• Journal of Chest Surgery
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• v.22 no.6
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• pp.1001-1012
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• 1989

In 1968, Carpentier and his associates introduced glutaraldehyde as a compound for preparing cardiac tissue valve, and this technique has provided a considerably more suitable and durable tissue valve substitute. To increase further durability of valve tissue, Reis and his colleagues designed a flexible stent to reduce the stress on the heterogeneous tissue valve mounted. However with the advent of more innovative mechanical valve currently, many bioprosthetic valves are being substituted by mechanical valves at our department of cardiothoracic surgery because of bioprosthetic valve failure. Main cause of bioprosthetic valves failure were calcification or/and tear of tissue valves. The purpose of this retrospective study is to clarify the relationship between the patients clinical profile during implantation of tissue valves and pathologic features of the failed bioprosthetic valve. From March, 1982 through June, 1988, 53 bioprosthetic heart valves that had been ex-planted from 45 patients at the department of cardiac surgery of Yonsei University Hospital were subjected to this study. The patients were 10 to 65 year-old [mean age: 30.3 yr] with 17 males and 28 females. Re-replacements of prosthetic valves were carried out twenty nine in mitral position, eight in aortic position and eight in both aortic and mitral position simultaneously. The grading and location for calcification of valves were verified by radiograms. The calcification of the explanted valves leaflets was graded from 0 to 4 plus according to Cipriano and associates method. The types of tear and perforation of leaflet were classified into four types as Ishihara has adopted initially in 1981. In younger age group under thirty three years, explanted tissue valves were significantly more affected in terms of grades of severity of valve calcification as compared with older age group [p < 0.035]. Valve calcification appeared more severe in male as compared to female [p< 0.002]. Ionescu-Shiley bovine pericardial bioprosthetic valves showed more severe calcification than Hancock porcine tissue valves [p< 0.035]. Calcium deposit was found very prevalent at the area of commissural attachment [86 % of all]. Type I of valve rupture was shown to be related with simultaneous calcification. However, the relation of explanted valve position, duration of implanted prosthetic valve, atrial fibrillation and anticoagulant therapy to the severity of bioprosthetic valve calcification were not significantly clear statistically [p > 0.05].

• Journal of Chest Surgery
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• v.26 no.9
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• pp.667-676
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• 1993

Boprosthetic cardiac valves fail from biological and metabolic as well as mechanical reasons, and the limited durability is the main factor of marked withdrawal in their clinical use. Starting the use of bioprosthetic valves in 1976, up to the end of 1992, the consecutive 178 patients have undergone re-replacement of glutaraldehyde-treated xenograft valves for primary tissue failure [PTF]among the patients who had initial valve replacement at Seoul national University Hospital. The explanted valves were 69 porcine aortic [51 Hancock, 12 Angell-Shiley and 6 Carentier-Edwards] and 141 bovine pericardial [129 standard-profile and 12 low-profile ionescu-Shiley] valwes, with an overall incidence of PTF of 15.2%. The operative mortality rate of re-replacement was 5.1%. Calcific degeneration and tissue damage in relation to calcification were the most frequent modes of PTF on gross examinatin of the explanted valves resulting hemodynamically in valvular regurgitation. The number of Hancocg porcine and the standard-profile Ionescu-Shiley valves in valves in mitral position failed more often from tissue damage [tears, holes, and loss or destruction of cuspal tissue] than calcification [68.3% vs. 39.0%, p<0.01] with resultant regurgitation in 61%, the Ionescu-Shiley valves in the same position in 53%. The tendency of more calcification than tissue damage[71.3% vs. 33.3%, p<0.001]with stenosis in 53%. The tendency of more calcification and immobility of cusps in the latter group was partly explainable by the inclusion of patients of pediatric age. Observation made in this study suggest : many of bioprosthetic valves would fail from calcification and tissue damage : some fail prematurely because of mechanical stress probably owing to the valve design in construction ; andeven those valves escaped early damage would be subject to calcify in the prolonged follow-up period. In conclusion, at the present time, the clinical use of bioprostheticxenograft valves seems to be quite limited until further improvement in biocompatibility and refinement in valve design in manufacture are achieved.

