Originally published in Volume 44 Issue 6 of Artificial Organs, 29 April 2020
1 OVERVIEW
The first heart transplantation (HTx) in Japan was carried out in Sapporo by Dr. J. Wada 8 months after Dr. C. Barnard performed the world’s first case in Cape Town, South Africa in 1967.1 After the recipient’s death, doubts spread through mass media about the brain death and indication to that patient with valvular disease, which led to demand that the surgeon be tried for murder.2 After this problematic case, organ transplantation from brain-dead donors was not carried out for the next three decades.
After long arguments about organ transplantation from brain-dead donors, and after suffering from another antitransplant action,3 the law allowing donation of the organs under brain death passed the Diet in 1997. HTx under legislation was started smoothly in 1999. However, over the next 10 years, organ donation was very limited because of the stringent law as donations were only possible under the presence of written will of the donor and acceptance from the family. In 2010, the law was revised as accepting the donation without donor’s written will and the number of HTx has increased significantly. The cumulative number of HTx has reached over 500 in 2019. However, HTx itself has been still limited not exceeding over 100 cases per year.
The development of devices for mechanical circulatory support (MCS) started very early in Japan, and two groups, one at the University of Tokyo (UT) and one at the National Cardiovascular Center (NCVC), began to develop extracorporeal ventricular assist devices (VADs) in the 1970s. The UT released the Zeon pump and the NCVC released the Toyobo pump in the 1980s.
Considering the long waiting period for the coming HTx era, efforts to introduce implantable VADs (left ventricular assist devices, LVADs) were conducted starting with pulsatile devices, HeartMate (HM), and Novacor, and then, moved toward the continuous flow LVADs. During the above period, Japanese original LVADs, the EVAHEART and the DuraHeart were developed.
Currently, the national supportive scheme for introducing durable LVADs has progressed under the academic autonomy system, and a significant increase of the newly implanted durable VADs has been over 100 in recent years. However, the indication of such VADs has been limited to bridge use for HTx and destination therapy (DT) has not been started.
In this article, the historical steps of clinical application of advanced therapeutic modalities such as VAD and HTx are reviewed to show how the people involved struggled and worked together.
This review has intended to cover the period from 1980s to mid-2010s when I worked mainly at Osaka University (Professorship was from 1991 to 2005).
2 DEVELOPMENT OF A VENTRICULAR ASSIST DEVICE IN JAPAN
2.1 University of Tokyo project
The UT project, specifically the team led by Prof. Kazuhiko Atsumi who made great contributions in the field of artificial organs, started in the early 1970s.4 The UT project with co-workers Drs. I. Fujimasa, K. Imachi, and S. Nitta (Tohoku University) developed a pneumatic sack-type pulsatile extracorporeal VAD in collaboration with Nippon Zeon Corp. (Tokyo) for the pump and Aishin Seiki Co. (Tokyo) for the driving console in the late 1970s.5 This UT-Zeon VAD (Zeon VAD, Figure 1) was applied in 1980 to a patient with postcardiotomy heart failure at Mitsui Memorial Hospital, Tokyo; this patient was the first to be supported by a VAD in Japan.6 The second application was carried out by Prof. Y. Sezai and his group at Nihon University.7
FIGURE 1
The UT team conducted a clinical trial for Zeon VAD from 1985 to 1989 applying it to postcardiotomy heart failure.8 In the later report for both Zeon and Toyobo pumps published in 1996,9 95 patients received a Zeon pump among 219 patients who had extracorporeal VAD application nationwide. In 1994, insurance reimbursement was approved, and until 1998 when this device was discontinued, a total 160 pumps were utilized.10 Dr. Atsumi regrettably passed away in December 2019 and I sincerely thank him for his great contribution to the development of MCS. This review pays tribute to his memory.
2.2 National Cardiovascular Center project
At the NCVC, Dr. Hisateru Takano, who initially worked at the First Department of Surgery of Osaka University (OU), moved to the Department of Artificial Organs at the Research Institute of NCVC after returning from the Texas Heart Institute, Houston, TX. At NCVC, he started the VAD project with colleagues represented by Drs. Y. Taenaka, T. Matsuda, T. Nakatani, S. Takatani, and M. Umezu. Under the support of Prof. Hisao Manabe (moved from OU to NCVC), the team developed their original pulsatile pump after animal experiments using goats11, 12 (Figure 2). Dr. Tetsuzo Akutsu, famous for his dedication to total artificial heart and VAD development at Texas Heart Institute, Houston, joined this project. The device was a diaphragmatic air-driven extracorporeal pump, and Toyobo Co. (Osaka) supported the project. This NCVC-Toyobo VAD (Toyobo VAD, Figure 3) was introduced to the clinical field with three different stroke volume pumps: 70, 40, and 20 mL. The first clinical application was achieved in 1982.
