Hong-Gook Lim

Long-term results of the arterial switch operation for ventriculo-arterial discordance

OBJECTIVES The arterial switch operation (ASO) has become the standard surgical procedure for transposition of the great arteries (TGA) or variants with an excellent early outcome. However, there are concerns regarding neopulmonary stenosis, neoaortic regurgitation (neoAR) associated with neoaortic root dilatation and coronary artery disease. METHODS A total of 220 early survivors of the ASO were included in this retrospective study between November 1987 and June 2011. The median age and weight at operation were 13 days (0-1768 days) and 3.52 kg (1.69-19 kg), respectively. The indications for the ASO included TGA with intact ventricular septum in 113 patients, TGA with ventricular septal defect in 90 and Taussig-Bing anomaly in 17 patients. The median follow-up period was 103.2 months (0.4-277.4 months). Statistical analyses with the Kaplan-Meier and Cox proportional hazards models were performed. RESULTS The actuarial late survival rate and freedom from reoperation at 23 years were 96.6 ± 1.3 and 81.9 ± 3.8%, respectively. Twenty-four (10.9%) patients underwent reoperations for right ventricular outflow tract obstruction in 10 patients, neoAR in four and coronary artery stenosis in three, etc. Freedom from neoAR of Grades IV, III and II at 23 years was 90.2 ± 6.6, 70.9 ± 9.6 and 20.3 ± 5.5%, respectively. The risk factors for neoAR were size discrepancy of the great arteries, aortic root dilatation after the ASO and follow-up duration after the ASO. NeoAR was significantly correlated with the size of aortic sinus and aortic sinotubular junction over time. Freedom from pulmonary stenosis (PS) of ≥ 36 and ≥ 20 mmHg at 23 years was 34.8 ± 18.0 and 17.7 ± 9.6%, respectively. The risk factors for PS were Taussig-Bing and arch anomalies. Coronary artery evaluation was performed in 95 (43.2%) patients with angiography, computed tomography or single-photon emission computed tomography, and five (5.3%) patients had abnormal coronary morphology or perfusion. Three patients underwent reoperation for coronary artery stenosis, and two had reversible perfusion defects in various regions, which were clinically not significant. Freedom from coronary events was 88.1 ± 6.4% at 22 years. A risk factor for coronary events was the single coronary artery. CONCLUSIONS The survival and functional outcomes of the ASO were excellent in the long-term. Strict serial surveillance is required to evaluate the long-term functional outcome of the ASO, particularly in a high-risk anatomy.

The long-term result of total repair for tetralogy of Fallot

OBJECTIVE The objective of this study was to evaluate the long-term outcome of total repair for tetralogy of Fallot. METHODS Between April 1986 and December 2007, a total of 734 patients underwent total repair for tetralogy of Fallot. There were 444 males and 290 females. The median age and weight were 17.2 months (0.4-329.6 months) and 9.5kg (2.6-53.5kg). The median follow-up duration was 150.2 months (1.9-356.2 months). RESULTS There were 27 early deaths (3.7%) and 13 late deaths. A longer cardiopulmonary bypass time and the use of total circulatory arrest were risk factors for early death. The overall survival rate was 94.8%, 92.8% and 92.8% at 10, 20 and 25 years, respectively. The presence of pulmonary atresia was a risk factor for long-term survival. Re-operation or re-intervention was required in 224 patients (31.7%). The most common causes of re-operation or re-intervention were pulmonary regurgitation in 109 patients and branch pulmonary artery stenosis in 127 patients. Freedom from re-operation or re-intervention rate was 81.5%, 68.9% and 46.6% at 5, 10 and 20 years, respectively. Reconstruction of the right ventricular outflow tract with other than non-trans-annular repair and branch pulmonary arterioplasty at the time of total repair were the risk factors for late re-operation or re-intervention. The use of a monocusp patch was not associated with early mortality or re-operation. At the latest follow-up, most patients were in the New York Heart Association functional class 1 or 2. CONCLUSIONS The long-term outcome of total repair for tetralogy of Fallot was satisfactory. A longer cardiopulmonary bypass time and the use of deep hypothermic circulatory arrest were associated with early mortality. The patients with pulmonary atresia have poorer late survival. Preservation of the pulmonary annulus can reduce the re-operation rate. A small pulmonary artery that requires augmentation may increase the risk of re-operation. The use of a monocusp in patients who underwent trans-annular repair has no benefit for early survival, the postoperative recovery and avoidance of re-operation. Age was not a risk factor for early mortality and re-operation.

