[How to Consider the Heart Transplantation from the Donor after Circulatory Death in Japan].

The donation of the organs after brain death (DBD) has increased after the revision of the law in 2010 and the total number of heart transplantation( HTx) has reached to over 500 in Japan. However, donor shortage is critical as the annual number as remaining under 100 with unneglectable number of waiting deaths. Recently, HTx under donation after controlled circulatory death( cDCD) has been promoted in United Kingdom (UK) and Australia with promising outcomes. The cDCD appears to be an important option to expand the donor pool in Japan. Nation-wide and cross-cutting action among transplantation organs is warranted. Status of cDCD HTx in abroad and the domestic issues are reviewed.

Clinical results with Jarvik 2000 axial flow left ventricular assist device: Osaka University Experience.

The aim of this study was to evaluate our clinical experience with the Jarvik 2000 axial flow pump (Jarvik Heart, Inc, New York, NY, USA), a miniature axial flow left ventricular assist device (LVAD). The clinical results of eight patients, who underwent LVAD implantation with the Jarvik 2000 (median age 55.0 years; six men) between 2005 and 2010, including two who participated in a multicenter clinical trial in Japan, were reviewed. Two patients underwent LVAD implantation as destination therapy. Four patients underwent Jarvik 2000 implantation via median sternotomy, while the other four underwent implantation via left thoracotomy. There were no major complications during surgery. Four patients were supported for more than 2 years. The longest support duration was 1,618 days. Six patients successfully bridged to heart transplantation after a median 725 days of support. One patient on destination therapy died of a cerebral infarction. The other patient on destination therapy had had the LVAD for 1,618 days. The overall survival rates at 1, 2, and 3 years were 100, 86, and 86%, respectively. The median postoperative serum lactate dehydrogenase level was 860.5 U/L at 1 month, 735 U/L at 6 months, and 692 U/L at 1 year. There were no fatal device-related infections. We found that the Jarvik 2000 with pin bearing could support patients with end-stage heart failure with acceptable mortality and morbidity rates. Further evaluations of the prevalence of thromboembolic and hemolytic events in patients with the new conical-bearing Jarvik 2000 are required.

[Cardiac tamponade due to ruptured coronary artery aneurysm associated with coronary-pulmonary artery fistula; report of a case].

We report a successful operative treatment of ruptured coronary artery aneurysm associated with coronary-pulmonary artery fistula. A 67-year-old woman was diagnosed with coronary artery fistula previously but observed without any treatment. She had medical examination at a previous hospital because of sudden onset of dyspnea, and transported to our institution with a diagnosis of cardiac tamponade. Multi-detector computed tomography (MDCT) showed massive pericardial effusion, coronary-pulmonary artery fistula and giant coronary artery aneurysm. We performed emergency operation. Under cardiopulmonary bypass, coronary artery fistula and aneurysm was resected. Postoperative MDCT showed almost complete exclusion of coronary artery fistula. Postoperative course was uneventful.

Efficacy of simulation training for beating heart coronary anastomosis using BEAT + YOUCAN simulator.

BACKGROUND: We sought to evaluate our distributed practice program developed for training for beating heart anastomosis by employing a novel beating heart simulator. METHODS: Eleven trainees watched and reviewed instructional video recordings of coronary anastomosis methods with a BEAT + YOUCAN training device, then performed coronary anastomosis procedures under a beating condition. Next, they participated in a four-hour training program developed by faculty surgeons. Ten different anastomosis components were assessed on a five-point rating scale (5, good; 3, average; 1, poor). After finishing the training program, each trainee again performed a coronary anastomosis procedure. Component scores were then compared before and after the training program. RESULTS: The mean time to completion of the procedure improved from 1033 ± 424 to 795 ± 201 s (p < 0.05). Assessment scores improved from 1.88 ± 0.41 to 2.57 ± 0.30 (p < 0.05). Improvements in some technical components related to handling of instruments were noted (p < 0.05), whereas no significant improvement was seen with arteriotomy, graft orientation, suture management, or knot tying after finishing the training program. CONCLUSION: Trainees who participated in our four-hour focused training program for coronary anastomosis with a novel beating heart simulator showed improved ability under the beating condition in regard to technical skills related to handling instruments.

