Tissue engineered heart valves: will a clinical application be possible?
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Bioprosthesis↗
Biomedical subjects
Shigeyuki Ozaki
Publications and source records attributed to Shigeyuki Ozaki.
Inhibition of neointimal proliferation in balloon-injured arteries using non-anticoagulant heparin-carrying polystyrene.
Non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) has a higher activity to inhibit proliferation and migration of smooth muscle cells (SMCs) than heparin (Hep), periodate-oxidized (IO4-) Hep, and periodate-oxidized alkaline-degraded low molecular weight (IO4-LMW-) Hep. Less than 10 microg/ml of NAC-HCPS significantly inhibited the proliferation and migration of SMCs in vitro, while over 10-fold higher concentrations of Hep, IO4-Hep, and IO4-LMW-Hep were required to obtain the same inhibition. On the other hand, neointimal growth (intimal cross-section area and intimal cross-section area/medial cross-section area ratio) in vivo following vascular injury 28 days after balloon denudation in a rat carotid artery was substantially inhibited with high dose of intravenous administration (total 30 mg) of respectively IO4-Hep, IO4-LMW-Hep, and NAC-HCPS. A low-dose (total 10 mg) administration of IO4-Hep and IO4-LMW-Hep did not prevent the neointimal growth when compared with the control; only NAC-HCPS (total 10 mg) was able to significantly inhibit the neointimal. Thus, NAC-HCPS has a more-than 10-fold larger activity to inhibit SMC activities such as proliferation and migration in vitro, when comparing with Hep, IO4-Hep, and IO4-LMW-Hep; NAC-HCPS also prevents neointimal growth in vivo at lower doses.
Animals↗
Effect of modified ultrafiltration on inflammatory mediators, coagulation factors, and other proteins in blood after an extracorporeal circuit.
Modified ultrafiltration (MUF) is a technique able to remove the excess body fluid and inflammatory mediators associated with the use of a cardiopulmonary bypass (CPB). It has been shown to reduce morbidity after cardiac operations in children. Application of MUF after adult cardiac operations has also been suggested being associated with a lower prevalence of early morbidity. However, the relationship between the concentration of mediators in the blood and postoperative morbidity remains yet to be proved. In this study, changes of various chemical mediators in the filtrate and blood before and after MUF have been evaluated in adult patients. Significant reductions of blood levels of inflammatory cytokines were not observed after MUF. On the other hand, MUF significantly elevated hematocrit, number of red cells, concentrations of albumine, coagulation Factor VII and X, platelet factor (PF)-4, and antithrombin (AT-) III.
Blood Cells↗
A new model to test the calcification characteristics of bioprosthetic heart valves.
BACKGROUND: Tissue degeneration and calcification are the two chief obstacles to the successful application of bioprosthetic heart valves. To enable the study of the durability of bioprosthetic heart valves and the efficacy of anti-calcification treatment, it has become necessary to develop animal models. The aim of this study is to validate a new model for implantation in the pulmonary position. METHODS: Three juvenile sheep underwent implantation of Carpentier-Edwards pericardial valves in the pulmonary position (experimental group). These three valves were compared with three Carpentier-Edwards pericardial valves in the aortic position in patients which had been explanted due to primary tissue failure (clinical group). The valves were analyzed. RESULTS: The findings of macroscopic, X-ray and light microscopic examination were very similar between the two groups. Scattered irregular calcification was seen near the commissures and at the base of the cusps in both groups. Quantitative calcium content analysis showed that calcification of the cusps had progressed to almost the same degree in both groups (experimental group, 3.7+/-0.2 micro g/mg dry tissue; clinical group, 4.3+/-0.3; p>0.05). In the experimental group, calcification in the commissural area of the cusp was pronounced (6.5+/-1.0). In the clinical group, calcification had also progressed in the commissural area of the cusp (6.0+/-1.5), and extended to the base area of the cusp (6.6+/-1.2). CONCLUSIONS: This model is promising for preclinical evaluation of bioprosthetic heart valves. The degree of calcification is not significantly different between our experimental results after three months of implantation in sheep and clinical results after 10 years of implantation in elderly patients. However, the pattern of calcification is somewhat different between the two groups.
Aged↗
Modified stentless porcine valve enhances accelerated cuspal calcification in the juvenile sheep model.