Anticalcification effects of decellularization, solvent, and detoxification treatment for genipin and glutaraldehyde fixation of bovine pericardium

OBJECTIVE Calcification plays a major role in the failure of bioprosthetic and other tissue heart valve substitutes. The objective of this study was to evaluate the anticalcification effect of decellularization and detoxification in glutaraldehyde (GA)/genipin- and solvent-fixed bovine pericardium using a rabbit intramuscular model which is effective for assessing calcification in bioprosthetic tissue. METHODS Bovine pericardial tissues were fixed with 0.5% GA/0.4% genipin in organic solvent (75% ethanol + 5% octanol, 75% ethanol + 5% octanediol, or 70% ethanol + 10% isopropanol) and post-treated with glycine, glutamic acid, or sodium bisulfite. Decellularization was performed with 0.25% sodium dodecylsulfate prior to fixation. The material characteristics of the treated tissues were assessed by thermal stability test, uniaxial mechanical test, and light microscopy. Stability of the treated tissue was measured by the resistance to enzymatic degradation using protease. The tissues were intramuscularly implanted into 4-week-old rabbits for 8 weeks, and the anti-α-Gal(Gal[alpha]1,3-Gal[beta]1,4GlcNAc-R) antibodies (immunoglobulin G) were measured at various time intervals after implantation. Explanted tissues were examined by light microscopy and calcium contents of the explanted tissues were measured. RESULTS Differently treated tissues resulted in no significant alterations in material characteristics and morphology. GA groups are superior to genipin groups in tissue cross-linking without difference according to addition of decellularization, organic solvent treatment, and detoxification by resistance toward pronase degradation. The titer of anti-α-Gal antibodies gradually increased after implantation in all study groups. The titer of anti-α-Gal antibodies increased less in genipin groups than in GA groups, and less with decellularization than without decellularization. The calcium contents of genipin groups (n = 75) were significantly lower than those of GA groups (n = 118) (28.55 ± 11.22 μg mg(-1) vs 37.16 ± 7.75 μg mg(-1), p < 0.001). Calcium contents decreased with decellularization, organic solvent treatment, and detoxification, irrespective of the type of organic solvent and amino acids. Inorganic phosphorus contents of genipin groups (n = 66) were significantly lower than those of GA groups (n = 103) (55.36 ± 26.98 μg mg(-1) vs 75.67 ± 23.44 μg mg(-1), p = 0.000). CONCLUSIONS Genipin fixation is a novel alternative to conventional GA fixation in vitro material assessment and in vivo anticalcification effect. The addition of decellularization, organic solvent treatment, and detoxification prevented calcification of GA/genipin-fixed bovine pericardium in the rabbit intramuscular implantation model, irrespective of the type of organic solvent and amino acids.

The Effect of Cardioplegic Solution-Induced Sodium Concentration Fluctuation on Postoperative Seizure in Pediatric Cardiac Patients

BACKGROUND Despite potential benefits of histidine-tryptophan-ketoglutarate (HTK) solution as a cardioplegic solution, it can cause hyponatremia, especially in pediatric patients. Fluctuations in the sodium concentration during cardiopulmonary bypass (CPB) can adversely affect the central nervous system. We evaluated the relationship between the cardioplegic solution, the fluctuation of sodium concentration, and the incidence of postoperative seizure in pediatric cardiac patients. METHODS The medical records of 628 patients were reviewed for the occurrence of a postoperative seizure, type of cardioplegic solution (HTK or del Nido solution), and intraoperative data. A change of sodium concentration exceeding 15 mmol/L (ΔNa>15) during CPB was defined as a significant fluctuation of sodium concentration. RESULTS Postoperative seizures were detected in 18 patients (2.9%). The ΔNa>15 was detected in 63 of 189 patients (33.3%) who received the HTK solution and in 14 of 439 patients (3.2%) who received the del Nido solution (p<0.001). The incidence of ΔNa>15 was strongly associated with postoperative seizure (odds ratio, 6.3; 95% confidence interval, 2.4 to 16.4, p=0.001). After adjusting for potential confounders, the ΔNa>15 remained significantly associated with postoperative seizure (odds ratio, 3.9; 95% confidence interval, 1.3 to 12.3, p=0.018). CONCLUSIONS Histidine-tryptophan-ketoglutarate solution during CPB frequently causes fluctuations of sodium concentration, usually combined with hyponatremia, which is associated with postoperative seizure. Special attention to sodium concentration is required, particularly when HTK solution is used in pediatric cardiac patients.