FIGURE 2
FIGURE 3
Pediatric type NCVC-Toyobo VAD (20 mL)13 was also applied in pediatric cases under limited clinical trials,14 but the recipients were in critical states including complex congenital heart disease and the outcomes were too limited to proceed to further clinical application.
In the report of the initial multi-institutional clinical trial published in 1989,15 92 patients were supported by this device for profound heart failure, primarily postcardiotomy failure. Initially, this system used left atrial drainage as inflow, and later in 1999, the inflow cannula was changed to a left ventricular apical type. The Toyobo VAD obtained government approval as a medical device in 1990 and was approved for insurance reimbursement in 1994.
2.3 Outcome of extracorporeal pulsatile VADs
Both Zeon and Toyobo VADs designed for adult patients opened the door for MCS in patients with acute heart failure. In 1996, a report on the initial phases of application that covered both VADs demonstrated that in a cohort of 207 patients the weaning rate was 50% and the survival rate was 26%.9 The results suggested the valuable role of VADs in the short-term management of acute heart failure.
The indication of these extracorporeal devices was gradually extended to chronic heart failure in the 1990s. HTx restarted in 1999 and in the 2007 registry of the Japanese Association for Clinical Ventricular Assist Systems (JACVAS),10 the total number applied to cardiomyopathy of Toyobo LV-type VAD was 201, and the duration of support ranged from 2 to 1,444 days with an average of 368 days. Of this cohort, 46 patients received a HTx, and the extracorporeal VAD was recognized as reliable device for bridge to transplantation (BTT) under careful and experienced management.
At OU, the Toyobo VAD was first implanted for BTT in early 1990s when I was starting my Chairmanship at the First Department of Surgery. Considering the coming HTx era, we extended the indication toward cardiomyopathy patients.16 In a series up to 2009,17 covering the period after restarting HTx, a total of 61 patients with cardiomyopathy or related diseases received this device, and the survival rate with the device between 2002 and 2007 was 66% at 6 months and 46% at 1 year. The role of this extracorporeal device for long-term support was shown to be very limited. Despite its limitation, we learned many valuable lessons from this, including efficient management of end-organ failure and the ideal timing for device implantation.18 However, the primary message learned was the necessity for durable implantable devices.
2.4 Nipro ventricular assist device
Since 2012, the Toyobo VAD has been managed by Nipro Co., Osaka. The Name of the Toyobo VAD was changed to Nipro VAD, and the total number of implants including the Toyobo VAD has exceeded 3,000 after the year 2000, including device replacement in approximately two-thirds of patients. This device, as well as the Zeon-VAD, must be appreciated for the important role in MCS therapy before implantable VADs became available. The Nipro-VAD was permitted for BTT in 2006, although BTT has been mostly performed by implantable devices, and its role may be expected in the bridge to candidacy or bridge to decision. Anyway, we are very proud of the achievements provided by Dr. Takano’s team at NCVC.
2.5 DR. TAKANO’s CONTRIBUTION
As the head of NCVC project, Dr. H. Takano has contributed to develop a NCVC-type VAD which has been widely applied saving many patients in Japan, particularly before the era of durable implantable VAD. He received many prizes including the Osaka Science Prize in 1987 and the Medical Prize of the Japanese Medical Association in 2003.
3 INTRODUCTION TO IMPLANTABLE PULSATILE VADs
3.1 HeartMate-I ventricular assist device
In the early 1990s, the government began to set the circumstances for the restart of HTx. Since then, we have moved toward introduction of durable implantable VADs for long-term support in consideration of BTT. The first step was made toward the HeartMate (HM)-I series (Thoratec Corp., Pleasanton, CA, USA), and Prof. Ryozo Omoto of Saitama Medical College organized the introduction of the pneumatic HM-IP by doctor’s license in 1994. The results were very convincing in durability and lower incidence of complication, and some patients had weaned from the device. Regarding the government approval, the device had to be changed to the next version, HM-VE, for the clinical trial from 2001 to 2003.19 These steps were very much influenced by the report of the REMATCH-TRIAL using HMX-XVE,20 and government approval for the medical device was achieved in 2008 for HM-XVE21; however, because of the slow pace of the government review, the HM-I series could not be approved for insurance reimbursement. This is a typical example of “device lag” during the early 2000s,22 like the case of the Novacor, as described below.
