Initial 2-year results of CardioCel® patch implantation in children

Initial 2-year results of CardioCel® patch implantation in children Abstract OBJECTIVES We present the initial 2-year results of CardioCel® patch (Admedus Regen Pty Ltd, Perth, WA, Australia) implantation in paediatric patients with congenital heart diseases. METHODS This was a single-centre retrospective study with prospectively collected data of all patients aged 18 years and under operated for congenital heart disease. The patch was introduced in 2014, with clinical practice committee approval and a special consent in case of an Ozaki procedure. Standard follow-up was performed with systematic clinical exams and echocardiograms. In case of reoperation or graft failure, the patch was removed and sent for a histological examination. RESULTS Between March 2014 and April 2016, 101 patients had surgical repair using a CardioCel patch. The mean age was 22 (±36.3) months, and the mean weight was 9.7 (±10.3) kg. No infections and no intraoperative implantation difficulties were associated with the patch. The median follow-up period was 212 (range 4–726) days. The overall 30-day postoperative mortality was 3.8% (n = 4), none of which were related to graft failure. Five children were reoperated because of graft failure, 4 of whom had the patch implanted for aortic and were aged less than 10 days. The indications for patch implantation in the aortic position were aortopulmonary window, truncus arteriosus, coarctation and aortic arch hypoplasia repair. The median time between the first and the second operation for graft failure was 245 (range 5–480) days. CONCLUSIONS Our experience shows that the patch is well tolerated in the septal, valvar and pulmonary artery positions. However, we experienced graft failures in infants in the aortic position. Congenital heart disease, Neonates, Aortic arch hypoplasia INTRODUCTION A wide range of congenital heart diseases requires the usage of a patch for repair, from septal defect closure [atrial septal defect (ASD), ventricular septal defect (VSD), partial atrial ventricular septal defect (pAVSD) or complete atrial ventricular septal defect], venous baffle (Senning or Mustard) and leaflet repair or neovalve reconstruction, to ventricular outflow tract reconstruction. Concerns are mainly focused on the evolution of the patch in outflow tract positions. The aim is to have a patch with a predictable evolution in both positions, under systemic pressure and pulmonary pressure. Medical device companies are still looking for the best patch, which should ideally be impermeable, thromboresistant, biocompatible, resistant to infection and which does not calcify or shrink over time. CardioCel® is a tissue-engineered ADAPT™ bovine pericardial patch known to have a good outcome in terms of preventing calcification and inflammation reactions [1–3]. The patch is first decellularized, then cross-linked with a very low concentration of glutaraldehyde and detoxified to remove any traces of glutaraldehyde. Finally, the patch is sterilized and stored in a glutaraldehyde-free solution. Therefore, it is a ready-to-use patch and does not require any rinsing. This material was introduced at the Royal Brompton Hospital in the beginning of 2014. In this study, we report our initial 2-year experience of CardioCel patch implantation in several positions in paediatric heart defects, including histological data in case of a reoperation. MATERIALS AND METHODS Materials From March 2014 to April 2016, 101 patients aged 18 years and under were treated for congenital heart disease using the CardioCel patch (Admedus Regen Pty Ltd, Perth, WA, Australia) at the Royal Brompton Hospital. The range of applications varied from septal implantation (e.g. ASD, VSD or atrioventricular septal defect and congenitally corrected transposition of the great arteries for Senning or Mustard venous baffle procedure) to pulmonary outflow tract repair (e.g. pulmonary atresia, stenosis, absence of pulmonary valve and aortopulmonary window and truncus arteriosus), left ventricular outflow tract repair (e.g. hypoplastic aortic arch, coarctation and interrupted aortic arch) and neoaortic valve creation according to the Ozaki technique, leaflet repair or monocusp replacement (e.g. aortic valve regurgitation or stenosis). Data were collected prospectively, and the study was performed retrospectively. Comorbidities reported were 8 preterm babies, 6 children with DiGeorge syndrome and 9 children with Down syndrome (Table 1). Table 1: Preoperative data Patients (n)  101  Age (months)     Mean (±SD)  21.6 (±36.3)   Median  7.07   Min–max  3 days–18 years  Weight (kg)     Mean (±SD)  9.7 (±10.3)   Median  6.7   Min–max  1.83–74  BSA     Mean (±SD)  0.43 (±0.29)   Min–max  0.15–1.89  Gender (%)     M/F  56/45  Comorbidities (%)     Preterm babies  8   DiGeorge syndrome  6   Down syndrome  9   Hypothyroidism  3  Cardiac diseases (%)     VSD/cAVSD/pAVSD  23/6/2   TOF/DORV  18/8   DCRV + VSD  1   Coarctation/arch hypoplasia  3/1   TAC/AP window  5/2   IAA/TGA  3/8   Aortic valve disease  6   Mitral valve disease  1   Tricuspid valve disease  1   Pulmonary atresia/stenosis  4/1   Absence of pulmonary valve  1   ccTGA  1   Functional univentricular  3  Patients (n)  101  Age (months)     Mean (±SD)  21.6 (±36.3)   Median  7.07   Min–max  3 days–18 years  Weight (kg)     Mean (±SD)  9.7 (±10.3)   Median  6.7   Min–max  1.83–74  BSA     Mean (±SD)  0.43 (±0.29)   Min–max  0.15–1.89  Gender (%)     M/F  56/45  Comorbidities (%)     Preterm babies  8   DiGeorge syndrome  6   Down syndrome  9   Hypothyroidism  3  Cardiac diseases (%)     VSD/cAVSD/pAVSD  23/6/2   TOF/DORV  18/8   DCRV + VSD  1   Coarctation/arch hypoplasia  3/1   TAC/AP window  5/2   IAA/TGA  3/8   Aortic valve disease  6   Mitral valve disease  1   Tricuspid valve disease  1   Pulmonary atresia/stenosis  4/1   Absence of pulmonary valve  1   ccTGA  1   Functional univentricular  3  Numbers equal percentages, because there are 101 patients. AP: aortopulmonary; BSA: body surface area; cAVSD: complete atrial ventricular septal defect; ccTGA: congenitally corrected transposition of the great arteries; DCRV: double-chambered right ventricle; DORV: double-outlet right ventricle; F: female; IAA: interrupted aortic arch; M: male; pAVSD: partial atrial ventricular septal defect; SD: standard deviation; TAC: truncus arteriosus; TGA: transposition of the great arteries; TOF: tetralogy of Fallot; VSD: ventricular septal defect. Operative procedure All open-heart surgeries were performed through a midline sternotomy with standard bypass cannulation (a single aortic cannula and double venous drainage), started after injecting 3 mg/kg of heparin into each patient. Operations were generally performed under moderate hypothermia (30–34 °C), and the heart was stopped with antegrade crystalloid or blood cardioplegia. Once the procedure was performed, patients were weaned off bypass, and before decannulation, a modified ultrafiltration was performed followed by protamine injection. Patients had either a standard or a delayed chest closure. Follow-up All patients had a close follow-up with a clinical examination, an echocardiogram during their daycare appointment and, if required, a computed tomography scan. In case of a reoperation where the patch was explanted, it was sent for a histological examination. RESULTS Preoperative findings The mean age was 22 (±36.3) months, and the mean weight was 9.7 (±10.3) kg. Fourteen (14%) patients were aged less than a month (Table 1). Operative findings The patch material was used for septal defect closure in 63 (62.3%) patients (ASD, n = 3; VSD, n = 54; complete atrial ventricular septal defect, n = 4 and pAVSD, n = 2), for vascular enlargement in 24 (23.7%) patients (ascending aorta, n = 4; aortic arch, n = 5 and pulmonary artery, n = 15), for right ventricular outflow tract enlargement in 16 (15.8%) patients (infundibulum enlargement patch, n = 11 and transannular path, n = 5), for valvular reconstruction in 10 (9.9%) patients (aortic cusp extension/monocusp repair, n = 4; Ozaki procedure, n = 2; mitral valve plasty, n = 3 and tricuspid plasty, n = 1) and for venous anastomosis in 1 (1%) patient (Senning