OBJECTIVE: Stent mounting of any bioprosthesis, induces a loss of mobility and reduces the effective valve orifice. By contrast, for stentless procedures, the higher surgical technicality remains a major obstacle for many surgeons. In an attempt to facilitate the insertion of the stentless porcine aortic valve (Toronto SPV), we tried to alter the design by lowering the invasive profile at the depth of the sinuses on both coronary sites. This could theoretically facilitate the implant of the modified stentless valve with an easygoing single layer suture at the challenging subcoronary level and make it more attractive for every surgeon. METHODS: Modifications of the standard model were done by lowering the profile at the depth of the sinuses on both coronary sites, whether by plication or excision of the protruding porcine aortic wall at the nadir of each coronary sinus. Nine juvenile sheep underwent implantation of stentless porcine aortic valves in pulmonary position: 3 standard Toronto SPV, 3 plicated Toronto SPV and 3 excised Toronto SPV. In each series, valves were explanted after 3 months. Valves were analyzed. RESULTS: The cusps of standard Toronto SPV were perfectly functioning and pliable, without visible calcification after three months. The calcium content of the cusps was less than those in the plicated and excised Toronto SPV (2.4 +/- 0.7 microg/mg versus 10.8 +/- 5.9 and 6.7 +/- 3.4 microg/mg). In the plicated and excised valves, calcification of the cusp was more pronounced in the commissural region (3.9 +/- 1.9, 29.0 +/- 16.7, 13.8 +/- 9.5 microg/mg in the standard, plicated and excised Toronto SPV, respectively). On the other hand, the aortic wall from the plicated Toronto SPV had more calcium than that from the other groups (53.6 +/- 6.3, 41.2 +/- 7.1, 45.2 +/- 7.4 microg/mg in the plicated, standard and excised Toronto SPV, respectively). CONCLUSIONS: The modification of stentless porcine valve enhanced accelerated cuspal calcification in the commissural region. It accentuated that the correct implantation technique for stentless procedures is extremely important in order to prevent early degeneration.
Animals↗
Remote preconditioning lessens the deterioration of pulmonary function after repeated coronary artery occlusion and reperfusion in sheep.
PURPOSE: We investigated whether remote organ preconditioning (RPC) can preserve pulmonary function following repeated myocardial ischemia/reperfusion in a model mimicking multi-vessel off-pump coronary artery bypass (OPCAB) revascularization. METHODS: Nine sheep (Group-RPC) underwent RPC by three episodes of five-minute occlusion and five-minute reperfusion of the iliac artery. Five sheep (Group-C) were time-matched controls. Afterwards, ten-minute occlusion and reperfusion of the left anterior descending, the first diagonal and the left circumflex coronary arteries were performed consecutively. Hemodynamic and respiratory parameters and arterial blood gases were measured until 120 min after the final coronary reperfusion. Anesthesia was maintained with halothane in oxygen and nitrous oxide. Animals were ventilated with a tidal volume of 15-20 mL.kg(-1) in a non-rebreathing system, and a respiratory rate 14-16 min, with 5-cm H(2)O positive end expiratory pressure after thoracotomy. RESULTS: Repeated coronary occlusion and reperfusion was associated in this experimental model with an increase in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) and a decrease in PaO(2) and PaO(2)/FIO(2) in Group-C. After 120 min reperfusion, PaO(2) and PaO(2)/FIO(2) in Group-RPC were higher (192 +/- 69 mmHg and 241 +/- 78 vs 115 +/- 54 mmHg and 129 +/- 64, P < 0.05), while PVR and PAP were lower than in Group-C. At 120 min of reperfusion, PaO(2) and PaO(2)/FIO(2) were inversely correlated with PVR (P < 0.01). CONCLUSIONS: RPC by transient occlusion of the iliac artery improves lung gas exchange after repeated coronary artery occlusion and reperfusion mimicking OPCAB surgery, and preserves low PVR in sheep.
Analysis of Variance↗
A tissue engineered heart valve implanted in a juvenile sheep model.
BACKGROUND: The tissue-engineered (TE) heart valve was developed to improve the durability of tissue heart valves. The aim of this study was to evaluate morphological and histological changes in a TE heart valve consisting of decellularized porcine matrices seeded with viable autologous vascular endothelial cells (AVEC). MATERIAL/METHODS: TE valves were implanted into the right ventricular outflow tract of eight juvenile sheep and explanted after 7 days, 3 and 6 months. The valves were evaluated visually, by invasive pressure measurements, X-ray, light microscopy, scanning, and transmission electron microscopy. The calcium content of the cusps was determined quantitatively by atomic absorption spectrometry. RESULTS: After valve implantation, all animals showed fast recovery with no complications during the observation period. Invasive pressure measurements presented a mean TE valve pressure gradient of 1.5+/-0.5 mm Hg at 3 and the same at 6 months. Light microscopy showed a monolayer of AVEC on all explanted heart valves, confirmed by scanning electron microscopy and immunohistochemical staining. X-ray examination of explanted TE heart valves showed no cusp calcification, confirmed by atomic absorption spectrometry. CONCLUSIONS: All explanted TE heart valves showed AVEC at the inner surface and ingrowth of fibroblast into the decellularized matrix, increasing during the observation period. The calcium contents were very low at explantation in these viable new heart valves.
Animals↗
Bioprosthetic tissue calcification: influence of blood contact and arterial pressure. an experimental study in rats and sheep.
