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Ann Thorac Surg 2005;79:1669-1675
© 2005 The Society of Thoracic Surgeons

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Original articles: Cardiovascular

Risk Factors, Dynamics, and Cutoff Values for Homograft Stenosis After the Ross Procedure

Department of Adult and Pediatric Cardiac Surgery, La Timone University Hospital, Marseille, France

Accepted for publication October 22, 2004.

^_* Address reprint requests to Dr Metras, Department of Thoracic and Cardiac Surgery, "La Timone" Children's Hospital, 264 Rue Saint Pierre, 13385, Marseille, France (E-mail: dmetras{at}mail.ap-hm.fr).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
BACKGROUND: The purpose of this study was to find homograft-related factors that might be associated with the development of stenosis after the Ross procedure, as well as to identify the natural dynamics of stenosis and find echographic cutoff values after one year of follow-up that might predict such an outcome.

METHODS: We followed up 71 patients (mean age, 24.27 ± 16.57 years) who had such a procedure prospectively by transthoracic echocardiography, between 1993 and 2002. Follow-up was 55.26 ± 29.63 months and was 90.14% complete. Homografts were harvested from heart-beating donors or cardiac transplant recipients. Allograft stenosis was analyzed and risk factors were identified by univariate, multivariate, and survival analysis methods. Stenosis was defined as a mean gradient greater than or equal to 20 mm Hg.

RESULTS: There were two reoperations and 21 homografts were stenotic at the last follow-up, ten of which were already so at one year after the procedure. Cox regression analysis revealed a transhomograft gradient greater than 9 mm Hg at 1 year after the procedure (hazard ratio [HR] = 10.04) and homograft size (HR = 0.75) as independent predictors for stenosis. Stenosis-free survival was 85.94 ± 4.35%, 75.51 ± 5.55%, and 68.56 ± 6.34 after 1, 3, and 5 years, respectively. A cutoff value of 9 mm Hg at 1 year of follow-up could predict different stenosis-free survival rates.

CONCLUSIONS: Homograft size is the most important homograft-related factor for stenosis. Most of the increase in transhomograft gradient occurs in the first 24 months. A gradient of 9 mm Hg or more after 1 year predicts the late occurrence of stenosis.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment References

 
Aortic valve replacement with a pulmonary autograft was first described in 1967 by Ross [1]. However, it was not until the last decade that it gained increasing acceptance, due in part to its excellent long-term results [2]. It has been shown, under experimental [3] and clinical conditions [4], that the pulmonary valve has a preserved growth potential, an excellent resistance to infection [5], a low reoperation rate [6–8], and no need for anticoagulant therapy, making it the aortic substitute of choice in children and young adults and an interesting alternative for other patients with refusal or contraindications to an anticoagulant regimen. Nevertheless, critics of this procedure argue against performing a two-valve replacement for one-valve disease, thus increasing the operative and reoperative risk in these patients. While reoperations for autograft dilation, accompanied or not by aortic incompetence, remain rare [6–8], and, for some authors, may be prevented by using modified operative techniques, such as pericardial [9] or felt reinforcement of the neoaortic suture lines, homograft stenosis [10] appears not to be related to surgical factors, thus being the biggest risk factor for reoperation in this particular setting. However, the rate of increase of the transhomograft gradient (THG) over time is unknown. Furthermore, no prognostic factors for stenosis on the early postoperative echocardiograms have been identified to date.

The Ross procedure was introduced in 1993 at our institution and has been performed with increasing frequency since then, in children and young adults as well as older patients. We attempted to find risk factors for homograft stenosis, to identify the natural dynamics of the THG and find cutoff values at the echocardiography performed one year after the procedure that might be associated with this outcome.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
Patient Population
From February 1993 to November 2002 we performed 71 consecutive Ross procedures in the adult and pediatric cardiac surgery units of our institution. The median patient age was 23.97 years (range, 2 months–68 years). There were 15 female and 56 male patients. Their preoperative pathology and previous interventions are presented in Table 1. The study was approved by our institutional review board and informed consent was obtained from each patient included.