procedure). There were no intraoperative difficulties while implanting the patch. The material was trimmed easily into the intentional shape and sutured easily without any major bleeding along the suture line. The bypass data are reported in Table 2. Table 2: Cardiopulmonary bypass data Bypass time (min)    Mean (±SD)  157 (±74)   Min–max  28–383  Aortic cross-clamp time (min)   Mean (±SD)  103 (±49)   Min–max  19–221  Temperature (°C)   Mean (±SD)  30 (±4)   Min–max  17–37  Bypass time (min)    Mean (±SD)  157 (±74)   Min–max  28–383  Aortic cross-clamp time (min)   Mean (±SD)  103 (±49)   Min–max  19–221  Temperature (°C)   Mean (±SD)  30 (±4)   Min–max  17–37  Numbers equal percentages, because there are 101 patients. SD: standard deviation. Postoperative findings The median hospital stay was 13 (range 5–525) days and the median postoperative period was 10 (range 4–125) days. The median follow-up period was 212 (range 4–726) days. Twenty-five (24.7%) patients had a delayed chest closure, almost half of whom (n = 11; 10.9%) were aged less than a month. No infections were related to the patch. The overall mortality was 3.9% (n = 4) and happened in the 30-day postoperative period. None of these deaths were related to graft failure. Recoarctation was defined by the echocardiogram in the event of a recurrence of a diastolic tail during follow-up. Only 1 patient required a computed tomography scan to better assess the aortic arch lesion and the different recoartation treatment options (balloon dilatation procedure or surgical procedure). Five (4.9%) patients were reoperated because of patch failure, 4 patients had the patch used for aortic angioplasty (2 in the ascending aorta and 2 in the aortic arch), 3 patients were aged less than 10 days and 1 patient had a monocusp replacement with this material. The median time between the first patch implantation and reoperation for patch failure was 245 (range 5–480) days. Four patients were reoperated not for patch failure and 2 patients required a venoarterial extracorporeal membrane oxygenation (V-A ECMO) after the complete repair operation. Mortality (n = 4) Two patients had a Taussig Bing anomaly with a hypoplastic aortic arch. One of them had a complete repair with an arterial switch operation, VSD closure and aortic arch enlargement at the age of 3 days. The patient then required a V-A ECMO a week after the repair. After 7 days under circulatory support, an attempt to wean off ECMO failed. The patient died subsequently after 15 days under V-A ECMO support. The second patient underwent a first palliation (bilateral pulmonary artery banding) before a complete repair with bilateral pulmonary artery plasty at the age of 4 months. The patient also required mechanical circulatory support with a V-A ECMO and died a month later. A third patient with Down syndrome had a complete atrial ventricular septal defect repair at the age of 4 months, had a straightforward postoperative course and died 2 weeks after discharge. The last patient had a background of biliary atresia, duodenal atresia, situs ambigus, dextrocardia, left isomerism, pAVSD and partial anomalous pulmonary venous connexion. The patient underwent a Ladd’s procedure before pAVSD and partial anomalous pulmonary venous connexion repair at the age of 7 months and eventually died after 28 days in the paediatric intensive care unit due to multiple organ failure. Reoperations Reoperations related to CardioCel patch complications (n = 5) The first case was a female infant with an antenatal diagnosis of Type A interrupted aortic arch, large aortopulmonary window with the right pulmonary artery rising from the aorta, multiple apical VSDs and a persistent left superior vena cava to coronary sinus (Table 3). The first surgery was performed at Day 6 of life, with a weight of 2.2 kg. The aortic arch was enlarged with a patch of CardioCel, the right pulmonary artery repaired with a patch of aortic homograft and the ASD and the main pulmonary artery (MPA) banded (pulmonary artery banding). The patient was discharged only after 5 weeks due to a sternal wound infection and dehiscence, was planned to be reviewed 2 weeks after discharge and a cardiac catheter was scheduled within 3 months after discharge. The latter showed a significant supravalvar aortic stenosis (mean pressure gradient of 43 mmHg). The patient was therefore reoperated 3 months after the first operation. It was found that a fibrous reaction had created a stenosis at the level of the suture line between the native aortic tissue and the CardioCel graft, which was then removed entirely and sent for histological examination. The aortic arch was reconstructed with a patch of pulmonary homograft. After 2 years of follow-up, the patient remained clinically well, and femoral pulses were fully palpable. The last echocardiogram showed a laminar flow in the aortic arch with a peak velocity of 3.5 m/s. Table 3: Redo cases related to the patch Diagnosis  Age at operation  Weight (kg)  Patch implantation  Delay between first operation and redo  Indication for reoperation  Coarctation  7 days  3.1  Aortic arch  8 months  Restenosis  Coarctation  3 days  5.5  Aortic arch  2 months  Restenosis  AP window  6 days  6.1  Ascending aorta  3 months  Supravalvar stenosis  Aortic regurgitation  4 years  22.7  Right coronary cusp  16 months  Aortic regurgitation and stenosis  Type IV truncus arteriosus  1 year  6.1  Ascending aorta  5 days  Supravalvar stenosis  Diagnosis  Age at operation  Weight (kg)  Patch implantation  Delay between first operation and redo  Indication for reoperation  Coarctation  7 days  3.1  Aortic arch  8 months  Restenosis  Coarctation  3 days  5.5  Aortic arch  2 months  Restenosis  AP window  6 days  6.1  Ascending aorta  3 months  Supravalvar stenosis  Aortic regurgitation  4 years  22.7  Right coronary cusp  16 months  Aortic regurgitation and stenosis  Type IV truncus arteriosus  1 year  6.1  Ascending aorta  5 days  Supravalvar stenosis  AP: aortopulmonary. The second patient was a female infant with an antenatal diagnosis of coarctation and bicuspid aortic valve. After a first failure of a complete repair through a left thoracotomy at Day 3 of life, weighing 3.1 kg, the patient was sent back to the theatre and had an enlargement of the aortic arch with a CardioCel patch through a midline sternotomy. A month after the sternotomy, the patient had a balloon angioplasty for a recoarctation (mean pressure gradient 45 mmHg), was discharged 2 months after admission and the last echo showed a good biventricular function with a mean gradient of 57 mmHg in the aortic arch. After 8 months of follow-up, the mean pressure gradient continued to rise, and a decision was made to reoperate. The previous patch, which had a hypertrophied intima and adventitia, was removed entirely and sent for histological examination. The aortic arch was then repaired using a pulmonary homograft patch. The postoperative echo showed a good coarctation repair with a maximum velocity of 2.1 m/s and no diastolic tail. The patient had a straightforward postoperative course and was discharged a week after the operation. The patient was last seen at the age of 20 months, and the echocardiogram showed an increasing velocity through the distal aortic arch to 2.75 m/s with a good pulsatility of the abdominal aorta and no diastolic continuation. The biventricular function remained excellent without ventricular hypertrophy. The third case was a 3-day-old, 2.9-kg male infant with an antenatal diagnosis of a discrete coarctation, who therefore had a complete repair through left thoracotomy using the CardioCel patch. The patient was discharged 2 weeks after admission with the last echo showing a mild flow acceleration across the aortic arch (Vmax = 1.5 m/s) without diastolic tail. Subsequently, 2 months later, the patient presented a significant clinical gradient between the upper body and the lower body. The echo showed a pulsatile abdominal aorta with a diastolic tail. The computed tomography scan showed a good size of the ascending aorta with a very large brachiocephalic trunk and a severe recoarctation immediately distal to it (Fig. 2). This lesion was considered not suitable for transcatheter balloon