• Journal of Chest Surgery
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• v.44 no.2
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• pp.99-107
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• 2011

Background: Calcification is the most frequent cause of clinical failure of bioprosthetic tissues fabricated from GA-fixed porcine valves or bovine pericardium. A multi-factorial approach using different mechanisms was recently developed to reduce the calcification of bioprosthetic tissues. The purpose of the present study was to evaluate the synchronized synergism of using L-arginine and $NaBH_4$, compared with ethanol and L-lysine, in glutaraldehyde treated porcine pericardium from the standpoint of calcification and tissue elasticity. Materials and Methods: Porcine pericardium was fixed at 0.625% GA (7 days at room temperature after 2 days at $4^{\circ}C$). An interim step of ethanol (80%; 1 day at room temperature) or L-lysine (0.1 M; 2 days at $37^{\circ}C$) or L-arginine (0.1 M; 2 days at $37^{\circ}C$) was followed by completion of the GA fixation. A final step of NaBH4 (0.1 M; 2 days at room temperature) was followed. Their tensile strength, thickness, and thermal stability were measured. Treated pericardia were implanted subcutaneously into three-week-old Sprague-Dawley rats for 8 weeks. Calcium content was assessed by atomic absorption spectroscopy and histology. Results: L-arginine and $NaBH_4$ pretreatment ($1.81{\pm}0.39$ kgf/5 mm p=0.001, $0.30{\pm}0.08$ mm p<0.001) significantly increased tensile strength and thickness compared with the control ($0.53{\pm}0.34$ kgf/5 mm, $0.10{\pm}0.02$ mm). In a thermal stability test, L-arginine and $NaBH_4$ pretreatment ($84.25{\pm}1.12^{\circ}C$, p=0.023) caused a significant difference from the control ($86.25{\pm}0.00^{\circ}C$). L-lysine and $NaBH_4$ pretreatment ($183.8{\pm}42.6$ ug/mg, p=0.804), and L-arginine and $NaBH_4$ pretreatment ($163.3{\pm}27.5$ ug/mg, p=0.621) did not significantly inhibit calcification compared to the control ($175.5{\pm}45.3$ ug/mg), but ethanol and $NaBH_4$ pretreatment did ($38.5{\pm}37.3$ ug/mg, p=0.003). Conclusion: The combined pretreatment using L-arginine and $NaBH_4$ after GA fixation seemed to increase the tensile strength and thickness of porcine pericardium, fixed with GA. Additionally, it seemed to keep thermal stability. However it could not decrease the calcification of porcine pericardium fixed with GA. $NaBH_4$ pretreatment seemed to decrease the calcification of porcine pericardium fixed with GA, but only with ethanol.

• Biotechnology and Bioprocess Engineering:BBE
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• v.10 no.3
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• pp.218-224
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• 2005

Surface modification of glutaraldehyde fixed bovine pericardium (GFBP) was success­fully carried out with hyaluronic acid (HA) derivatives. At first, HA was chemically modified with adipic dihydrazide (ADH) to introduce hydrazide functional group into the carboxyl group of HA backbone. Then, GFBP was surface modified by grafting HA-ADH to the free aldehyde groups on the tissue and the subsequent HA-ADH hydrogel coating. HA-ADH hydrogels could be prepared through selective crosslinking at low pH between hydrazide groups of HA-ADH and crosslinkers containing succinimmidyl moieties with minimized protein denaturation. When HA­ADH hydrogels were prepared at low pH of 4.8 in the presence of erythropoietin (EPO) as a model protein, EPO release was continued up to $85\%$ of total amount of loaded EPO for 4 days. To the contrary, only $30\%$ of EPO was released from HA-ADH hydrogels prepared at pH=7.4, which might be due to the denaturation of EPO during the crosslinking reaction. Because the carboxyl groups on the glucuronic acid residues are recognition sites for HA degradation by hyaluronidase, the HA-ADH hydrogels degraded more slowly than HA hydrogels prepared by the crosslinking reaction of divinyl sulfone with hydroxyl groups of HA. Following a two-week subcutaneous implantation in osteopontin-null mice, clinically significant levels of calcification were observed for the positive controls without any surface modification. However, the calcification of surface modified GFBP with HA-ADH and HA-ADH hydrogels was drastically reduced by more than $85\%$ of the positive controls. The anti-calcification effect of HA surface modification was also confirmed by microscopic analysis of explanted tissue after staining with Alizarin Red S for calcium, which followed the trend as observed with calcium quantification.

• Journal of Chest Surgery
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• v.24 no.9
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• pp.837-842
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• 1991

Calcification is a major problem in glutaraldehyde-preserved bioprosthetic valves. We have used bovine pericardium processed in a solution containing 0.625% glutaraldehyde, 0.05M HEPES buffer and 0.26% magnesium chloride in saline. And, we also treated the glutaraldehyde-preserved bovine pericardium with a surfactant, Triton X - 100 to reduce calcification. To evaluate the degree of calcification. 4 kinds of pericardial xenografts, group I [Xenomedica, equine pericardial xenografts], group II [0.625% glutaraldehyde-preserved bovine pericardiums], group III [0.5% Triton X - 100 treated bovine pericardiums], and group IV [1.2% Triton X - 100 treated bovine pericardiums] were implanted in subcutaneous layer of growing rabbits, and they were explanted about 3 months later. The mean calcium contents[%/mg of dry tissue] of 0.5% and 1.2% Triton X - 100 treated bovine pericardiums [80.0$\pm$27.1%: 78.6$\pm$47.0% respectively] were lower than those of glutaraldehyde-preserved bovine pericardiums[126.2$\pm$29.8] [p=0.05]. Thus, under the conditions of subcutaneous implantation in rabbits, Triton X - 100 was efficient in calcification mitigation.