3.2 The Novacor ventricular assist device
In 1990s, we learned of encouraging results of the Novacor (World Heart Co., Ottawa, Canada) for BTT in the USA23 through Drs. R. Kormos and P. Portner. The decision to introduce this device was made by Prof. Hitoshi Koyanagi (Tokyo Women’s Medical University, TWMU), and the clinical trial began in 1996 providing the strategy for long-term use.24 Medtronic Co. Japan (Tokyo) supported introduction of this device to Japan, and the insurance reimbursement was finally approved in 2004, but 2 years later, the company stopped its manufacture. The first case of HTx under legislation had a chance to receive the Novacor for BTT use, as described below.
3.3 The summary of implantable pulsatile VADs
The above-described development and clinical application of the MCS devices is well described in a report by S. Takatani in 2005.25 The series of VAD applications at OU for chronic heart failure reported in 1999 showed 7 out of 16 patients already had implantable VADs at that time. This trend is observed by comparing data from JACVAS25 between 2006 and 2015 (Table 1).
| Period | Total | NCVC-Toyobo | UT-Zeon | Implantable VADs | EXCOR | Others |
|---|---|---|---|---|---|---|
| -2006 | 749 | 515 | 160 | 63 | 0 | 11 |
| 2007-2015 | 679 | 521 | 0 | 113 | 14 | 31 |
| Total | 1428 | 1036 | 160 | 176 | 14 | 42 |
- Abbreviations: NCVC, National Cardiovascular Center, UT, University of Tokyo; VAD, ventricular assist device. EXCOR: Berlin Heart Inc. (Berlin, Germany).
4 ROTARY BLOOD PUMPS AND TEMPORARY SUPPORT SYSTEM
Since early 1980s, Prof. Yukihiko Nosé and his group at the Cleveland Clinic, joined by many Japanese cardiac surgeons, have established a research project centered on chronic nonpulsatile perfusion in large animal models, contributing to development of centrifugal pumps capable of clinical application.26 For circulatory support to acute hemodynamic collapse, the BP50 centrifugal pump (3M Co., Minneapolis MN, USA) was the main device used as temporary support in various cases of postcardiotomy heart failure.27 In the early 1990s, extending this acute support using centrifugal pumps, we introduced a portable system of circulatory and respiratory support combining with a membrane oxygenator. This percutaneous cardiopulmonary support system was released as PCPS, a style of ECMO.28 Since then, the PCPS system has been widely utilized as a less invasive and rapidly applicable life support system. In addition to the NCVC (Dr. Y. Sasako and Dr. E. Tatsumi),29 OU and TWMU30 groups worked hard to promote PCPS, Prof. S. Takatani, Tokyo Medical and Dental University, has started the project introducing a small magnetic levitated centrifugal pump which has been continued in Europe.31 In our research project, a less-invasive left ventricular support system has been proposed using a trans-septal approach to advance the inflow cannula to the left atrium for left ventricular support without thoracotomy.32, 33
5 VENTRICULAR ASSIST DEVICE SYSTEMS WITH CONTINUOUS FLOW PUMPS
In the field of continuous flow VADs, we are very proud to have two devices of Japanese origin: the EVAHEART and the DuraHeart. EVAHEART (Sun Medical Technology Research Corp., Suwa, Nagano, Japan) was invented by Dr. K. Yamazaki, Professor at TWMU from 2009 to 2016, and the DuraHeart (Terumo Corp., Japan) by Dr. Y. Akamatsu and Dr. C. Nojiri. Also, we must remember that the development of both devices was strongly supported by Prof. Koyanagi of TUMU.
5.1 The EVAHEART project
Dr. Kenji Yamazaki began his project on a new centrifugal pump at Suwa, Nagano in 1991.34 The idea was concentrated on the cool-seal system for nonbearing pumps, and physiological performance provided the blood flow pattern with large pulsatility, corresponding to the contraction of the native heart.35 This project was supported by the following groups: TWMU, Waseda University (Prof. M. Umezu), and University of Pittsburgh (Dr. R. Kormos). The group developed a new centrifugal pump (EVAHEART, Figure 4) in 1996. After the in vivo tests at Pittsburgh and establishment of EVAHEART Medical USA in 2002, the first-in-human use was performed in 2005 at TWMU.35 The clinical trial continued to 2008 covering 18 patients,36 and the system obtained government approval as a medical device in 2004 and insurance reimbursement was obtained in 2010.
FIGURE 4
In the postapproval survey report in 201437 a total of 96 patients had this VAD between 2011 and 2013. The results showed the survival rates on the device were 93.4% at 6 months and 87.7% at 1 and 2 years. The inflow cannula of this device has been revised to titanium-mesh coating in 2013. In 2014, the US clinical trial project for BTT has started. To the end of 2019, total number of implants has reached 191, of which 74 had HTx and 55 are on-going. Recently, a new small-sized version, EVAHEART-2 has been introduced.