dilation. Consequently, the patient was reoperated through a midline sternotomy. All the CardioCel tissue, which seemed to have a very thick intima, was removed and sent for histological examination. A patch of pulmonary homograft was used to repair the gap. On the last follow-up at the age of 19 months, the patient remained asymptomatic with palpable femoral pulses. The last echocardiogram showed a peak velocity of 3 m/s and a peak gradient of 26 mmHg at the level of the distal anastomosis. Two other reoperations were performed on children who had their first operation at an older age: at 1 and 4 years. The one who was operated at 1 year of age was a female infant with hypothyroidism, Type 1 truncus arteriosus with VSD and a hypoplastic arch. The patient underwent a palliative procedure: bilateral pulmonary artery banding before the complete repair. Six days after the repair, the patient was reoperated because of severe supra-aortic valvar stenosis. The 4-year-old boy who suffered from an aortic regurgitation because of a coaptation defect of the right coronary artery cusp had a first valvoplasty using the CardioCel patch to replace the right coronary leaflet. Sixteen months later, the patient was reoperated for mixed (regurgitation and stenosis) aortic valve disease and had a Ross procedure (Figure 1). Figure 1: View largeDownload slide The Kaplan–Meier showing freedom from reoperation due to patch failure after 24 months of follow-up. Figure 1: View largeDownload slide The Kaplan–Meier showing freedom from reoperation due to patch failure after 24 months of follow-up. Reoperations not related to the patch (n = 2) The first patient was a 7-month-old girl who had a post-natal diagnosis of severe mitral valve regurgitation, aortic regurgitation, false aneurysm in the ascending aorta and patent ductus arteriosus due to an endocarditis. The ascending aorta and the aortic valve were repaired with a patch of CardioCel, and a complex mitral valve repair was performed to obtain a good leaflet coaptation. Six days later, a follow-up echo showed severe mitral valve regurgitation. This second attempt to repair the mitral valve took place after 6 weeks of treatment with antibiotics and was performed using a patch of CardioCel. The patient was discharged 10 days after the patient’s second surgery and progressively developed significant mitral valve stenosis and regurgitation with pulmonary hypertension. The patient subsequently underwent mitral valve replacement 7 months after the second repair. During this mechanical mitral valve (St Jude 17 mm) replacement, the CardioCel patch used for the previous mitral valve repair appeared unchanged, was removed and sent for histological examination. The postoperative course went straightforward and the patient was discharged after 20 days because of a lung infection, with the adequate warfarinization. On discharge, the chest X-ray was clear and the last echocardiogram before discharge showed good biventricular function with good movement of the mitral valve disc. The other patient was an ex-preterm male infant with pulmonary atresia, VSD and major aortopulmonary collateral arteries who was first operated at the age of 6 years and had a transannular patch implantation with CardioCel between the right ventricle and the MPA. The patient was operated 11 months later for complete repair. The MPA was reconstructed, therefore the previous patch was removed and the VSD closed. Histological examination Specimens cut from the explanted patch material were stained with 3 different types of stains, magnified and photographed. All 3 patients with the patch explanted from the aortic position had a similar stenosis mechanism related to the patch. Macroscopic examination revealed a fragment with a hard consistency. At the level of the suture line, a fibrointimal thickening reaction known as a neointimal reaction appeared to be responsible for this vascular stenosis. Signs of acute inflammatory reaction or features to suggest dehiscence at the site of surgical anastomosis were not detected. The CardioCel patch, which appeared in the Masson’s trichrome stain as loosely scattered decellularized elastic fibres, seemed to remain intact underneath this reaction. Another special stain, the elastic tissue fibres–Verhoeff’s Van Gieson (EVG) stain, confirmed the presence of intact scattered elastic fibres within the patch with only slight disruption and minor fragmentation. The pre-existing media wall fragments showed normal elastic fibres with no significant disruption or fragmentation. The homogenous collagen stream that constitutes the patch material did not show any signs of dystrophic calcification. The adventitia was responsible of a chronic inflammatory reaction, known as neo-adventitia. To understand this reaction, CD3, CD5 and CD20 stains showed predominantly lymphocytic and histiocytic inflammatory cells. On the other hand, the neointimal layer showed only sporadic CD34 positivity. None of the cases presented signs of evident endothelial layer, which challenges the biocompatibility of the material. CardioCel patches explanted from both the mitral valve and the MPA did not present the same patterns with no neointimal reaction. In these cases, the patch material appeared to be free of new vessel formation or infiltration of inflammatory cells, and no evident calcification was found (Figure 3). Figure 2: View largeDownload slide Computed tomography angiography scan reconstruction of the aortic arch of Patient 3. The proximal aortic arch, where the patch was sutured is narrowed and a balloon dilatation did not seem suitable to correct this lesion. Figure 2: View largeDownload slide Computed tomography angiography scan reconstruction of the aortic arch of Patient 3. The proximal aortic arch, where the patch was sutured is narrowed and a balloon dilatation did not seem suitable to correct this lesion. Figure 3: View largeDownload slide Histological examination of the patch removed from the second case. The patch was placed in the aortic arch for coarctation repair. Images show the same sample with 3 different staining techniques (A–C) and an unused CardioCel® patch (D) was stained with H&E for comparison. (A) The sample with the H&E stain and (D) the raw CardioCel patch show the absence of nuclei in the patch and the neointima. (B) The sample with the Masson’s trichrome stain shows that the patch mainly consists of homogenous collagen fibres. (C) In the sample with the EVG stain, one is able to differentiate between collagen and other with connective tissue. A mixture of collagen and thin elastin fibres surrounding the fibroblasts within the area of fibrointimal thickening can be observed. EVG: elastic tissue fibres–Verhoeff’s Van Gieson; H&E: haematoxylin and eosin. *: neo-adventicia; a: Cardiocel collagen patch; b: neo-intima. Figure 3: View largeDownload slide Histological examination of the patch removed from the second case. The patch was placed in the aortic arch for coarctation repair. Images show the same sample with 3 different staining techniques (A–C) and an unused CardioCel® patch (D) was stained with H&E for comparison. (A) The sample with the H&E stain and (D) the raw CardioCel patch show the absence of nuclei in the patch and the neointima. (B) The sample with the Masson’s trichrome stain shows that the patch mainly consists of homogenous collagen fibres. (C) In the sample with the EVG stain, one is able to differentiate between collagen and other with connective tissue. A mixture of collagen and thin elastin fibres surrounding the fibroblasts within the area of fibrointimal thickening can be observed. EVG: elastic tissue fibres–Verhoeff’s Van Gieson; H&E: haematoxylin and eosin. *: neo-adventicia; a: Cardiocel collagen patch; b: neo-intima. DISCUSSION Our 2-year experience showed a good handling characteristic of the material by the surgeons for implantation during the procedure, and no infections were related to it. The patch had a good behaviour in low-pressure areas without creating any stenosis because of calcification or thickness. However, we experienced early graft failure under high pressures because of a tremendous intimal reaction, which has not been previously reported for this type of patch. Our