prosthetic valve endocarditis group.
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Reoperation
Twenty-one patients (10.8%) required reoperation for significant homograft valve dysfunction due to structural valve deterioration (n = 12), false aneurysm (n = 3), homograft valve endocarditis (n = 3), or other reason, as displayed in Table 4. Mean length of time between the initial ARR and reoperation was 67.8 months ± 41.6 months. Six patients reoperated on for structural valve deterioration received an aortic valve replacement (mechanical prosthesis, n = 5; biological prosthesis, n = 1), 3 patients had a Bentall procedure, 2 patients had an aortic valve and supracoronary ascending aorta replacement, and 1 patient had a second homograft implantation. Patients reoperated on for homograft endocarditis received a second homograft implantation, a Shelhigh bioconduit (Shelhigh, Millbum, New Jersey) and mechanical aortic valve replacement, respectively. Six patients (28.6%) died after reoperation. Three patients died after reoperation for endocarditis of the homograft, 2 patients after reoperation for false aneurysm and 1 patient after reoperation for structural valve deterioration. Three of these patients underwent a second or third reoperation. Five- and 10-year freedom from reoperation is 94.5% ± 1.8% and 76.5 ± 5.3%, as presented in Figure 2.
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Fig 2. Freedom from reoperation after homograft aortic root replacement, overall group (solid circles).
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Endocarditis
Endocarditis of the homograft valve was reported in 4 patients (3.2%) of whom 1 was treated with antibiotics for 6 weeks, and 3 required reoperation. The medically treated patient recovered completely, but all patients reoperated on for endocarditis of the homograft died soon after the reoperation. The indication for the initial ARR was native valve endocarditis for 3 patients and prosthetic valve endocarditis for 1 patient. The recurrent endocarditis developed 4, 20, 92, and 114 months after the initial operation. The microorganism initially found in the blood culture was different in the second blood cultures in all patients with a recurrent endocarditis of the homograft. The actuarial freedom from endocarditis of the homograft at 5 and 10 years was 99.5% ± 0.5% and 93.5% ± 3.5%, respectively.
Structural Valve Deterioration
Reoperation and replacement of the aortic homograft due to structural valve deterioration was reported in 12 patients. Mean length of time between initial ARR and reoperation was 75.3 months (range, 16 to 121). One patient was in the process of evaluation for reoperation due to structural valve deterioration at the end of the follow-up period. One patient died after reoperation for structural valve deterioration. Actuarial freedom from structural valve deterioration at 5 and 10 years was 98.1% ± 1.1% and 85.8% ± 4.5%, respectively.
Thromboembolism
One patient developed thromboembolism resulting in stroke with permanent sequel after 61 months of the initial operation. Like thromboembolism, anticoagulant-related bleeding events (n = 0) were rarely seen.
Other Complications
During follow-up, 22 patients needed a definitive pacemaker.
Homograft Valve Function
Echocardiographic evaluation of the homograft function was performed by most cardiologists when there was a clinical indication. Otherwise, this study was repeated once in 24 months, approximately. A recent echocardiographic evaluation is defined as an echocardiographic study within 24 months before April 30, 2003, the closing date for follow-up. A recent echocardiographic assessment of the homograft valve function was available in 124 patients (71.3%). Data from this evaluation are listed in Figure 3. There was 1 patient in the follow-up group period of 0 to 3 years who had a grade III aortic regurgitation. This patient had no complaints, and the clinical situation was acceptable. The follow-up group period of 4 to 6 years had a predominantly favorable result. Most patients with a severe grade III or IV aortic regurgitation were in the group with the longest follow-up. All these patients were in the evaluation for a reoperation. Also the percentage of grade II aortic regurgitation was increasing.
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Fig 3. Echocardiographic data: aortic regurgitation during follow-up. Open bars = trivial; light shaded bars = mild; dark shaded bars = moderate; black bars = severe. (yrs = years.)
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Comment
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Since the beginning of homograft aortic valve replacement in our center, the freestanding aortic root replacement has been the technique of choice for the reasons previously described [10]. In brief, being a geometrically single functional unit of the homograft at the implantation, it is expected to reduce both early and late postoperative regurgitation [12, 13]. More than half of the patients in our series had active endocarditis (n = 125), and we believe that in such complex aortic root disease the aortic root replacement technique offers additional advantages because it can fill subannular defects with the muscular cuff of the soft annulus and help restore atrioventricular continuity. More recently, however, we would also consider implanting a biological valve conduit in aortic valve endocarditis [14]. The rationale is based on several observations. Firstly, the promising initial results with the conduit. Secondly, these valves are readily available on the shelf in all seizes, so the operation can be performed immediately if necessary. Finally, the overall results from our series for reoperations on the homograft root are disappointing: a reoperation on the calcified homograft root is not only challenging for the surgeon, but also especially for the patient.
At the evaluation of results of homograft series one must clearly identify whether viable or nonviable valves are being implanted; and when fresh valves are used, how fresh they are, as was pointed out by O'Brien and associates [9]. According to this, we have good results of the cryopreserved homografts comparable to those described in other series [15–19]. Overall survival at 10 years was 70.8%, similar to the 73% survival at 9 years demonstrated by Takkenberg and associates [15], 74% survival at 10 years reported by Doty and associates [16], and 85% survival at 8 years in the series of Kirklin and associates [17].
Cryopreserved aortic homograft demonstrates excellent freedom from thromboembolism in this series. In the first 3 months postoperative acenocoumarol is the choice of oral anticoagulation. After this period, it is switched to acetylsalicylic acid. Only one thromboembolic event was reported on a mean follow-up of 5.8 years. It is not clear whether this extremely low rate is reliable. Usually very little information on minor thromboembolic events is available, be it from the patient or from the patient's physician. On the other hand, important thromboembolic events tend to be well documented. Anyway, the overall low incidence of thromboembolic events in our series confirms the findings of other groups. Endocarditis of the homograft developed in 4 patients of whom 3 were reoperated on, and 1 patient was medically treated. Doty and associates [16] reported only 1 case of homograft endocarditis in 117 patients. In their series only 15 patients (13%) had clinical evidence of aortic valve endocarditis, compared with 125 patients (58.7%) with aortic valve endocarditis in our series. Kirklin and associates [17] reported 3 cases of endocarditis of the homograft in 178 patients followed up for 9 years. Endocarditis was reported as preoperative indication in 41 patients (23%) in their series.
To date, with a mean follow-up of 5.8 years, there was structural valve deterioration reported in 12 patients. The freedom from structural valve deterioration at 5 years in our series is acceptable and similar to other comparable studies [15–18]. From our results, structural valve degeneration occurred early (less than 5 years) in 4 patients. This has influenced considerably our strategy as to which patients should benefit from a homograft valve. In the earlier phase of the study, the homografts were offered to young adults and patients with endocarditis. Nowadays, in our institution, homografts are seldom offered to young adults, but are still considered for endocarditis patients.
Reoperations for homograft dysfunction carried a high mortality in our series. This was particularly so in patients with homograft endocarditis. It has been our strategy to remove the complete homograft root at reoperation for endocarditis. This has proven to be not the simplest of solutions. Reoperation in the nonendocarditis group had a more favorable outcome, because a less aggressive surgery could be performed.
In conclusion, cryopreserved aortic homografts function well on mid-term evaluation. The incidence of structural valve failure is acceptable. Reoperations for homograft endocarditis carry a high mortality rate.
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Abstract
Introduction
