Asian Cardiovasc Thorac Ann 2004;12:154-158
© 2004 Asia Publishing EXchange Ltd
Early Result of Heart Transplantation in Japan: Osaka University Experience
Norihide Fukushima, MD,
Yuji Miyamoto, MD,
Shigeaki Ohtake, MD,
Yoshiki Sawa, MD,
Toshiki Takahashi, MD,
Motonobu Nishimura, MD
Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
For reprint information contact: Norihide Fukushima, MD Tel: 81 6 6879 3154 Fax: 81 6 6879 3163 Email: nori{at}surg1.med.osaka-u.ac.jp 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
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ABSTRACT
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Since the new organ transplantation law was established in 1997, 17 heart transplantations have been performed in Japan, 7 of which were carried out at Osaka University Hospital. Recipient diagnosis was dilated cardiomyopathy in 2, dilated phase of hypertrophic cardiomyopathy in 4, and post-myocarditis cardiomyopathy in 1. Ages ranged from 8 to 49 years with a mean of 35.3 years. Five patients were bridged with a left ventricular assist device. The waiting period was 182–977 days (mean, 643 days). There was no early or late death during follow-up of 1–4.8 years. Under a standard triple-drug regimen using mycophenolate, there were 3 rejection episodes greater than grade 3 in 2 patients, and humoral rejection requiring plasmapheresis in one. A young boy whose donor was a hemodynamically compromised adult developed neurological sequelae after resuscitation following ventricular tachycardia. All patients were discharged and went back to work or their regular daily life. Although the donor shortage is still severe in Japan, the resumption of heart transplantation has been satisfactory, and left ventricular assist devices have played a crucial role.
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INTRODUCTION
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Heart transplantation (HTx) has been internationally established as a treatment for end stage heart failure.1 There are over 4000 HTx operations per year, with a 5-year survival rate of approximately 70%. In our country, however, HTx has not been practiced because of our unique cultural background and the social attitude to organ transplantation. During recent decades, various efforts such as campaigns for organ transplantation and petitions to the government have been made by thoracic surgeons and cardiologists to establish social support for restarting HTx, which culminated in legislation in October 1997 allowing HTx to recommence. The first heart transplant was performed in February 1999 with success.2 Since then, 17 HTx operations have been performed in 3 registered hospitals: Osaka University, National Cardiovascular Center, and Tokyo Women’s Medical College. The early results of the 7 transplants carried out in Osaka University Hospital are described herein.
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PATIENTS AND METHODS
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The recipients were 5 males and 2 females, with ages ranging from 8 to 49 years (mean, 35.3 years). The underlying diseases are shown in Table 1
. The waiting period for a donor was 182 to 977 days (mean, 643 days), and 5 patients underwent HTx after circulatory support for 20 to 1087 days (mean, 468 days) with a left ventricular assist device (LVAD): a Novacor (Baxter Healthcare Corp., Novacor Division, Oakland, CA, USA) in 2, a TCI-IP (Thermo Cardiosystem, Woburn, MA, USA) in 2, and a Toyobo-NCVC (Toyobo, Tokyo, Japan) in 1. One patient with a Novacor LVAD had been waiting mostly at home for nearly 3 years, and the others were in hospital. The donor ages ranged from 22 to 58 years (mean, 37.1 years). The donor blood type was identical to the recipient in all cases. The body weight ratios were within the standard index except in the case of an 8-year old boy with a ratio of 240% (Table 2). The panel reactive antibody (PRA) and the prospective crossmatch were negative in all cases at the time of HTx. One donor heart was procured from a local hospital and 6 came from distant institutions via helicopter or chartered aircraft within 27–210 min (mean, 113 min). Donor (D) to recipient (R) cytomegalovirus (CMV) matching was D+/R+ in 5, D+/R– in 1, and D–/R– in 1. In the case of D+/R–, prophylaxis against CMV infection (intravenous immunoglobulin and ganciclovir) was given. The CMV deoxyribonucleic acid was measured by the protein chain reaction, messenger ribonucleic acid was measured by the nucleic acid sequence-based amplification method, and serum CMV antigen was monitored.3 If these parameters increased, ganciclovir was given. The donor hearts were harvested as previously described.4 The heart was arrested with modified glucose insulin potassium solution containing 250 mg·L–1 of methylprednisolone sodium succinate (Solumedrol; Upjohn, Kalamazoo, MI, USA) and 3 mEq·L–1 of magnesium sulfate. The coronary vascular bed was washed with modified Collins solution to replace the cardioplegic solution, and the heart was immersed in modified Collins solution containing 3 mEq·L–1 of magnesium sulfate at 4°C in triple isolation bags.