findings show that the patch becomes mainly stenotic in infants after enlarging the aortic arch, which we believe is a result of the mismatch between the elasticity of the native aorta and the CardioCel patch under systemic pressure. The blood flow creates shear stress against the aortic wall and can cause this intimal hypertrophy reaction leading to severe aortic stenosis. In the literature, Tremblay et al. [4] compared the mechanical properties between the aorta and prosthetic material and found that an important factor contributing to the phenomenon of stenosis is a mismatch of the mechanical properties [5]. Because the bovine pericardium is much stiffer than the native aortic tissue, the compliance between the 2 tissues is different and in combination with the suture line and the surgical injury, this can create intimal proliferation [1]. Another vascular surgery study, which reports the main advantages of the bovine pericardial patch, such as resistance to infection and great elasticity for carotid endarterectomy, has also shown that the most important factor for restenosis was intimal hyperplasia in the area at or near the patch [6]. However, preclinical studies seem to have promising results regarding the evolution of this bovine pericardial patch treated with the multistep ADAPT pathway, especially in terms of preventing calcification. Neethling et al. [2] showed that after multistep ADAPT (delipidized, decellularized, denucleased, fixed and detoxified) treatment, bovine pericardium patches implanted in subcutaneous rat models demonstrated less calcification. Another study on sheep models showed good resistance to calcification from the Cardiocel patch compared to an autologous pericardium patch treated with glutaralgehyde in mitral and pulmonary valvular position after 7 months in place [3]. Further, results from a clinical study from South Africa, in which 30 patients received this patch, showed safe and efficacious use without complications. The age range was 3 months to 13 years and 2 patients had the patch implanted in the aorta. The follow-up at 12 months showed a good outcome without thickening, thrombus formation or calcification on the echocardiogram or magnetic resonance imaging report. However, the follow-up in this study was not complete, and the magnetic resonance imaging was performed randomly on 10 patients without specific information about the evolution of the patch for aortic root enlargement [1]. Another study found aortic stenosis at follow-up in infants without any clinical significance or reoperation [7]. However, the outcome in aortic valvular position seemed more promising according to a study on sheep models with neoaortic valve reconstruction following the Ozaki procedure. Six months after the procedure, the echocardiogram showed a high coaptation area of the leaflet and minimal calcification on the explanted specimens [8]. Other types of patches have been used for congenital heart disease operations such as the CorMatrix (CorMatrix; CorMatrix Cardiovascular, Inc., Atlanta, GA, USA) and the Matrix Patch™. The CorMatrix patch is a decellularized porcine small intestine submucosa and can be repopulated with native cells. In the literature, this patch was used for a hemi-Fontan baffle operation and later removed for the complete Fontan operation. The explanted patches after a range of 18–26 months in vivo underwent histological examinations, which showed fibrosis, chronic inflammation and foreign body giant cell reaction in all the specimens. Some of these even presented signs of dystrophic calcification [9]. The Matrix Patch is a cell-free equine pericardial patch and showed good results in the descending aorta of a sheep. Indeed, the patch was removed after 4 months and was well preserved under systemic pressure without any signs of calcification but with a monolayer of endothelial-like cells found on histological examination [10]. This patch has a very smooth consistency, similar to fresh autologous pericardium and is therefore not easy to manipulate, trim and suture without twisting. Also, long-term follow-up data on a paediatric population have not been published as yet. To perform a complete repair, surgical techniques often use patch material. Consequently, part of reason for reoperation can be patch failure. Thus, many tissue engineers are still seeking the perfect patch with the following characteristics: good biocompatibility, resistance to infection, durable without calcifying or shrinking and a predictable outcome [11]. The development of the CardioCel patch (AdmedusRegen Pty Ltd) is an important milestone in preventing early calcification in young recipients who are particularly susceptible to complications [12] due to calcification of the graft. However, our experience shows that the CardioCel material can suffer from thick neointimal proliferation, potentially causing obstruction in the aortic position in neonates and infants. Conflict of interest: none declared. REFERENCES 1 Neethling WM, Strange G, Firth L, Smit FE. Evaluation of a tissue-engineered bovine pericardial patch in paediatric patients with congenital cardiac anomalies: initial experience with the ADAPT-treated CardioCel(R) patch. Interact CardioVasc Thorac Surg  2013; 17: 698– 702. Google Scholar CrossRef Search ADS PubMed  2 Neethling W, Brizard C, Firth L, Glancy R. Biostability, durability and calcification of cryopreserved human pericardium after rapid glutaraldehyde-stabilization versus multistep ADAPT(R) treatment in a subcutaneous rat model. Eur J Cardiothorac Surg  2014; 45: e110– 7. Google Scholar CrossRef Search ADS PubMed  3 Brizard CP, Brink J, Horton SB, Edwards GA, Galati JC, Neethling WM. New engineering treatment of bovine pericardium confers outstanding resistance to calcification in mitral and pulmonary implantations in a juvenile sheep model. J Thorac Cardiovasc Surg  2014; 148: 3194– 201. Google Scholar CrossRef Search ADS PubMed  4 Tremblay D, Zigras T, Cartier R, Leduc L, Butany J, Mongrain R et al.   Comparison of mechanical properties of materials used in aortic arch reconstruction. Ann Thorac Surg  2009; 88: 1484– 91. Google Scholar CrossRef Search ADS PubMed  5 Yaliniz H, Salih OK, Atalay A, Keklik V, Gocen U, Topcuoglu MS et al.   Short- and mid-term results of xenograft-bovine pericardial patch in the repair of intracardiac defects: final results of a single-centre study. Cardiol Young  2014; 24: 510– 4. Google Scholar CrossRef Search ADS PubMed  6 Li X, Guo Y, Ziegler KR, Model LS, Eghbalieh SD, Brenes RA et al.   Current usage and future directions for the bovine pericardial patch. Ann Vasc Surg  2011; 25: 561– 8. Google Scholar CrossRef Search ADS PubMed  7 Sobieraj M, Cudak E, Mrówczyński W, Nałęcz TK, Westerski P, Wojtalik M. Application of the CardioCel bovine pericardial patch—a preliminary report. Kardiochir Torakochirurgia Pol  2016; 3: 210– 2. 8 Meuris B, Ozaki S, Neethling W, De Vleeschauwer S, Verbeken E, Rhodes D et al.   Trileaflet aortic valve reconstruction with a decellularized pericardial patch in a sheep model. J Thorac Cardiovasc Surg  2016; 152: 1167– 74. Google Scholar CrossRef Search ADS PubMed  9 Nelson JS, Heider A, Si MS, Ohye RG. Evaluation of explanted cormatrix intracardiac patches in children with congenital heart disease. Ann Thorac Surg  2016; 102: 1329– 35. Google Scholar CrossRef Search ADS PubMed  10 Dohmen PM, da Costa F, Lopes SV, Vilani R, Bloch O, Konertz W. Successful implantation of a decellularized equine pericardial patch into the systemic circulation. Med Sci Monit Basic Res  2014; 20: 1– 8. Google Scholar CrossRef Search ADS PubMed  11 Pok S, Jacot JG. Biomaterials advances in patches for congenital heart defect repair. J Cardiovasc Transl Res  2011; 4: 646– 54. Google Scholar CrossRef Search ADS PubMed  12 Bourguignon T, Bouquiaux-Stablo AL, Candolfi P, Mirza A, Loardi C, May MA et al.   Very long-term outcomes of the Carpentier-Edwards Perimount valve in aortic position. Ann Thorac Surg  2015; 99: 831– 7. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Interactive CardioVascular and Thoracic Surgery Oxford University Press

Initial 2-year results of CardioCel® patch implantation in children

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1569-9293