Cell-mediated immunomodulation of chemokine receptor 7-expressing porcine sertoli cells in murine heterotopic heart transplantation.

BACKGROUND Sertoli cells (SC) have immunomodulative properties, and chemokine receptor 7 (CCR7) can optimize the systemic immunomodulatory effect by guiding SC from the periphery to the secondary lymphoid organs. METHODS The effect of immortalized neonatal porcine SC (NPSCi) was evaluated by analysis of cytokine levels. Hyporesponsiveness to donor cells was determined by MLC and analysis of splenocyte phenotypes using a murine allogeneic skin graft model. The effect of CCR7-expressing NPSCi (NPSCi-CCR7) combined with cobra venom factor (CVF) was evaluated using a heterotopically transplanted murine allogeneic heart model. RESULTS Expression of immune cytokines was markedly modulated by NPSCi. The lymphocyte proliferation and splenocyte phenotypes were significantly suppressed by NPSCi-CCR7. Although pre-transplantation of NPSCi or NPSCi-CCR7 did not prolong graft survival of allogeneic cardiac grafts, CVF treatment facilitated pre-transplantation of NPSCi-CCR7 to prolong survival of allogeneic cardiac grafts (25.5 +/- 7.05 vs 9.5 +/- 0.58 days, p < 0.01). CONCLUSIONS NPSCi may be used as a powerful immunomodulatory tool, and our strategy to traffic NPSCi to lymphoid organs using CCR7 optimizes the systemic immunomodulatory effect in vivo. With the help of initial immunosuppression for humoral mechanisms using CVF, the host immune response against allogeneic cardiac grafts can be effectively ameliorated by immunomodulation of the cellular mechanism with NPSCi-CCR7.

Development of a next-generation tissue valve using a glutaraldehyde- fixed porcine aortic valve treated with decellularization, α-galactosidase, space filler, organic solvent and detoxification

OBJECTIVES Conventional crosslinking with glutaraldehyde (GA) renders cardiac xenografts inert, non-biodegradable and non-antigenic, but is a main cause for dystrophic calcification due to phospholipids, free aldehyde groups and residual antigenicity. A significant immune reaction to the galactose-α-1,3 galactose β-1,4-N-acetylglucosamine (α-Gal) of a GA-fixed cardiac xenograft occurs, leading to calcification. We developed a next-generation α-Gal-free tissue valve with GA-fixed cardiac xenografts, treated using a novel combined anticalcification protocol including immunological modification, which was demonstrated effective in a small animal study. METHODS Porcine aortic valves were decellularized with 1% sodium dodecyl sulphate, 1% Triton X-100 and 1% sodium lauroyl sarcosinate and immunologically modified with α-galactosidase. The valves were treated by a polyethylene glycol space filler, fixed with GA in 75% ethanol + 5% octanol and detoxified with glycine. We manufactured the tissue valve with the porcine aortic valve mounted on a Nitinol (nickel-titanium memory alloy) plate. The tissue valve was placed under in vitro mock circulation, and durability from mechanical stress was evaluated for 100 days. Ten sheep underwent mitral valve replacement with the tissue valve, and haemodynamic, radiological, immunohistopathological and biochemical results were obtained for 18 months after implantation. RESULTS The in vitro circulation experiment demonstrated that the valve functioned well with good morphology. Eight sheep survived for 1, 2, 5, 10, 14, 53, 546 and 552 days after mitral valve replacement, but two sheep did not survive. An evaluation by echocardiography and cardiac catheterization demonstrated good haemodynamic status and function of the mitral valve at 18 months after implantation. The xenografts were well preserved without a α-Gal immune reaction or calcification based on the immunological, radiographic, microscopic and biochemical examinations. CONCLUSIONS We developed a next-generation α-Gal-free tissue valve with simultaneous use of multiple anticalcification therapies and novel tissue treatments such as decellularization, immunological modification with α-galactosidase, space filler, an organic solvent and detoxification. Future investigations should evaluate α-Gal-free substitutes such as our tissue valve, and a future clinical study is warranted based on these promising preclinical results.