A standard Lower-Shumway anastomosis was performed in the 5 patients who had undergone LVAD implantation.5 The modified technique of Bailey and colleagues6 was used in the child because there was a large difference in the body size between the donor (45kg) and the recipient (18 kg). In one patient with no LVAD, a modified bicaval anastomosis was performed because he had no previous surgery.7 The total ischemic time ranged from 178 to 249 min (mean, 218 min), mostly within the 240 min which might be the upper limit of ischemic time. Leukocyte depleted terminal blood cardioplegia was given antegradely in 6 patients and retrogradely in 1 prior to aortic declamping.4
The immunosuppressive regimen consisted of steroid, cyclosporine, and azathioprine or mycophenolate mofetil. In cases of renal dysfunction only, antithymocyte globulin was given for 7 days prophylactically. Methylprednisolone (500 mg) was given prior to aortic declamping and 3 doses of 125 mg were given intravenously. Subsequently, oral prednisolone 20 mg was given daily and gradually tapered to 5 mg daily within 6 months. Intravenous cyclosporine 0.1 mg·kg–1 daily was given continuously, followed by oral cyclosporine 3 mg·kg–1 twice daily. The target peak plasma level of cyclosporine was gradually reduced from 350 to 200 ng·mL–1 within 1 year. In the first 3 cases, azathioprine was replaced with mycophenolate mofetil because of liver dysfunction in 2 patients (Figure 1) and suspected coronary graft atherosclerosis in one who had received the heart of an elderly female donor. The 4 most recent patients were given mycophenolate mofetil from the outset.
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Figure 1. Post-transplant course of Case 1. CsA = cyclosporine; dHCM = dilated phase of hypertrophic cardiomyopathy; ISHLT = histological grading of cellular rejection recommended by International Society for Heart and Lung Transplantation; LVAD = left ventricular assist device; MMF = mycophenolate mofetil; yrs = years.
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Endomyocardial biopsies were carried out weekly in the first month, biweekly for 3 months, monthly for 6 months, and then yearly. Cellular rejection was diagnosed according to standard guidelines.8 If cellular rejection greater than grade 3A was detected, intravenous methylprednisolone (1 g daily) was given 3 times early posttransplant or when the graft function was impaired. Otherwise, oral prednisolone (100 mg daily) was given for 3 days. Intravascular ultrasound and coronary angiography were routinely used to investigate coronary graft atherosclerosis at 3 months and annually posttransplant. Coronary angiography only was carried out in the child.
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RESULTS
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There were no early or late deaths during the mean follow-up period of 33 months. There were 2 cardiac events early after HTx (Table 3). The first was in the 8-year old boy whose donor was a small adult female, he suffered depressed cardiac function due to prolonged resuscitation following brain injury. The first and second listed adult recipients had refused to receive this heart, the boy was the next candidate. His cardiac function had progressively deteriorated under dopamine support over several months, and his parents were very anxious about his prognosis because his younger brother had died of the same disease several months earlier. The donor cardiac function (left ventricular ejection fraction of 40%, and mild mitral regurgitation) was thought to be acceptable for HTx into a small child.9,10 It took nearly 2 hours to wean the child from cardiopulmonary bypass under adrenaline infusion, and the sternum was closed simultaneously because the heart was not decompressed by widely opening the left pleural cavity. He developed ventricular tachycardia during the first postoperative night. After resuscitation with temporary extracorporeal membrane oxygenation, his heart function gradually recovered to normal, but he developed a neurological complication. The second event occurred one week after HTx (Case 4). The patient’s PRA (T-cell) level was 82% at the time of LVAD implantation, but it became negative during 1087 days of Novacor LVAD support. As the prospective crossmatch was negative, he underwent HTx. However, he developed acute hemodynamically compromised rejection one week after HTx. A biopsy showed grade 2 rejection, but the specific antibody against donor spleen cells increased and immunoglobulin-G and M and complement components C3 and C4 were immunohistologically stained on the vessels in the myocardium. Humoral rejection was diagnosed and treated successfully with 2 treatments of plasmapheresis, an intravenous steroid pulse, and antithymocyte globulin. Normal cardiac function was restored within 1 week (Figure 2). The other 5 patients had no hemodynamic problems during the early postoperative period.
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Figure 2. Post-transplant course of Case 4. ATG = antithymocyte globulin; CMV = cytomegalovirus; CNI = calcineurin inhibitor; CsA = cyclosporine, dHCM = dilated phase of hypertrophic cardiomyopathy; FK506 = tacrolimus, ISHLT = histological grading of cellular rejection recommended by the International Society for Heart and Lung Transplantation; iv = intravenous administration; LVAS = left ventricular assist support; MMF = mycophenolate mofetil; PE = plasma exchange; po = oral administration; PRD = prednisolone; Tx = transplantation; yrs = years.