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1569-9285
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Abstract

Abstract OBJECTIVES We present the initial 2-year results of CardioCel® patch (Admedus Regen Pty Ltd, Perth, WA, Australia) implantation in paediatric patients with congenital heart diseases. METHODS This was a single-centre retrospective study with prospectively collected data of all patients aged 18 years and under operated for congenital heart disease. The patch was introduced in 2014, with clinical practice committee approval and a special consent in case of an Ozaki procedure. Standard follow-up was performed with systematic clinical exams and echocardiograms. In case of reoperation or graft failure, the patch was removed and sent for a histological examination. RESULTS Between March 2014 and April 2016, 101 patients had surgical repair using a CardioCel patch. The mean age was 22 (±36.3) months, and the mean weight was 9.7 (±10.3) kg. No infections and no intraoperative implantation difficulties were associated with the patch. The median follow-up period was 212 (range 4–726) days. The overall 30-day postoperative mortality was 3.8% (n = 4), none of which were related to graft failure. Five children were reoperated because of graft failure, 4 of whom had the patch implanted for aortic and were aged less than 10 days. The indications for patch implantation in the aortic position were aortopulmonary window, truncus arteriosus, coarctation and aortic arch hypoplasia repair. The median time between the first and the second operation for graft failure was 245 (range 5–480) days. CONCLUSIONS Our experience shows that the patch is well tolerated in the septal, valvar and pulmonary artery positions. However, we experienced graft failures in infants in the aortic position. Congenital heart disease, Neonates, Aortic arch hypoplasia INTRODUCTION A wide range of congenital heart diseases requires the usage of a patch for repair, from septal defect closure [atrial septal defect (ASD), ventricular septal defect (VSD), partial atrial ventricular septal defect (pAVSD) or complete atrial ventricular septal defect], venous baffle (Senning or Mustard) and leaflet repair or neovalve reconstruction, to ventricular outflow tract reconstruction. Concerns are mainly focused on the evolution of the patch in outflow tract positions. The aim is to have a patch with a predictable evolution in both positions, under systemic pressure and pulmonary pressure. Medical device companies are still looking for the best patch, which should ideally be impermeable, thromboresistant, biocompatible, resistant to infection and which does not calcify or shrink over time. CardioCel® is a tissue-engineered ADAPT™ bovine pericardial patch known to have a good outcome in terms of preventing calcification and inflammation reactions [1–3]. The patch is first decellularized, then cross-linked with a very low concentration of glutaraldehyde and detoxified to remove any traces of glutaraldehyde. Finally, the patch is sterilized and stored in a glutaraldehyde-free solution. Therefore, it is a ready-to-use patch and does not require any rinsing. This material was introduced at the Royal Brompton Hospital in the beginning of 2014. In this study, we report our initial 2-year experience of CardioCel patch implantation in several positions in paediatric heart defects, including histological data in case of a reoperation. MATERIALS AND METHODS Materials From March 2014 to April 2016, 101 patients aged 18 years and under were treated for congenital heart disease using the CardioCel patch (Admedus Regen Pty Ltd, Perth, WA, Australia) at the Royal Brompton Hospital. The range of applications varied from septal implantation (e.g. ASD, VSD or atrioventricular septal defect and congenitally corrected transposition of the great arteries for Senning or Mustard venous baffle procedure) to pulmonary outflow tract repair (e.g. pulmonary atresia, stenosis, absence of pulmonary valve and aortopulmonary window and truncus arteriosus), left ventricular outflow tract repair (e.g. hypoplastic aortic arch, coarctation and interrupted aortic arch) and neoaortic valve creation according to the Ozaki technique, leaflet repair or monocusp replacement (e.g. aortic valve regurgitation or stenosis). Data were collected prospectively, and the study was performed retrospectively. Comorbidities reported were 8 preterm babies, 6 children with DiGeorge syndrome and 9 children with Down syndrome (Table 1). Table 1: Preoperative data Patients (n)  101  Age (months)     Mean (±SD)  21.6 (±36.3)   Median  7.07   Min–max  3 days–18 years  Weight (kg)     Mean (±SD)  9.7 (±10.3)   Median  6.7   Min–max  1.83–74  BSA     Mean (±SD)  0.43 (±0.29)   Min–max  0.15–1.89  Gender (%)     M/F  56/45  Comorbidities (%)     Preterm babies  8   DiGeorge syndrome  6   Down syndrome  9   Hypothyroidism  3  Cardiac diseases (%)     VSD/cAVSD/pAVSD  23/6/2   TOF/DORV  18/8   DCRV + VSD  1   Coarctation/arch hypoplasia  3/1   TAC/AP window  5/2   IAA/TGA  3/8   Aortic valve disease  6   Mitral valve disease  1   Tricuspid valve disease  1   Pulmonary atresia/stenosis  4/1   Absence of pulmonary valve  1   ccTGA  1   Functional univentricular  3  Patients (n)  101  Age (months)     Mean (±SD)  21.6 (±36.3)   Median  7.07   Min–max  3 days–18 years  Weight (kg)     Mean (±SD)  9.7 (±10.3)   Median  6.7   Min–max  1.83–74  BSA     Mean (±SD)  0.43 (±0.29)   Min–max  0.15–1.89  Gender (%)     M/F  56/45  Comorbidities (%)     Preterm babies  8   DiGeorge syndrome  6   Down syndrome  9   Hypothyroidism  3  Cardiac diseases (%)     VSD/cAVSD/pAVSD  23/6/2   TOF/DORV  18/8   DCRV + VSD  1   Coarctation/arch hypoplasia  3/1   TAC/AP window  5/2   IAA/TGA  3/8   Aortic valve disease  6   Mitral valve disease  1   Tricuspid valve disease  1   Pulmonary atresia/stenosis  4/1   Absence of pulmonary valve  1   ccTGA  1   Functional univentricular  3  Numbers equal percentages, because there are 101 patients. AP: aortopulmonary; BSA: body surface area; cAVSD: complete atrial ventricular septal defect; ccTGA: congenitally corrected transposition of the great arteries; DCRV: double-chambered right ventricle; DORV: double-outlet right ventricle; F: female; IAA: interrupted aortic arch; M: male; pAVSD: partial atrial ventricular septal defect; SD: standard deviation; TAC: truncus arteriosus; TGA: transposition of the great arteries; TOF: tetralogy of Fallot; VSD: ventricular septal defect. Operative procedure All open-heart surgeries were performed through a midline sternotomy with standard bypass cannulation (a single aortic cannula and double venous drainage), started after injecting 3 mg/kg of heparin into each patient. Operations were generally performed under moderate hypothermia (30–34 °C), and the heart was stopped with antegrade crystalloid or blood cardioplegia. Once the procedure was performed, patients were weaned off bypass, and before decannulation, a modified ultrafiltration was performed followed by protamine injection. Patients had either a standard or a delayed chest closure. Follow-up All patients had a close follow-up with a clinical examination, an echocardiogram during their daycare appointment and, if required, a computed tomography scan. In case of a reoperation where the patch was explanted, it was sent for a histological examination. RESULTS Preoperative findings The mean age was 22 (±36.3) months, and the mean weight was 9.7 (±10.3) kg. Fourteen (14%) patients were aged less than a month (Table 1). Operative findings The patch material was used for septal defect closure in 63 (62.3%) patients (ASD, n = 3; VSD, n = 54; complete atrial ventricular septal defect, n = 4 and pAVSD, n = 2), for vascular enlargement in 24 (23.7%) patients (ascending aorta, n = 4; aortic arch, n = 5 and pulmonary artery, n = 15), for right ventricular outflow tract enlargement in 16 (15.8%) patients (infundibulum enlargement patch, n = 11 and transannular path, n = 5), for valvular reconstruction in 10 (9.9%) patients (aortic cusp extension/monocusp repair, n = 4; Ozaki procedure, n = 2; mitral valve plasty, n = 3 and tricuspid plasty, n = 1) and for venous anastomosis in 1 (1%) patient (Senning procedure). There were no intraoperative difficulties while implanting the patch. The material was trimmed easily into the intentional shape and sutured easily without any major bleeding along the suture line. The bypass data are reported in Table 2. Table 2: Cardiopulmonary bypass data Bypass time (min)    Mean (±SD)  157 (±74)   Min–max  28–383  Aortic cross-clamp time (min)   Mean (±SD)  103 (±49)   Min–max  19–221  Temperature (°C)   Mean (±SD)  30 (±4)   Min–max  17–37  Bypass time (min)    Mean (±SD)  157 (±74)   Min–max  28–383  Aortic cross-clamp time (min)   Mean (±SD)  103 (±49)   Min–max  19–221  Temperature (°C)   Mean (±SD)  30 (±4)   Min–max  17–37  Numbers equal percentages, because there are 101 patients. SD: standard deviation. Postoperative findings The median hospital stay was 13 (range 5–525) days and the median postoperative period was 10 (range 4–125) days. The median follow-up period was 212 (range 4–726) days. Twenty-five (24.7%) patients had a delayed chest closure, almost half of whom (n = 11; 10.9%) were aged less than a month. No infections were related to the patch. The overall mortality was 3.9% (n = 4) and happened in the 30-day postoperative period. None of these deaths were related to graft failure. Recoarctation was defined by the echocardiogram in the event of a recurrence of a diastolic tail during follow-up. Only 1 patient required a computed tomography scan to better assess the aortic arch lesion and the different recoartation treatment options (balloon dilatation procedure or surgical procedure). Five (4.9%) patients were reoperated because of patch failure, 4 patients had the patch used for aortic angioplasty (2 in the ascending aorta and 2 in the aortic arch), 3 patients were aged less than 10 days and 1 patient had a monocusp replacement with this material. The median time between the first patch implantation and reoperation for patch failure was 245 (range 5–480) days. Four patients were reoperated not for patch failure and 2 patients required a venoarterial extracorporeal membrane oxygenation (V-A ECMO) after the complete repair operation. Mortality (n = 4) Two patients had a Taussig Bing anomaly with a hypoplastic aortic arch. One of them had a complete repair with an arterial switch operation, VSD closure and aortic arch enlargement at the age of 3 days. The patient then required a V-A ECMO a week after the repair. After 7 days under circulatory support, an attempt to wean off ECMO failed. The patient died subsequently after 15 days under V-A ECMO support. The second patient underwent a first palliation (bilateral pulmonary artery banding) before a complete repair with bilateral pulmonary artery plasty at the age of 4 months. The patient also required mechanical circulatory support with a V-A ECMO and died a month later. A third patient with Down syndrome had a complete atrial ventricular septal defect repair at the age of 4 months, had a straightforward postoperative course and died 2 weeks after discharge. The last patient had a background of biliary atresia, duodenal atresia, situs ambigus, dextrocardia, left isomerism, pAVSD and partial anomalous pulmonary venous connexion. The patient underwent a Ladd’s procedure before pAVSD and partial anomalous pulmonary venous connexion repair at the age of 7 months and eventually died after 28 days in the paediatric intensive care unit due to multiple organ failure. Reoperations Reoperations related to CardioCel patch complications (n = 5) The first case was a female infant with an antenatal diagnosis of Type A interrupted aortic arch, large aortopulmonary window with the right pulmonary artery rising from the aorta, multiple apical VSDs and a persistent left superior vena cava to coronary sinus (Table 3). The first surgery was performed at Day 6 of life, with a weight of 2.2 kg. The aortic arch was enlarged with a patch of CardioCel, the right pulmonary artery repaired with a patch of aortic homograft and the ASD and the main pulmonary artery (MPA) banded (pulmonary artery banding). The patient was discharged only after 5 weeks due to a sternal wound infection and dehiscence, was planned to be reviewed 2 weeks after discharge and a cardiac catheter was scheduled within 3 months after discharge. The latter showed a significant supravalvar aortic stenosis (mean pressure gradient of 43 mmHg). The patient was therefore reoperated 3 months after the first operation. It was found that a fibrous reaction had created a stenosis at the level of the suture line between the native aortic tissue and the CardioCel graft, which was then removed entirely and sent for histological examination. The aortic arch was reconstructed with a patch of pulmonary homograft. After 2 years of follow-up, the patient remained clinically well, and femoral pulses were fully palpable. The last echocardiogram showed a laminar flow in the aortic arch with a peak velocity of 3.5 m/s. Table 3: Redo cases related to the patch Diagnosis  Age at operation  Weight (kg)  Patch implantation  Delay between first operation and redo  Indication for reoperation  Coarctation  7 days  3.1  Aortic arch  8 months  Restenosis  Coarctation  3 days  5.5  Aortic arch  2 months  Restenosis  AP window  6 days  6.1  Ascending aorta  3 months  Supravalvar stenosis  Aortic regurgitation  4 years  22.7  Right coronary cusp  16 months  Aortic regurgitation and stenosis  Type IV truncus arteriosus  1 year  6.1  Ascending aorta  5 days  Supravalvar stenosis  Diagnosis  Age at operation  Weight (kg)  Patch implantation  Delay between first operation and redo  Indication for reoperation  Coarctation  7 days  3.1  Aortic arch  8 months  Restenosis  Coarctation  3 days  5.5  Aortic arch  2 months  Restenosis  AP window  6 days  6.1  Ascending aorta  3 months  Supravalvar stenosis  Aortic regurgitation  4 years  22.7  Right coronary cusp  16 months  Aortic regurgitation and stenosis  Type IV truncus arteriosus  1 year  6.1  Ascending aorta  5 days  Supravalvar stenosis  AP: aortopulmonary. The second patient was a female infant with an antenatal diagnosis of coarctation and bicuspid aortic valve. After a first failure of a complete repair through a left thoracotomy at Day 3 of life, weighing 3.1 kg, the patient was sent back to the theatre and had an enlargement of the aortic arch with a CardioCel patch through a midline sternotomy. A month after the sternotomy, the patient had a balloon angioplasty for a recoarctation (mean pressure gradient 45 mmHg), was discharged 2 months after admission and the last echo showed a good biventricular function with a mean gradient of 57 mmHg in the aortic arch. After 8 months of follow-up, the mean pressure gradient continued to rise, and a decision was made to reoperate. The previous patch, which had a hypertrophied intima and adventitia, was removed entirely and sent for histological examination. The aortic arch was then repaired using a pulmonary homograft patch. The postoperative echo showed a good coarctation repair with a maximum velocity of 2.1 m/s and no diastolic tail. The patient had a straightforward postoperative course and was discharged a week after the operation. The patient was last seen at the age of 20 months, and the echocardiogram showed an increasing velocity through the distal aortic arch to 2.75 m/s with a good pulsatility of the abdominal aorta and no diastolic continuation. The biventricular function remained excellent without ventricular hypertrophy. The third case was a 3-day-old, 2.9-kg male infant with an antenatal diagnosis of a discrete coarctation, who therefore had a complete repair through left thoracotomy using the CardioCel patch. The patient was discharged 2 weeks after admission with the last echo showing a mild flow acceleration across the aortic arch (Vmax = 1.5 m/s) without diastolic tail. Subsequently, 2 months later, the patient presented a significant clinical gradient between the upper body and the lower body. The echo showed a pulsatile abdominal aorta with a diastolic tail. The computed tomography scan showed a good size of the ascending aorta with a very large brachiocephalic trunk and a severe recoarctation immediately distal to it (Fig. 2). This lesion was considered not suitable for transcatheter