• Journal of Chest Surgery
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• v.29 no.10
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• pp.1111-1117
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• 1996

Structural deterioration of the bioprosthetic xenograft valves due to primary tissue failure occurs in two modes: from fatigue lesions with tear and wear with or without calcification and from calcification with obstruction. Two groups of consecutive 56 patients with the Hancock porcine ortic valve(HM) and of 1 13 patients with the standard-profile onescu-Shiley bovine pericardial valve(ISM) explanted from mitral position at the time of re-replacement surgery for primary tissue failure at Seoul national University Hospital until 1994, were studied for clinical and pathological features. Their ages at primary implant were 31.9 $\pm$9.2 years In HM and 30.4$\pm$ 12.5 years in ISM. Hemodrnamic dysfunction of the failed mitral bloprostheses were predominantly insufficiency in HM(64.3%) and stenosis in ISM(51.3%)(p<0.001). Pathologic findings of the explanted mitral valves reflected these hemodynamic changes, revealing failure more often from tissue damage(tears and wears) in HM and more often from calcification in ISM(p< 0.001). Explant period(from primary implant to explant) was relatively short in ISM(8.7$\pm$2.6years), compared with the one in HM(10.4 $\pm$2.6 years)(p<0.001). In conclusion, both the Hancock and the lonescu-shiley valves would fail from calcification as well as issue damage. However, while the Hancock porcine valves in mitral position failed more frequently from tissue failure and insufficiency, the standard-profile lonescu-Shiley pericardial valves did from calcification and stenosis, especially in young pAtients . Although the possibility of less occurrence of valve failure from mechanical reasons may be expected with newer generation bloprostheses, it does not seem to Improve durability significantly unless further refinement in antimineralization is achieved. Therefore, clinical use of the glutaraldehyde-treated bioprosthetic valves is, at present, limited to the patients of advanced age groups.

• Journal of Chest Surgery
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• v.31 no.11
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• pp.1023-1030
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• 1998

Background: Calcific degeneration limits durabilities of the bioprosthetic tissues implanted in the human body. The direct coupling sulphonated polyethyleneoxide(PEO-SO3) to the bioprosthetic tissues after glutaraldehyde(GA) fixation and the removal of residual aldehyde groups from the tissues can augment the effect of calcification-resistance. Materials and methods: To study the anti-calcification effect by PEO-SO3 modification and the removal of the residual aldehyde groups of tissues, surface modified bovine pericardia(BP-PEO-SO3) were preserved in aseptic saline to wash out GA(saline group) and 0.65% GA solution(GA group). And then above two groups and PERIGUARD (Bio-vascular. Co.) (product group) were evaluated with respects to calcium contents and microscopic findings using in vivo implantation models at carotid and femoral artery and peritoneum of 8 adult dogs. Results: In the tissues retrieved from carotid artery, calcium content was significantly decreased in saline group than in other two groups(saline; 2.89±0.31 vs. GA; 6.14±1.08 vs. product; 22.82±5.00 mg/g of dried tissue; p<0.05). In the tissues retrieved from femoral artery and peritoneum, calcium amount was also decreased in saline group than in other two groups, but not reached the significant difference between groups. On the other hand, the pathologic findings of pericardial tissues showed marked destructuction in GA group compared to the other two groups. Conclusions: In this study, covalently PEO-SO3 bound to bovine pericardium decreased calcifications and the anti-calcification effect of BP-PEO-SO3 could be augmented by the washing out the residual aldehyde groups using saline after GA fixation. Conclusively, the PEO-SO3 modified bovine pericardium is highly resistant to calcification and can be useful for the development of calcification-resistant cardiovascular patches and valves.