Short- and Long-Term Results of Triple Valve Surgery: A Single Center Experience

Triple valve surgery is usually complex and carries a reported operative mortality of 13% and 10-yr survival of 61%. We examined surgical results based on our hospitals experience. A total of 160 consecutive patients underwent triple valve surgery from 1990 to 2006. The most common aortic and mitral valve disease was rheumatic disease (82%). The most common tricuspid valve disease was functional regurgitation (80%). Seventy-four percent of the patients were in New York Heart Association (NYHA) class III and IV. Univariate and multivariable analyses were performed to identify predictors of early and late survival. Operative mortality was 6.9% (n=11). Univariate factors associated with mortality included old age, preoperative renal failure, postoperative renal failure, pulmonary complications, and stroke. Of them, postoperative renal failure and stroke were associated with mortality on multivariable analysis. Otherwise, neither tricuspid valve replacement nor reoperation were statistically associated with late mortality. Survival at 5 and 10 yr was 87% and 84%, respectively. Ninety-two percent of the patients were in NYHA class I and II at their most recent follow-up. Ten-year freedom from prosthetic valve endocarditis was 97%; from anticoagulation-related hemorrhage, 82%; from thromboembolism, 89%; and from reoperation, 84%. Postoperative renal failure and stroke were significantly related with operative mortality. Triple valve surgery, regardless of reoperation and tricuspid valve replacement, results in acceptable long-term survival.

Differences in xenoreactive immune response and patterns of calcification of porcine and bovine tissues in α-Gal knock-out and wild-type mouse implantation models

OBJECTIVES Although bioprostheses are widely used in cardiovascular surgery, their durability is limited due to degeneration. Degeneration of bioprostheses limiting its clinical use results from multiple factors, and immune reaction has been considered to be one of the most important factors. The study objectives were to compare the mechanical characteristic differences of porcine and bovine prostheses, assess the differences in immune reaction among different species and tissues as well as elucidate bioprosthetic failure patterns in α-Gal knock-out (KO) and wild-type mouse implantation models. METHODS Six groups of different xenogeneic tissues (porcine pericardium, aortic valve, aortic wall; bovine pericardium, aortic valve and aortic wall) were implanted into the subcutaneous tissue of the wild-type mouse (n = 4) and the KO mouse (n = 4) (four xenogeneic tissue segments per each mouse). Mechanical and chemical tests, including tensile strength measurement and thermal stability test for pericardial tissues and pronase test for different xenogeneic tissues, were performed before implantation. Anti-α-Gal antibody titres (IgM and IgG antibodies) were measured using serum enzyme-linked immunosorbent assay analyses before implantation and 30, 60 and 90 days after implantation. Implanted tissues were harvested after 90 days and studied for histopathology and quantification of calcification. RESULTS There were no significant differences in tensile strength and shrinkage temperature between the porcine and bovine pericardia, although the bovine pericardia showed a greater elasticity than the porcine pericardia (elongation at tensile strength, 74.8 ± 4.5% vs 50.0 ± 8.7%, P < 0.001). Resistance towards pronase degradation was not different among the groups of tissues (Groups 1-6, 89.1 ± 7.6, 95.1 ± 1.8, 90.3 ± 5.3, 93.7 ± 3.3, 89.1 ± 2.4 and 89.1 ± 3.0%, respectively; P = 0.061). The IgM titres of the α-Gal KO mice were significantly higher at 30 days after implantation (0.71 ± 0.27 vs 1.07 ± 0.48, P = 0.004), whereas the IgG titres of the α-Gal KO mice remained higher until 60 days after implantation (at 30 days, 0.81 ± 0.07 vs 1.28 ± 0.79, P = 0.017; at 60 days, 0.54 ± 0.16 vs 1.43 ± 1.10, P = 0.045) than those of the wild-type mice. Calcium levels of tissues implanted into the α-Gal KO mice were significantly higher than those implanted into the wild-type mice regardless of tissue type (from Groups 1-6, 4.72 ± 1.75 vs 27.76 ± 22.73 μg/mg; 3.05 ± 1.04 vs 15.90 ± 6.98 μg/mg; 2.13 ± 1.48 vs 29.76 ± 30.71 μg/mg; 1.02 ± 0.53 vs 5.97 ± 1.40 μg/mg; 3.18 ± 3.41 vs 30.55 ± 66.69 μg/mg; 6.21 ± 5.56 vs 21.65 ± 17.77 μg/mg, all P ≤ 0.002). CONCLUSIONS Chronic immune response to the α-Gal antigen may cause more severe tissue calcification in α-Gal KO mice. Removal of α-Gal antigenicity is strongly advised in xenogeneic bioprosthetic tissue implantation.