Japanese guidance for ventricular assist devices/total artificial hearts.

To facilitate research and development (R&D) and to expedite the review processes of medical devices, the Ministry of Health, Labor and Welfare (MHLW) and the Ministry of Economy, Trade and Industry (METI) founded a joint committee to establish guidance for newly emerging technology. From 2005 to 2007, two working groups held discussions on ventricular assist devices and total artificial hearts, including out-of-hospital programs, based on previous guidance documents and standards. Based on this discussion, the METI published the R&D Guidelines for innovative artificial hearts in 2007, and in 2008 the MHLW published a Notification by Director regarding the evaluation criteria for emerging technology.

[The role and perspective of recipient transplant coordinator in Japan].

The transplant recipient coordinator (RCo) has an important role in the clinical arena of organ transplantation for better patient management and successful outcome. In Japan, the step towards organization of RCo system has been in progress along with the increase of living-related liver transplantation as well as the start of transplantation from brain-dead donors. Considering its limited numbers and lack of national educational system, the Japanese Society of Transplantation recently has organized to start the new certification system for RCo setting prerequisites for application, educational programs and method of examination.

The Jarvik 2000 left ventricular assist device as a bridge to transplantation: Japanese Registry for Mechanically Assisted Circulatory Support.

BACKGROUND: The Jarvik 2000 ventricular assist device features a miniaturized intraventricular pump and an intermittent low-speed function that facilitates aortic valve opening. Despite its long history, little is known about the Jarvik device with regard to post-implantation outcomes. METHODS: Prospectively collected data from 13 participating hospitals were extracted from the Japanese Registry for Mechanically Assisted Circulatory Support database to analyze mortality, morbidity and de-novo aortic regurgitation. Data on 83 patients who underwent implantation of the Jarvik 2000 were reviewed. Median support duration was 191 (maximum 758) days. All recipients underwent implantation as a bridge to transplantation. RESULTS: Overall survival proportions at 1 and 2 years were 85.0% and 79.3%, respectively. Nine patients were in INTERMACS Level 1, and 28 patients were on mechanical circulatory support at the time of implantation. Causes of death included stroke, infection and device malfunction. Three patients had their device removed: 2 at the time of heart transplantation and 1 after recovery of the left ventricle. Common adverse events included major bleeding (27.7%), new infection (31.3%), stroke (20.5%) and device malfunction (20.5%). De-novo aortic regurgitation was observed in 17 patients, 6 of whom developed at least moderate regurgitation during follow-up. CONCLUSIONS: Mid-term survival after Jarvik 2000 implantation was satisfactory and comparable to that reported by other national and international registries (INTERMACS and IMACS) for continuous-flow LVADs. De novo aortic regurgitation occurred despite the intermittent low-speed effect of this device, with some recipients experiencing progressive worsening of aortic regurgitation within 2 years post-implantation.

Therapeutic effects of roxithromycin in interleukin-10-deficient colitis.

BACKGROUND: A limited number of therapeutic strategies are currently available to treat patients with inflammatory bowel disease (IBD). Interleukin-10 (IL-10)-deficient mice, well characterized as an experimental model of IBD, develop severe chronic colitis because of aberrant Th1 responses. Roxithromycin (RXM), a macrolide antibiotic, has received attention because it offers not only antibacterial but also immunosuppressive effects. We examined the immunosuppressive effect of RXM on the development of IBD. METHODS: To test the efficacy of short-term administration of RXM, elder IL-10-deficient mice (16-20 weeks old) with established colitis were orally treated for 10 days with RXM (20 mg/kg per day). To test the long-term preventive effects of RXM, for 20 weeks young adult IL-10-deficient mice (4-5 weeks old) also were administered RXM orally (20 mg/kg per day). RESULTS: The short-term treatment-oriented administration of RXM reduced the degree of inflammatory change and lowered serum amyloid A in IL-10-deficient mice with severe colitis. Mononuclear cells from the lamina propria of RXM-treated large intestines showed lower production of IFN-gamma than did those from diseased mice that were untreated. Long-term prevention-oriented administration of RXM suppressed the development of severe colitis and decreased production of IFN-gamma and IL-12. In addition to its expected immunosuppressive effect, RXM treatment also decreased the level of Bacteroides vulgatus, a Gram-negative anaerobe. CONCLUSIONS: The anti-inflammatory changes observed in IL-10-deficient mice resulted from the efficacy of RXM as an immunosuppressant as well as from its efficacy as an antibiotic. According to our findings, RXM would seem to have significant potential as a preventive and/or therapeutic agent for IBD.