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There were 3 episodes of cellular rejection greater than grade 3A in 2 patients; all episodes were treated successfully with an intravenous steroid pulse or oral steroids. In the case of humoral rejection (2 episodes of grade 3A rejection and one of sustained grade 2 rejection), tacrolimus was substituted for cyclosporine at 18 months after HTx, and there was no episode of rejection greater than grade 2 thereafter. There was no evidence of coronary arteriosclerosis apart from donor-transmitted coronary artery disease. Serum total cholesterol and triglyceride levels were controlled within the normal ranges by statin treatment in 6 patients.11 One patient had 2 episodes of pneumonia treated successfully by intravenous antibiotics. Occasional increases in CMV parameters were detected but there was no clinical manifestation except in a D+/R– case who developed primary CMV hepatitis.
The follow-up ranged from 12 to 57 months with a mean of 33 months. All patients showed well-preserved cardiac function, including the child who had developed early cardiac dysfunction. Although there was no or only mild tricuspid regurgitation in all patients postoperatively, two developed moderate tricuspid regurgitation, probably due to the biopsies. The immunosuppressive drugs were smoothly tapered in all cases, and prednisolone was discontinued successfully 5 months after HTx in the child. All patients were discharged, 4 have returned to their previous work, 2 are seeking employment, and the child is attending a school for the handicapped (Table 3
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DISCUSSION
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This is actually a small series of HTx when looked at internationally, but the first steps of this medical strategy have been watched intensely in our country because there was a long period of negativity towards organ transplantation, particularly from brain-dead donors. There has been no mortality among the 17 recipients treated under the new legislation. Thus, the initial resumption of HTx has been successful in this difficult cultural and social context.
The strategies of donor evaluation, donor heart harvest, transplantation procedures, and follow-up are generally similar to those currently conducted abroad. We have introduced some modifications in terms of donor evaluation and management, myocardial preservation, and immunosuppression regimen. Donor cardiac function was evaluated by our own procurement team, and this team determined whether or not the heart was acceptable. For example, if the donor was given a large amount of catecholamine, echocardiograms were performed serially during a gradual reduction of the dose of catecholamine; if cardiac function was still acceptable after discontinuation of catecholamine, we decided to transplant this heart. As the donor shortage is very severe in Japan, we need to use more marginal donor hearts than in other countries. In fact, 13 of the 17 donor hearts were marginal. However, hepatitis B or C positive donors have not yet been transplanted. The methods of cardiac arrest, storage, and reperfusion were as previously described in preservation experiments.4 Briefly, the heart was arrested with low-potassium crystalloid cardioplegic solution, the coronary vascular bed was washed with high-potassium preservation solution, and the heart was immersed in it. Finally, the heart was replenished with leukocyte-depleted warm-blood terminal cardioplegia, as widely utilized in routine cardiac surgery, prior to aortic declamping.12 In this series, all hearts resumed beating spontaneously, even in the child.
Immunosuppressive regimens were slightly modified by introducing mycophenolate mofetil in all because an international multicenter trial showed excellent results of mycophenolate mofetil in HTx.13 As cyclosporine was used from the outset, the cyclosporine levels were stable, which resulted in fewer episodes of cellular rejection, as described previously.14 As the initial steroid dose was low, none of the patients suffered an episode of infection early post-transplant. Although the human leukocyte antigen of all patients, except the first case, was matched to the donor only in less than one locus, only two had cellular rejection. From this point, the triple immunosuppressive regimen was effective in preventing cellular rejection. We encountered one episode of acute hemodynamically compromised rejection in a patient supported by a LVAD for nearly 3 years. Although his T-cell PRA and prospective crossmatch were negative at the time of HTx and he had no hyperacute rejection, he had hemodynamically compromised humoral rejection. In such cases, plasmapheresis which directly reduces serum immunoglobulins and antithymocyte globulin that reduces the helper function of T-cells, enhancing antibody formation, might be useful. Fortunately, this case did not require methotrexate or cyclophosphamide infusion. However, the patient had sustained cellular rejection and required the substitution of tacrolimus instead of cyclosporine. This case illustrates the importance of meticulous management and monitoring in patients, even those with a currently low PRA level, if the PRA has been high previously.15
In this series, 5 of the 7 patients were bridged with a LVAD. Bridging to HTx with a LVAD has increased significantly worldwide during the last decade, from 30% in 1990 to 46% in 2000.1 In our country, donor availability is very limited, with a mean waiting period in status-1 patients of longer than 14 months compared to 56 days in the ISHLT report.1 Regarding the selection of the LVAD, we had used the commercially available paracorporeal pneumatic device (Toyobo - NCVC LVAD) for short-term support before, but currently the role of this device has been extended to long-term support comparable to implantable types. The National Cardiovascular Center team has been using this device as a bridge to HTx and has shown good results of long-term support.16 On the other hand, we are currently using an implantable LVAD because its expected support period may be longer than that of the extracorporeal type. All devices used in this series provided good support for patients with severe cardiac failure during the waiting period or before listing. The 1-year survival rate of 16 patients with an implantable LVAD is 82%.