balloon dilation. Consequently, the patient was reoperated through a midline sternotomy. All the CardioCel tissue, which seemed to have a very thick intima, was removed and sent for histological examination. A patch of pulmonary homograft was used to repair the gap. On the last follow-up at the age of 19 months, the patient remained asymptomatic with palpable femoral pulses. The last echocardiogram showed a peak velocity of 3 m/s and a peak gradient of 26 mmHg at the level of the distal anastomosis. Two other reoperations were performed on children who had their first operation at an older age: at 1 and 4 years. The one who was operated at 1 year of age was a female infant with hypothyroidism, Type 1 truncus arteriosus with VSD and a hypoplastic arch. The patient underwent a palliative procedure: bilateral pulmonary artery banding before the complete repair. Six days after the repair, the patient was reoperated because of severe supra-aortic valvar stenosis. The 4-year-old boy who suffered from an aortic regurgitation because of a coaptation defect of the right coronary artery cusp had a first valvoplasty using the CardioCel patch to replace the right coronary leaflet. Sixteen months later, the patient was reoperated for mixed (regurgitation and stenosis) aortic valve disease and had a Ross procedure (Figure 1). Figure 1: View largeDownload slide The Kaplan–Meier showing freedom from reoperation due to patch failure after 24 months of follow-up. Figure 1: View largeDownload slide The Kaplan–Meier showing freedom from reoperation due to patch failure after 24 months of follow-up. Reoperations not related to the patch (n = 2) The first patient was a 7-month-old girl who had a post-natal diagnosis of severe mitral valve regurgitation, aortic regurgitation, false aneurysm in the ascending aorta and patent ductus arteriosus due to an endocarditis. The ascending aorta and the aortic valve were repaired with a patch of CardioCel, and a complex mitral valve repair was performed to obtain a good leaflet coaptation. Six days later, a follow-up echo showed severe mitral valve regurgitation. This second attempt to repair the mitral valve took place after 6 weeks of treatment with antibiotics and was performed using a patch of CardioCel. The patient was discharged 10 days after the patient’s second surgery and progressively developed significant mitral valve stenosis and regurgitation with pulmonary hypertension. The patient subsequently underwent mitral valve replacement 7 months after the second repair. During this mechanical mitral valve (St Jude 17 mm) replacement, the CardioCel patch used for the previous mitral valve repair appeared unchanged, was removed and sent for histological examination. The postoperative course went straightforward and the patient was discharged after 20 days because of a lung infection, with the adequate warfarinization. On discharge, the chest X-ray was clear and the last echocardiogram before discharge showed good biventricular function with good movement of the mitral valve disc. The other patient was an ex-preterm male infant with pulmonary atresia, VSD and major aortopulmonary collateral arteries who was first operated at the age of 6 years and had a transannular patch implantation with CardioCel between the right ventricle and the MPA. The patient was operated 11 months later for complete repair. The MPA was reconstructed, therefore the previous patch was removed and the VSD closed. Histological examination Specimens cut from the explanted patch material were stained with 3 different types of stains, magnified and photographed. All 3 patients with the patch explanted from the aortic position had a similar stenosis mechanism related to the patch. Macroscopic examination revealed a fragment with a hard consistency. At the level of the suture line, a fibrointimal thickening reaction known as a neointimal reaction appeared to be responsible for this vascular stenosis. Signs of acute inflammatory reaction or features to suggest dehiscence at the site of surgical anastomosis were not detected. The CardioCel patch, which appeared in the Masson’s trichrome stain as loosely scattered decellularized elastic fibres, seemed to remain intact underneath this reaction. Another special stain, the elastic tissue fibres–Verhoeff’s Van Gieson (EVG) stain, confirmed the presence of intact scattered elastic fibres within the patch with only slight disruption and minor fragmentation. The pre-existing media wall fragments showed normal elastic fibres with no significant disruption or fragmentation. The homogenous collagen stream that constitutes the patch material did not show any signs of dystrophic calcification. The adventitia was responsible of a chronic inflammatory reaction, known as neo-adventitia. To understand this reaction, CD3, CD5 and CD20 stains showed predominantly lymphocytic and histiocytic inflammatory cells. On the other hand, the neointimal layer showed only sporadic CD34 positivity. None of the cases presented signs of evident endothelial layer, which challenges the biocompatibility of the material. CardioCel patches explanted from both the mitral valve and the MPA did not present the same patterns with no neointimal reaction. In these cases, the patch material appeared to be free of new vessel formation or infiltration of inflammatory cells, and no evident calcification was found (Figure 3). Figure 2: View largeDownload slide Computed tomography angiography scan reconstruction of the aortic arch of Patient 3. The proximal aortic arch, where the patch was sutured is narrowed and a balloon dilatation did not seem suitable to correct this lesion. Figure 2: View largeDownload slide Computed tomography angiography scan reconstruction of the aortic arch of Patient 3. The proximal aortic arch, where the patch was sutured is narrowed and a balloon dilatation did not seem suitable to correct this lesion. Figure 3: View largeDownload slide Histological examination of the patch removed from the second case. The patch was placed in the aortic arch for coarctation repair. Images show the same sample with 3 different staining techniques (A–C) and an unused CardioCel® patch (D) was stained with H&E for comparison. (A) The sample with the H&E stain and (D) the raw CardioCel patch show the absence of nuclei in the patch and the neointima. (B) The sample with the Masson’s trichrome stain shows that the patch mainly consists of homogenous collagen fibres. (C) In the sample with the EVG stain, one is able to differentiate between collagen and other with connective tissue. A mixture of collagen and thin elastin fibres surrounding the fibroblasts within the area of fibrointimal thickening can be observed. EVG: elastic tissue fibres–Verhoeff’s Van Gieson; H&E: haematoxylin and eosin. *: neo-adventicia; a: Cardiocel collagen patch; b: neo-intima. Figure 3: View largeDownload slide Histological examination of the patch removed from the second case. The patch was placed in the aortic arch for coarctation repair. Images show the same sample with 3 different staining techniques (A–C) and an unused CardioCel® patch (D) was stained with H&E for comparison. (A) The sample with the H&E stain and (D) the raw CardioCel patch show the absence of nuclei in the patch and the neointima. (B) The sample with the Masson’s trichrome stain shows that the patch mainly consists of homogenous collagen fibres. (C) In the sample with the EVG stain, one is able to differentiate between collagen and other with connective tissue. A mixture of collagen and thin elastin fibres surrounding the fibroblasts within the area of fibrointimal thickening can be observed. EVG: elastic tissue fibres–Verhoeff’s Van Gieson; H&E: haematoxylin and eosin. *: neo-adventicia; a: Cardiocel collagen patch; b: neo-intima. DISCUSSION Our 2-year experience showed a good handling characteristic of the material by the surgeons for implantation during the procedure, and no infections were related to it. The patch had a good behaviour in low-pressure areas without creating any stenosis because of calcification or thickness. However, we experienced early graft failure under high pressures because of a tremendous intimal reaction, which has not been previously reported for