[The system problems related to thoracic surgery practices in japan; message from the Japanese association for thoracic surgery].

The thoracic surgery practice in Japan has characteristics such as strong burden to surgeons and young trainees for high-risk procedures under poor health care manpower system and less qualification for their high-level practices. The presence of too many numbers of certified surgeons and teaching hospitals for cardiac, general thoracic and esophageal surgeries has been well recognized providing low quality maintenance and poor training system. The Japanese Association for Thoracic Surgery has recently made a step towards to open the data of hospital quality promoting the discussion to reunify the hospitals and surgeons into reasonable numbers to respond to the social demand. The new 2-year postgraduate clinical training and also a new specialty medical board approval for advertisement have provided various problems and controversies, and we must make efforts to overcome these problems by providing new strategies to make our practices more qualified.

Longer preservation of cardiac performance by sheet-shaped myoblast implantation in dilated cardiomyopathic hamsters.

OBJECTIVES: Cell therapy is a promising strategy for ischemic cardiomyopathy. However, the direct injection method has limitations for generalized cell delivery, especially in dilated cardiomyopathy (DCM). We hypothesized that a sheet-shaped myoblast graft would be superior to direct injection for improving cardiac performance in DCM. METHODS: Male 27-week-old BIO TO-2 (DCM) hamsters that showed moderate cardiac remodeling were used as recipients. Myoblasts isolated from BIO F1B hamsters were cultured on dishes coated with poly(N-isopropylacrylamide), a temperature-responsive polymer, and spontaneously detached as a sheet-shaped graft at 20 degrees C without enzymatic treatment. Three different therapies were conducted: (1) sheet-shaped myoblast graft implantation (S group, n=29); (2) myoblast injection (M group, n=28); and (3) sham operation (C group, n=28). In the S group, two sheet-shaped myoblast grafts were implanted on the left ventricle (LV) wall, and in the M group, myoblasts were injected into the right ventricle (RV) and LV walls. RESULTS: After the sheet-shaped myoblast grafts were implanted, echocardiography demonstrated that the dilated LV dimension was significantly reduced, whereas the hearts in other groups showed a progression of LV dilation. The fractional shortening in the M and C groups decreased significantly while that in the S group was maintained at the preoperative level for 3 months after the operation. Histological examination demonstrated that in the S group, the LV wall thickness was increased, with viable myoblasts, and myocardial fibrosis was decreased compared with the other groups. Immunohistochemical staining demonstrated alpha-sarcoglycan and beta-sarcoglycan expression on the basement membrane of the cardiomyocytes in the S group but not in the other groups. The life expectancy was significantly prolonged in the S group. CONCLUSION: Sheet-shaped myoblast graft implantation improved cardiac performance and prolonged life expectancy, associated with a reduction in myocardial fibrosis and re-organization of the cytoskeletal proteins in DCM hamsters. Thus, sheet-shaped autologous myoblast graft implantation may induce restoration of the heart in DCM.

Orthotropic heart transplantation for adult congenital heart disease: a case with heterotaxy and dextrocardia.

A 41-year-old male with heterotaxy (left isomerism) and dextrocardia composed by single ventricle, absent inferior vena cava, bilateral superior vena cava (SVC), common atrioventricular valve has received orthotopic heart transplantation (HTx) after long waiting period as Status-1. Reconstructions of bilateral SVC and hepatic vein route were successful without use of prosthetic material, and the donor heart was placed in the left mediastinum. In spite of satisfactory early recovery, the patient expired 4 months after transplantation mainly from fungal infection which developed following humoral rejection. HTx for adult patients with complex congenital heart disease is demanding in technical as well as pre- and post-transplant management, and indication should be critically determined.

Heart transplantation for adults with congenital heart disease: current status and future prospects.