Follow-Up
Two patients died 6 months after the procedure from causes unrelated to the pulmonary homograft. Five more patients were lost to follow-up. All other patients were followed by transthoracic echocardiography and clinical examination yearly after the procedure. Follow-up was 55.26 ± 29.63 months and was complete in 64 patients (90.14%).

Echographic Data
Serial transthoracic echographic measurements were performed at discharge, and then yearly thereafter, by the same in-house cardiologist whenever possible (81.15% of patients) or by the referring cardiologist in the remaining cases (18.85%). All patients that were not lost to follow-up had an echographic examination between September 2003 and May 2004. Resting transthoracic echocardiograms were created with 2.5-MHz ultrasound transducers (Hewlett-Packard Sonos 2500 System; Hewlett-Packard Co, Andover, MA) in standard longitudinal and cross-sectional views and were recorded on videotape. Maximum velocities across the pulmonary valve were calculated by a continuous-wave Doppler imaging transducer. To determine the pressure gradient, the Bernoulli equation was used. To assess pulmonary homograft regurgitation, pulsed wave, continuous wave, and color flow Doppler were performed. Semiquantitative assessment from grade 0 to 3 of pulmonary homograft regurgitation was based on the length and width of the regurgitant jet and the distance that it reaches into the right ventricular outflow tract (RVOT) on the parasternal short-axis view.

Homograft Characteristics
There were 62 pulmonary and 2 aortic homografts. The median donor age was 40 years (range, 9 to 65 years). Mean allograft diameter was 23.85 ± 2.81 mm. Conservation time was defined as the interval between harvesting and implantation (42.66 ± 50.43 months). There was no warm ischemic time as all homografts were harvested from cardiac transplant recipients (39.68%) or heart-beating donors (60.32%) according to French law. Cold ischemic time was defined as the interval between harvesting and cryopreservation (2.46 ± 1.18 days).

Homograft Conservation
After harvesting, the allografts were transported in Roswell Park Memorial Institute (RPMI) nr. 1640 solution to the local tissue bank, then kept in antibiotic solution for 14 to 18 hours at 4°C and finally cryopreserved by gradual freezing (–1°C/min) up to –150°C. The exact protocol is presented in Table 2. All homografts were exposed to this protocol, which was not changed for the duration of our study.

Statistical Analysis
Wilcoxon's test for matched samples was used to compare homograft annulus size and the mean transhomograft gradient over time. Fisher's exact test was used to compare the occurrence of homograft stenosis according to dichotomous variables. The Mann-Whitney test served for assessing continuous data that might be associated with this outcome. Multivariate analysis using the Cox proportional hazard method was carried out for the variables that were found associated with stenosis or were marginally significant (p < 0.2) in the univariate analysis. Only patients whose homografts were not stenotic at one year and whose follow-up was greater than two years were included when the influence of the transhomograft gradient at one year was assessed, in order to avoid predicting "stenosis by stenosis." Freedom from stenosis was estimated using the Kaplan-Meier method and the resulting curves compared by the log-rank test. The test statistics, as well as the 95% confidence limits (CL) (70% confidence limits in figures), are presented where appropriate. All values are expressed as mean ± standard deviation (SD) except survival data, which are presented as percent ± standard error of the mean (SEM). For all tests, a two-tailed p value of 0.05 was considered to assess statistical significance. For statistical software analysis, Intercooled Stata version 8.2 for Macintosh (Stata Corp, College Station, TX) was used.

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
There were two reoperations in our cohort. One 20-year-old patient developed stenosis of his 24-mm pulmonary homograft 4 years after the Ross procedure, with dilation of his right ventricle. The cardiac angiography performed in the build-up to his reoperation revealed a calcified homograft on its anterior surface, with a stenosis that was localized close to the distal anastomosis. The diameter of the homograft measured at the level of the stenosis was 11 mm, while the internal diameter of the homograft was 24 mm. The intraoperative findings confirmed the angiographic data: the stenosis was localized at approximately 10 mm distal from the pulmonary cusps. A pulmonary monocusp plasty was performed. The second patient who was reoperated upon was a one and a half year old child, who had the primary procedure at the age of 4 months. His primary right ventricular outflow conduit was a 17-mm aortic homograft. He exhibited an accelerated rate of graft calcification and stenosis, with a THG of 50 mm Hg, 11 months after the Ross procedure. Right heart catheterization revealed an extremely calcified graft with stenosis localized close to the distal anastomosis (Fig 1). Reoperation was carried out after an unsuccessful pulmonary angioplasty attempt. The pathologic lesion was a calcified ridge located approximately 5 mm away from the distal anastomosis. He had his pulmonary outflow reconstructed with a 22-mm pulmonary homograft. Three more patients had a mean THG greater than 40 mm Hg at the latest echographic examination and are being closely followed for signs of decreasing tolerance, such as right ventricular dilation.