BACKGROUND AND AIM OF THE STUDY: Several animal models are currently used to study bioprosthetic tissue calcification. The study aim was to evaluate the influence of species and environmental factors (blood contact and arterial pressure) on valve tissue mineralization. METHODS: Glutaraldehyde-fixed porcine cusps and aortic wall samples were implanted subcutaneously in rats (n = 6) and sheep (n = 18). In sheep, similar samples were also implanted into the jugular vein (blood contact) and carotid artery (blood contact and arterial pressure). Tissue was explanted at intervals up to three months and evaluated macroscopically, and by X-radiography, light and electron microscopy and calcium content measurement. RESULTS: After eight weeks in the subcutaneous position, glutaraldehyde-fixed cusps were severely calcified in rats, but not in sheep (78.6 +/- 28.3 and 0.3 +/- 0.5 microg Ca/mg, respectively; p <0.001). Aortic wall samples were calcified in both species, but less in sheep (p <0.001). In sheep, blood contact without arterial pressure (venous implants) significantly increased the calcification of cusp and even more of aortic wall tissue. Arterial pressure had no effect on calcification of aortic wall tissue. CONCLUSION: Major inter-species inconsistencies were found in valve tissue calcification after subcutaneous implantation. In sheep, blood contact increased tissue calcification significantly, mainly in aortic wall samples. Arterial pressure did not enhance mineralization of aortic wall tissue.
Animals↗
Influence of blood contact on the calcification of glutaraldehyde-pretreated porcine aortic valves.
BACKGROUND: The rat subcutaneous model reproduces clinically observed mineralization of bioprosthetic tissues. However, the effectiveness of antimineralization treatment can be overestimated in subcutaneous implants, since specimens using this model are not subjected to mechanical and dynamic stress or blood-surface contact. The purpose of this study was to evaluate the influence of blood contact on the calcification of bioprosthetic valves. METHODS: Glutaraldehyde-pretreated porcine aortic valves were prepared. Aortic wall and cusp discs were implanted subcutaneously in six rats for 8 weeks and were implanted within the jugular vein wall in six sheep for 3 and 6 months (blood contact model). Tissue discs were analyzed by gross inspection, radiography and light microscopy. Calcium content was determined by atomic absorption spectrometry. RESULTS: X-ray and light microscopic examination showed calcification in the cusps to be higher than that in the aortic wall in the rat subcutaneous model. On the other hand, in the blood contact model, the cusps were slightly calcified and calcification in the aortic wall was more pronounced. Calcium analysis in rats revealed more calcium in the cusp than in the aortic wall (71.5+/-9.7 g/mg dry tissue vs. 53.7+/-2.6, p=0.09). Tests for calcium content of the jugular vein samples in sheep showed significantly more calcium in the aortic wall than in the cusp (3 months, 7.9+/-1.5 vs. 0.3+/-0.1, p<0.0001; 6 months, 77.2+/-6.1 vs. 27.2+/-10.2, p=0.0002). In addition, aortic wall and cusp calcification significantly increased with time. CONCLUSIONS: These data suggest that the results from the rat subcutaneous model were completely opposite to those for the blood contact model. This study confirms the need to include blood contact as a factor in in vivo pre-clinical valve testing.
Animals↗
Valved jugular vein segments for right ventricular outflow tract reconstruction in young sheep.
OBJECTIVE: This study was undertaken to investigate the degeneration and calcification of valved bovine jugular vein segments for right ventricular outflow tract reconstruction in juvenile sheep. METHODS: Seven valved bovine jugular vein conduits (Contegra model 220; VenPro Corporation, Irvine, Calif) and 3 control conduits (MH100; Medtronic, Inc, Minneapolis, Minn) were implanted in the pulmonary artery in young sheep. After 20 weeks the conduits were explanted and qualitatively analyzed by epicardial echocardiography, gross examination, x-ray analysis, light microscopy, and transmission electron microscopy. Calcification was determined quantitatively by flame atomic absorption spectrometry. RESULTS: Two Contegra conduits could not be analyzed because of endocarditis. All other Contegra conduits functioned well, with preserved structure and minimal calcification. The control MH100 conduits exhibited extensive fibrous sheathing, with calcification of the aortic wall portion and the commissural part of the Hancock valve. CONCLUSIONS: The Contegra conduit's performance was clearly superior to that of the control MH100 conduit when implanted in the pulmonary artery position in juvenile sheep for 5 months.
Animals↗
Tissue engineering of an auto-xenograft pulmonary heart valve.
To improve the durability of stentless valves without losing their excellent hemodynamic function, a new-generation auto-xenograft was developed and evaluated. A piece of vein was harvested from 3 juvenile sheep 6 weeks before implantation of the valve. Endothelial cells from the vein material were cultivated and used to reendothelialize a decellularized porcine pulmonary valve. The tissue-engineered valve was implanted into the right ventricular outflow tract of the juvenile sheep. It was explanted after 100 days and assessed macroscopically as well as by x-ray, light microscopy (hematoxylin and eosin staining and von Kossa staining), and scanning electron microscopy. Calcium content of the cusps was determined quantitatively by atomic absorption spectrometry. The sheep implanted with the valve recovered quickly without any problems during the observation period. X-ray examination of the 3 explanted valves showed no cusp calcification, which was confirmed by histological study. Atomic absorption spectrometry showed low tissue calcium content. A clinical safety and feasibility trial with an allograft valve prepared the same way showed excellent short-term results in 6 patients.
Adult↗