The social setting for HTx in our country is still unfavorable, although the initial results are encouraging. There are many issues including the stringent legislation and related social systems as well as less support in society for donor card distribution and donation itself. In particular, donation from those under 15 years old has not been accepted, and many children have to go abroad to undergo HTx. However, overseas transplantation may not be supported in the near future. These issues are very critical and it is essential for medical professionals as well as the government to promote organ transplantation in order to save the many patients suffering from severe end stage heart failure.
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REFERENCES
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- Hosenpud JD, Bennett LE, Keck BM, Fiol B, Boucek MM, Novick RJ. The Registry of the International Society for Heart and Lung Transplantation: 15th official report–1998. J Heart Lung Transplant
1998;17:656–68.[Medline]
- Matsuda H, Fukushima N, Sawa Y, Nishimura M, Matsumiya G, Shirakura R. First brain dead donor heart transplantation under new legislation in Japan. Jpn J Thorac Cardiovasc Surg
1999;47:499–505.[Medline]
- Aono T, Kondo K, Miyoshi H, Tanaka-Taya K, Kondo M, Osugi Y, et al. Monitoring of human cytomegalovirus infections in pediatric bone marrow transplant recipients by nucleic acid sequence-based amplification. J Infect Dis
1998;178;1244–9.[Medline]
- Fukushima N, Shirakura R, Nakata S, Kaneko M, Sawa Y, Matsuwaka R, et al. Effects of terminal cardioplegia with leukocyte-depleted blood on heart grafts preserved for 24 hours. J Heart Lung Transplant
1992;11:676–82.[Medline]
- Shumway NE, Lower RR, Stofer RC. Transplantation of the heart. Adv Surg
1966;2:265–84.[Medline]
- Bailey L, Concepcion W, Shattuck H, Huang L. Method of heart transplantation for treatment of hypoplastic left heart syndrome. J Thorac Cardiovasc Surg
1986;92:1–5.[Abstract]
- Kitamura S, Nakatani T, Bando K, Sasako Y, Kobayashi J, Yagihara T. Modification of bicaval anastomosis technique for orthotopic heart transplantation. Ann Thorac Surg
2001;72:1405–6.[Abstract/Free Full Text]
- Billingham ME, Cary NR, Hammond ME, Kemnitz J, Marboe C, McCallister HA, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant
1990;9:587–93.[Medline]
- Fullerton DA, Gundry SR, Alonso de Begona J, Kawauchi M, Razzouk AJ, Bailey LL. The effects of donor-recipient size disparity in infant and pediatric heart transplantation. J Thorac Cardiovasc Surg
1992;104:1314–9.[Abstract]
- Fukushima N, Gundry SR, Razzouk AJ, Bailey LL. Growth of oversized grafts in neonatal heart transplantation. Ann Thorac Surg
1995;60:1659–63.[Abstract/Free Full Text]
- Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med
1995;333:621–7.[Abstract/Free Full Text]
- Sawa Y, Matsuda H. Myocardial protection with leukocyte depletion in cardiac surgery. Semin Thorac Cardiovasc Surg
2001;13:73–81.[Medline]
- Kobashigawa J, Miller L, Renlund D, Mentzer R, Alderman E, Bourge R, et al. Randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate Mofetil Investigators. Transplantation
1998;66:507–15.[Medline]
- Banner NR, David OJ, Leaver N, Davis J, Breen J, Johnston A, et al. Pharmacokinetics of oral cyclosporine (Neoral) in heart transplant recipients during the immediate period after surgery. Transpl Int
2002;15:649–54.[Medline]
- DeNofrio D, Rho R, Morales FJ, Kamoun M, Kearns J, Dorozinsky C, et al. Detection of anti-HLA antibody by flow cytometry in patients with a left ventricular assist device is associated with early rejection following heart transplantation. Transplantation
2000;69:814–8.[Medline]
- Nakatani T, Sasako Y, Kobayashi J, Yamamoto F, Kumon K, Kosakai Y, et al. Application of ventricular assist systems for end-stage cardiomyopathy patients as a bridge to heart transplant or recovery. Transplant Proc
1999;31:2000–1.[Medline]
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ABSTRACT
INTRODUCTION