View larger version (70K): [in this window] [in a new window]   Fig 1. Angiographic images of severe calcification of the homograft walls (top) and stenosis (arrow) localized close to the distal anastomosis (bottom). This patient was one of two to be reoperated for hemodynamically significant stenosis.

Receiver operating curves (ROC) of the THG at one year found a cutoff value of 9 mm Hg (Youden index 42.53%) as having the best balance of specificity-sensitivity for predicting homograft stenosis at the last follow-up (area under the curve = 0.7926). (Fig 2). Patients were divided into two groups according to this value: group A (< 9 mm Hg) and group B ( 9 mm Hg).

View larger version (11K): [in this window] [in a new window]   Fig 2. Receiver operating characteristic (ROC) curve (dotted line) depicting the sensitivity to 1-specificity relationship of the various transhomograft gradients at one year of follow-up for predicting late stenosis. The diagonal line represents the reference line.

View larger version (13K): [in this window] [in a new window]   Fig 3. Kaplan-Meier freedom from homograft stenosis. The dashed lines represent the 70% confidence limits.

View larger version (16K): [in this window] [in a new window]   Fig 4. Kaplan-Meier freedom from stenosis in group A (homograft gradient < 9 mm Hg at one year) and group B (homograft gradient 9 mm Hg at one year). There were 19 patients who developed stenosis in group B, while only 4 of the homografts in group A became stenotic (p = 0.029, log-rank).

View larger version (13K): [in this window] [in a new window]   Fig 5. Box plot of the mean change in transhomograft gradient over time, in the two groups: group A (homograft gradient < 9 mm Hg at one year) and group B (homograft gradient 9 mm Hg at one year). The values on the horizontal axis represent years of follow-up.

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

After the reconstruction of the RVOT, stenosis can be located at a specific site, usually downstream from the pulmonary valve close to the distal anastomosis, as was the case with the 2 patients that were reoperated upon, or it can be circumferential [12]. Most patients exhibited a constant decrease in pulmonary graft size at all levels, including the pulmonary annulus, in our population.

Aortic, rather than pulmonary, homografts do calcify in an accelerated manner when placed in the RVOT [13, 14]. This was linked to the higher elastin and intrinsic calcium content of the aortic wall [15]. Of the mechanical factors, homograft size has been found to be a significant factor which influences survival in most studies [10, 13, 16] and our results are consistent with these results as homograft diameter was found to be an independent predictor of late stenosis. This is especially true in the pediatric population. Indeed, children less than three years of age have an accelerated growth and they quickly outgrow their valve. This was the reason why we aggressively oversized the implanted homograft, regardless of the patients' pulmonary annulus size. Only 4 of 64 homografts were smaller than 20 mm in size in our series and all were implanted in children less than one year of age. This might explain why recipient age was not found to be a significant factor for the development of graft stenosis after 4.6 ± 2.46 years of follow-up in our series. Another explanation might be that, in spite of the fact that 14.06% (95% CL 6.63% and 25.02%) of our patients were less than 3 years old, our sample included many young adults, which might obscure the influence of very young age on graft stenosis. However, Forbess and colleagues [16], whose sample included 28.64% children less than one year of age found homograft size, rather than patient age, to be the most important independent predictor for homograft failure, defined as homograft replacement.