• Journal of Chest Surgery
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• v.42 no.6
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• pp.685-695
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• 2009

Background: Calcification is the most frequent cause of clinical failure of bioprosthetic tissues that are fabricated from Glutaraldehyde (GA)-fixed porcine valve or bovine pericardium. We recently used a multi-factorial approach of employing different mechanisms to investigate how to reduce the calcification of bioprosthetic tissues. The purpose of the present study was to evaluate the synchronized synergism using ethanol, L-lysine and $NaBH_4$ in glutaraldehyde treated porcine pericardium from the standpoint of calcification and tissue elasticity. Material and Method: Porcine pericardium was fixed with 0.625% GA (commercial fixation). An interim step of ethanol (80%; 1 day at room temperature) or L-lysine (0.1 M; 2 days at $37^{\circ}C$) or $NaBH_4$ (0.1 M; 2 days at room temperature) was followed by completion of the GA fixation (2 days at $4^{\circ}C$ and 7 days at room temperature). The tensile strength and thickness of the samples were measured. The treated pericardiums were implanted subcutaneously into three-week old Sprague-Dawley rats for 8 weeks. The calcium content was assessed by atomic absorption spectroscopy and the histology of the samples. Result: The amount of calcium in the pericardium pretreated with ethanol (13.6${\pm}$10.0 ug/mg, p=0.008), L-lysine (15.3${\pm}$1.0 ug/mg, p=0.002) and both (16.1${\pm}$11.1 ug/mg, p=0.012) was significantly reduced compared with the control (51.2${\pm}$8.5 ug/mg). However, $NaBH_4$ pretreatment (65.7${\pm}$61.8 ug/mg, p=0.653) and combined pretreatment that including ethanol, L-lysine and $NaBH_4$ (92.9${\pm}$58.3 ug/mg, p=0.288) were not significantly different from the controls(51.2${\pm}$8.5 ug/mg). Both the combined pretreatment using ethanol and L-lysine (7.60${\pm}$1.55, p=0.76) and the combined pretreatment that included ethanol, L-lysine and $NaBH_4$ (7.47${\pm}$1.85, p=0.33) increased the tensile strength/thickness ratio compared with that of the controls (4.75${\pm}$1.88). Conclusion: The combined pretreatment using ethanol and L-lysine seemed to decrease the calcification of porcine pericardium fixed with glutaraldehyde, as compared to single pretreatment, and it increase the tissue elasticity, but to the degree that showed synchronized synergism. $NaBH_4$ pretreatment seemed to increase the calcification of porcine pericardium, irrespective of whether single or combined pretreatment was used.

• Journal of Chest Surgery
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• v.51 no.4
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• pp.283-285
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• 2018

A 73-year-old woman who underwent combined bioprosthetic mitral valve replacement, tricuspid ring annuloplasty, and coronary artery bypass grafting 12 years previously visited our clinic due to aggravated dyspnea caused by structural valve deterioration of the mitral prosthesis. Because aortic or femoral artery cannulation and cross-clamping would have a high risk of stroke owing to severe calcification of the ascending aorta and ilio-femoral vessels, and because there was a risk of redo sternotomy due to the patent bypass grafts, a comprehensive approach including axillary artery cannulation, a minimally invasive right thoracotomy approach, and a clampless hypothermic fibrillatory arrest technique was used during redo mitral valve replacement.

• Journal of Chest Surgery
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• v.21 no.4
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• pp.619-629
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• 1988

The increasing number of replacement of the substitute cardiac valves were seen in these 2 years. Out of a total 1,408 patients with cardiac valve replacement, 54 required replacement of the substitute valves. Fifty-nine substitute valves replaced were 43 in mitral, 14 in aortic and 2 in tricuspid positions; and they were 36 Ionescu-Shiley, 15 Hancock and 3 Angell-Shiley bioprosthetic valves and 3 St. Jude Medical and 2 Bjork-Shiley prosthetic valves. Primary tissue failure was the most frequent reason of replacement[38 patients] followed by paravalvular leak[9 patients], prosthetic valve endocarditis[6 patients] and valve thrombosis[1 patient] in order. The most pronounced pathology of the failed xenograft valves seen in the primary tissue failure group was calcification and fixation of the cusps with or without tear and defect of the cuspal tissue. The operative mortality rate was 7.4%. Fifty early survivors were followed up for a total of 82.6 patient-years and there was no late death. Actuarial survival rate was 92.3*3.8% at 6 years after surgery. Although the definite tendency toward early and accelerated degeneration of the xenograft valves has been seen in patients younger than 20 to 25 years of age, no strict age limit from where the tissue failure slows down could be determined. The requirement of the ideal substitute valves would be the durability of the recently developed mechanical prostheses armed with the low thrombogenicity of the bioprostheses. At the present time, the need of compromise in selection between less thrombogenic bioprosthetic and more durable mechanical valves should be stressed. The difficulty in choice is yet important in patients of middle age and children where the use of homograft valves may be one of the solution despite of certain limitations from sociomedical reasons.