this type of patch. Our findings show that the patch becomes mainly stenotic in infants after enlarging the aortic arch, which we believe is a result of the mismatch between the elasticity of the native aorta and the CardioCel patch under systemic pressure. The blood flow creates shear stress against the aortic wall and can cause this intimal hypertrophy reaction leading to severe aortic stenosis. In the literature, Tremblay et al. [4] compared the mechanical properties between the aorta and prosthetic material and found that an important factor contributing to the phenomenon of stenosis is a mismatch of the mechanical properties [5]. Because the bovine pericardium is much stiffer than the native aortic tissue, the compliance between the 2 tissues is different and in combination with the suture line and the surgical injury, this can create intimal proliferation [1]. Another vascular surgery study, which reports the main advantages of the bovine pericardial patch, such as resistance to infection and great elasticity for carotid endarterectomy, has also shown that the most important factor for restenosis was intimal hyperplasia in the area at or near the patch [6]. However, preclinical studies seem to have promising results regarding the evolution of this bovine pericardial patch treated with the multistep ADAPT pathway, especially in terms of preventing calcification. Neethling et al. [2] showed that after multistep ADAPT (delipidized, decellularized, denucleased, fixed and detoxified) treatment, bovine pericardium patches implanted in subcutaneous rat models demonstrated less calcification. Another study on sheep models showed good resistance to calcification from the Cardiocel patch compared to an autologous pericardium patch treated with glutaralgehyde in mitral and pulmonary valvular position after 7 months in place [3]. Further, results from a clinical study from South Africa, in which 30 patients received this patch, showed safe and efficacious use without complications. The age range was 3 months to 13 years and 2 patients had the patch implanted in the aorta. The follow-up at 12 months showed a good outcome without thickening, thrombus formation or calcification on the echocardiogram or magnetic resonance imaging report. However, the follow-up in this study was not complete, and the magnetic resonance imaging was performed randomly on 10 patients without specific information about the evolution of the patch for aortic root enlargement [1]. Another study found aortic stenosis at follow-up in infants without any clinical significance or reoperation [7]. However, the outcome in aortic valvular position seemed more promising according to a study on sheep models with neoaortic valve reconstruction following the Ozaki procedure. Six months after the procedure, the echocardiogram showed a high coaptation area of the leaflet and minimal calcification on the explanted specimens [8]. Other types of patches have been used for congenital heart disease operations such as the CorMatrix (CorMatrix; CorMatrix Cardiovascular, Inc., Atlanta, GA, USA) and the Matrix Patch™. The CorMatrix patch is a decellularized porcine small intestine submucosa and can be repopulated with native cells. In the literature, this patch was used for a hemi-Fontan baffle operation and later removed for the complete Fontan operation. The explanted patches after a range of 18–26 months in vivo underwent histological examinations, which showed fibrosis, chronic inflammation and foreign body giant cell reaction in all the specimens. Some of these even presented signs of dystrophic calcification [9]. The Matrix Patch is a cell-free equine pericardial patch and showed good results in the descending aorta of a sheep. Indeed, the patch was removed after 4 months and was well preserved under systemic pressure without any signs of calcification but with a monolayer of endothelial-like cells found on histological examination [10]. This patch has a very smooth consistency, similar to fresh autologous pericardium and is therefore not easy to manipulate, trim and suture without twisting. Also, long-term follow-up data on a paediatric population have not been published as yet. To perform a complete repair, surgical techniques often use patch material. Consequently, part of reason for reoperation can be patch failure. Thus, many tissue engineers are still seeking the perfect patch with the following characteristics: good biocompatibility, resistance to infection, durable without calcifying or shrinking and a predictable outcome [11]. The development of the CardioCel patch (AdmedusRegen Pty Ltd) is an important milestone in preventing early calcification in young recipients who are particularly susceptible to complications [12] due to calcification of the graft. However, our experience shows that the CardioCel material can suffer from thick neointimal proliferation, potentially causing obstruction in the aortic position in neonates and infants. Conflict of interest: none declared. REFERENCES 1 Neethling WM, Strange G, Firth L, Smit FE. Evaluation of a tissue-engineered bovine pericardial patch in paediatric patients with congenital cardiac anomalies: initial experience with the ADAPT-treated CardioCel(R) patch. Interact CardioVasc Thorac Surg  2013; 17: 698– 702. Google Scholar CrossRef Search ADS PubMed  2 Neethling W, Brizard C, Firth L, Glancy R. Biostability, durability and calcification of cryopreserved human pericardium after rapid glutaraldehyde-stabilization versus multistep ADAPT(R) treatment in a subcutaneous rat model. Eur J Cardiothorac Surg  2014; 45: e110– 7. Google Scholar CrossRef Search ADS PubMed  3 Brizard CP, Brink J, Horton SB, Edwards GA, Galati JC, Neethling WM. New engineering treatment of bovine pericardium confers outstanding resistance to calcification in mitral and pulmonary implantations in a juvenile sheep model. J Thorac Cardiovasc Surg  2014; 148: 3194– 201. Google Scholar CrossRef Search ADS PubMed  4 Tremblay D, Zigras T, Cartier R, Leduc L, Butany J, Mongrain R et al.   Comparison of mechanical properties of materials used in aortic arch reconstruction. Ann Thorac Surg  2009; 88: 1484– 91. Google Scholar CrossRef Search ADS PubMed  5 Yaliniz H, Salih OK, Atalay A, Keklik V, Gocen U, Topcuoglu MS et al.   Short- and mid-term results of xenograft-bovine pericardial patch in the repair of intracardiac defects: final results of a single-centre study. Cardiol Young  2014; 24: 510– 4. Google Scholar CrossRef Search ADS PubMed  6 Li X, Guo Y, Ziegler KR, Model LS, Eghbalieh SD, Brenes RA et al.   Current usage and future directions for the bovine pericardial patch. Ann Vasc Surg  2011; 25: 561– 8. Google Scholar CrossRef Search ADS PubMed  7 Sobieraj M, Cudak E, Mrówczyński W, Nałęcz TK, Westerski P, Wojtalik M. Application of the CardioCel bovine pericardial patch—a preliminary report. Kardiochir Torakochirurgia Pol  2016; 3: 210– 2. 8 Meuris B, Ozaki S, Neethling W, De Vleeschauwer S, Verbeken E, Rhodes D et al.   Trileaflet aortic valve reconstruction with a decellularized pericardial patch in a sheep model. J Thorac Cardiovasc Surg  2016; 152: 1167– 74. Google Scholar CrossRef Search ADS PubMed  9 Nelson JS, Heider A, Si MS, Ohye RG. Evaluation of explanted cormatrix intracardiac patches in children with congenital heart disease. Ann Thorac Surg  2016; 102: 1329– 35. Google Scholar CrossRef Search ADS PubMed  10 Dohmen PM, da Costa F, Lopes SV, Vilani R, Bloch O, Konertz W. Successful implantation of a decellularized equine pericardial patch into the systemic circulation. Med Sci Monit Basic Res  2014; 20: 1– 8. Google Scholar CrossRef Search ADS PubMed  11 Pok S, Jacot JG. Biomaterials advances in patches for congenital heart defect repair. J Cardiovasc Transl Res  2011; 4: 646– 54. Google Scholar CrossRef Search ADS PubMed  12 Bourguignon T, Bouquiaux-Stablo AL, Candolfi P, Mirza A, Loardi C, May MA et al.   Very long-term outcomes of the Carpentier-Edwards Perimount valve in aortic position. Ann Thorac Surg  2015; 99: 831– 7. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Journal

Interactive CardioVascular and Thoracic SurgeryOxford University Press

Published: Mar 1, 2018

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