Mechanical factors are not the only ones proposed to play a role in the process of calcification and retraction of homografts in the RVOT. Allogenic cryopreserved cells can induce lymphocyte proliferation in vitro [17] and antibodies against donor-specific human leukocyte antigen (HLA) [18–20] have been found in the recipient shortly after a homograft implantation in vivo. There is conflicting evidence regarding whether HLA and blood group (ABO) mismatch may be linked to the development of graft stenosis. Some studies identified HLA-DR [21] and ABO mismatch [21, 22] as risk factors, at least in the pediatric population and when mostly aortic homografts are used [22], while others failed to do so [23]. Furthermore, blood group antigens are absent on the endothelial surface of heart valves, so ABO matching might not be necessary [24]. In our series, blood group and Rh mismatch were unrelated to this outcome and HLA-matching was not done because data were not available for all homografts in the study.

Other homograft-related factors that have been found to play a role in this process are younger donor age [10, 25] and shorter warm ischemic time [10]. Both of these factors translate into a higher viability. Younger donor age is also related to a smaller homograft diameter. Niwaya and colleagues [25] found younger donor age an independent risk factor for this outcome even when patient age was forced into the model. All our homografts came from heart-beating donors, according to French Law. Warm ischemic time was therefore zero and it may have resulted in more viable allografts. This may have influenced our relatively high rate of stenosis, as most valve banks worldwide, in the United States as well as Europe, do harvest from heart-beating as well as nonheart-beating donors.

Stark and colleagues [26] found cryopreservation, rather than antibiotic sterilization, to be detrimental to the late function of the homograft. Interestingly, homografts preserved in antibiotic-nutrient solution functioned well in the experience of Ross [2] and in subsequent reports [27]. While viability is desirable for homografts in the aortic position for preserved collagen synthesis by donor fibroblasts and, thus, increased resistance to mechanical stress, it seems detrimental to pulmonary position homografts, where it may induce an immune response in the host, which may ultimately lead to valve or conduit failure. It is precisely this immune response that decellularized pulmonary homografts promise to restrain, and preliminary results have been encouraging [28]; however, they may not be as readily available as "classic" homografts.

The hypothesis that immunologic mechanisms are implicated in the degeneration of allografts in the pulmonary position is further supported by the pattern of increase in THG, with most of the increase occurring in the first 24 months after the procedure. The importance of the echographic examination performed one year after the implant is stressed by the cutoff value of 9 mm Hg, which can predict different stenosis-free survival rates. This can have a practical value for the timing of postoperative surveillance: indeed, only 4 of the 32 patients whose THG were inferior to 9 mm Hg at one year developed homograft stenosis over a follow-up period of 59.25 ± 27.94 months (range, 19.46 to 127.93 months).

This study has important limitations. Our sample size may have limited the influence of more subtle factors that may be implicated in pulmonary homograft stenosis. In particular, there were not enough patients less than one year of age for us to better assess whether this critical age group is at risk for the outcome we defined. Furthermore, a longer follow-up is always desirable to evaluate better the validity of these results. Finally, all our homografts came from heart-beating donors with zero ischemic time, therefore our results are specific to this subgroup of patients and may not be applicable to cryopreserved homografts with longer warm ischemic times, as are those from most valve banks. Nevertheless, in our series homograft size was the only homograft-related variable independently implicated in the development of stenosis, most of the increase in THG took place in the first 24 months, and a gradient of 9 mm Hg or more at the echographic examination performed one year after the procedure was an independent predictor of late stenosis.

	Appendix

 
Variables that were included in the multivariate analysis were the following: group B status, donor age, recipient age, homograft diameter, cryopreservation time, cold ischemic time, cardiopulmonary bypass time, and cross-clamp time. Factors with a p value less than 0.2 in the univariate analysis that were not included were: donor age less than 30 years, recipient age less than 25 years, homograft size less than 24 mm, as dichotomous variables and conservation time, as a continuous variable. These were not added as their influence was already accounted for in the multivariate model by the variables included; eg, homograft size less than 24 mm is accounted for by homograft size as a continuous variable, etc, and conservation time is the sum between the cold ischemic time and the cryopreservation time.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Horea Feier Olivier Ghez Alberto Riberi Thierry Caus Bernard Kreitmann Dominique Metras Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Feier, H. Articles by Metras, D. Search for Related Content PubMed PubMed Citation Articles by Feier, H. Articles by Metras, D. Related Collections Valve disease