Histologic Characteristics and Mechanical Properties of Bovine Pericardium Treated with Decellularization and α-Galactosidase: A Comparative Study.

Background Bioprostheses for cardiovascular surgery have limitations in their use following as calicification. α-galactosidase epitope is known as a stimulant of immune response and then shows a progressing calcification. The objective of this study was to evaluate histologic characteristics and mechanical properties of decellularization and treated with α-galactosidase. Materials and Methods Bovine pericardial tissues were allocated into three groups: fixation only with glutaraldehyde, decellularization with sodium dodesyl sulfate and decellularization plus treatment with α-galactosidase. We confirmed immunohistological characteristics and mechanical properties as fatigue test, permeability test, compliance test, tensile strength (strain) test and thermal stability test. Results Decellularization and elimination of α-gal were confirmed through immunohistologic findings. Decellularization had decreased mechanical properties compared to fixation only group in permeability (before fatigue test p=0.02, after fatigue test p=0.034), compliance (after fatigue test p=0.041), and tensile strength test (p=0.00). The group of decellularization plus treatment with α-galactosidase had less desirable mechanical properties than the group of decellularization in concerns of permeability (before fatigue test p=0.043) and strain test (p=0.001). Conclusion Favorable decellularization and elimination of α-gal were obtained in this study through immunohistologic findings. However, those treatment including decellularization and elimination of α-gal implied the decreased mechanical properties in specific ways. We need more study to complete appropriate ioprosthesis with decellularization and elimination of α-gal including favorable mechanical properties too.

A Comparative Study on Mechanical and Biochemical Properties of Bovine Pericardium After Single or Double Crosslinking Treatment

Background and Objectives Glutaraldehyde (GA) has been used as a representative method of tissue preservation in cardiovascular surgery. However, GA has showed limited durability including calcification, mechanical failure and toxicity. To overcome those unsolved problems, we analyzed the crosslinking differences of primary amines, GA and genipin in their mechanical and biochemical properties with a single or double crosslinking agent for clinical application. Materials and Methods Samples were divided into 3 groups; control, single crosslinking fixation and double crosslinking fixation after decellurarization using bovine pericardium. For analysis of the biochemical and mechanical properties of each crosslinking method, tensile strength, percentage strain, thermal stability, resistance to pronase, nynhydrin and cytotoxicity test were studied. Results Combined hexamethylene diamine and suberic acid in the carbodiimide hydrochloride/N-hydroxysucinimide solution (EDC/NHS) after decellurarization, tensile strength and strain percentage were not statistically significant compared to the single crosslinking treated groups (p>0.05). Tissue crosslinking stability was weak in single treatment of diphenylphosphoryl azide, suberic acid, low concentration of EDC, hexamethylene diamine and procyanidin groups, but thermal stability and resistance to the pronase and ninhydrin were markedly increased in concentrated EDC/NHS or after combined double treatment with low concentration of GA or genipin (p<0.001). Conclusion Single or double crosslinking with low concentration of carbodiimide, diphenylphosphonyl azide, procyanidin, suberic acid and hexane diamine were not as effective in mechanical, biochemical, cytotoxic and crosslinking properties compared to GA or genipin fixation, but their mechanical and chemical properties were much improved when combined with low concentrations of GA or genipin in the double crosslinking process.