Increased survival rates after corrective or palliative surgery for complex congenital heart disease (CHD) in infancy and childhood are now being coupled with increased numbers of patients who survive to adulthood with various residual lesions or sequelae. These patients are likely to deteriorate in cardiac function or end-organ function, eventually requiring lifesaving treatment including heart transplantation. Although early and late outcomes of heart transplantation have been improving for adult survivors of CHD, outcomes and pretransplant management could still be improved. Survivors of Fontan procedures are a vulnerable cohort, particularly when single ventricle physiology fails, mostly with protein-losing enteropathy and hepatic dysfunction. Therefore, we reviewed single-institution and larger database analyses of adults who underwent heart transplantation for CHD, to enable risk stratification by identifying the indications and outcomes. As the results, despite relatively high early mortality, long-term results were encouraging after heart transplantation. However, further investigations are needed to improve the indication criteria for complex CHD, especially for failed Fontan. In addition, the current system of status criteria and donor heart allocation system in heart transplantation should be arranged as suitable for adults with complex CHD. Furthermore, there is a strong need to develop ventricular assist devices as a bridge to transplantation or destination therapy, especially where right-sided circulatory support is needed.

Amelioration of pulmonary emphysema by in vivo gene transfection with hepatocyte growth factor in rats.

BACKGROUND: Hepatocyte growth factor (HGF) is an important mitogen and morphogen that contributes to the repair process after lung injury. The goal of the present study was to characterize its role in pulmonary emphysema, which may lead to the development of new treatment strategies with HGF. METHODS AND RESULTS: HGF mRNA and protein levels in lung tissue and plasma from elastase-induced emphysema rats transiently increased, then declined significantly to below the basal level in a time-dependent manner (P<0.01). Furthermore, changes in HGF were correlated with histologically progressive emphysematous changes and deterioration in pulmonary physiology. Use of the HVJ (hemagglutinating virus of Japan) envelope method resulted in successful transfection of cDNA encoding human HGF, as demonstrated by an efficient expression of HGF in alveolar endothelial and epithelial cells. Transfection of HGF resulted in a more extensive pulmonary vasculature and inhibition of alveolar wall cell apoptosis, and those effects led to improved exercise tolerance and gas exchange (P<0.05), which persisted for more than 1 month. CONCLUSIONS: Decreased HGF expression due to a failure in sustained endogenous production after injury was associated with emphysema-related histopathologic and physiological changes in the present rat model. In addition, induction of HGF expression by a gene-transfection method resulted in improved pulmonary function via inhibition of alveolar cell apoptosis, enhancement of alveolar regeneration, and promotion of angiogenesis.

Significant inhibition of human CD8(+) cytotoxic T lymphocyte-mediated xenocytotoxicity by overexpression of the human decoy Fas antigen.

BACKGROUND: Human CD8(+) CTL-mediated killing may be important for xenograft rejection. The purpose of this study was to explore the preventing methods for CTL-mediated xenocytotoxicity by overexpression of human decoy Fas, which lacks a death domain in its cytoplasmic region, by binding competition with endogenous pig Fas. Moreover, the cytoprotective effect of this CTL-killing of membrane-bound human FasL, which is resistant to metalloproteolytic cleavage, was also assessed. METHODS: Human CTL were generated by the stimulation of human PBMC with swine endothelial cells (SEC) and human IL-2, subsequently a CD8(+) population were selected by magnetic beads and employed as the effector cells. Stable SEC transfectants expressing either decoy Fas or membrane-bound FasL were established. Double-transfectants were also created. The amelioration of cytotoxicity to these transfectants was examined with Cr release assay. RESULTS.: Human CD8(+) CTL were highly detrimental against parental SEC. This CTL-killing was strongly inhibited by anti-FasL mAb treatment, however partial suppression was observed by Concanamycin A treatment. The overexpression of either decoy Fas or membrane-bound FasL in SEC markedly inhibited CTL-xenocytotoxicity. The double expressions of these molecules also significantly reduced this xenocytotoxicity despite the low levels of expression of either decoy Fas or membrane-bound FasL. CONCLUSION: These findings indicate that the strong xenocytotoxicity of human CD8(+) CTL is mediated mainly by the Fas/FasL pathway. The overexpression of either decoy Fas or membrane-bound FasL were quite effective in preventing CTL-killing. Furthermore, the combined expression of both molecules in pig cells may create a window of opportunity for prolonging xenograft survival.