5.2 The DuraHeart project
The origin of this project at Terumo Corp. goes back to 1991, and Dr. Akamatsu who invented magnetically suspended impeller system at Kyoto University38 joined to this project collaborating with NTN Co. (Osaka) in 1994. Dr. Chisato Nojiri, cardiac surgeon at TWMU, joined this project after returning from Utah, where she was inspired by Drs. D.B. Olsen and W.J. Kolff. In 1991, Dr. Nojiri moved to Terumo Corporation Medical Science Research Center as a visiting research fellow, under the support of Dr. T. Akutsu. This project at Terumo Research Center developed the prototype DuraHeart39, 40 (Figure 5), and in 2000, the base of research was moved to the US for further refinement and Terumo Heart Inc. (Ann Arbor, MI, USA) began the European trial in 2004. The CE mark was obtained in 2007 supported by many European cardiac surgeons.41 In Japan, an additional clinical trial was started in 2008, and device obtained the government approval in 2010 and was release to the market in 2011.
FIGURE 5
In the OU project42, 23 patients received this device without early death, and all were followed from 176 to 999 days (average 559 days). The all Japan implants in postmarketing surveillance have reached to 87 in 82 patients until the end of March 2017, when the DuraHeart was discontinued for commercial supply.
Dr. Nojiri passed away in 2015 at the age of 63 years, and we must remember her work, which was dedicated to introducing the third generation of implantable VADs of centrifugal pumps.
5.3 The Jarvik 2000 story in Osaka
Dr. Robert Jarvik has been well-known as the inventor of the total artificial heart (Jarvik-7) and continued to develop the LVAD, releasing the Jarvik 2000 (Jarvik Inc., New York, NY, USA), a new axial-type continuous flow VAD mainly delivered in Europe.43 I met with him at international meetings such as ISHLT (International Society for Heart and Lung Transplantation) (Figure 6) and had a good discussion about this device’s role and its potential future applications in Japan. Also, I visited Mr. Stephen Westaby at the John Radcliffe Hospital, Oxford, UK. He has been one of the main investigators conducting chronic animal model experiments. We had a fruitful discussion about future of MCS (Figure 7).
FIGURE 6
This attempt was personally intended to show the outstanding progress of MCS to the Japanese cardiologists who only know the limitation of extracorporeal VADs in chronic heart failure.
The clinical trial was started with the pin-bearing type device and later it was changed to the cone-bearing type which showed improved results with reduced incidence of thrombus formation in the device.44 After long discussions between Japanese officials and the FDA, the insurance reimbursement was obtained in 2013. Using the national registry data obtained from the Japanese Registry for Mechanically Assisted Circulatory Support (J-MACS), the outcome and risk analyses demonstrated satisfactory results in a cohort of 83 patients exclusively implanted with the cone-bearing device betweeen 2014 and 2016.45 The unique characteristics of small size and the ability of the blood pump to fit within the left ventricle are well suited for Japanese patients. Century Medical Inc. (Tokyo) has accepted our proposal as the cooperating company and I personally appreciate their continuing support.
5.4 Heartmate-II
Regarding the continuous-flow implantable VADs, the appearance of the durable axial flow pump HeartMate-II (HM-II) has greatly changed the world of assisted circulation. The HM-II was introduced to Japan in 2010 and after short period of clinical trials,46, 47 the insurance reimbursement for BTT was granted in 2012. Afterward, the indication for DT was examined, but the decision has not been made yet.
The number of implants of above-described implantable VADs picked up from the data of JACVAS10 in 2013 is shown in Table 2.
| Device | Implants -2013 | Reached to HTx |
|---|---|---|
| HeartMate IP | 17 | 2 |
| HeartMate VE | 7 | 3 |
| Novacor | 27 | 10 |
| EVAHEART | 119 | 14 |
| DuraHeart | 50 | 16 |
| Jarvik2000 | 17 | 10 |
| HeartMate II | 48 | 5 |
| HVAD | 10 | 1 |
| EXCOR | 4 | 1 |
| Subtotal | 299 | 62 |
| Zeon/Toyobo | 536 | 120 |
| Total | 835 | 182 |
Note
HVAD; HeartWare Inc, Miami Lakes, FL, USA. EXCOR: Berlin Heart Inc., Berlin, Germany.
6 HEART TRANSPLANTATION: RESTARTED IN 1999
6.1 Overseas transport to Houston for BTT
Before restarting HTx, we encountered a high school boy with dilated cardiomyopathy who developed severe heart failure at Osaka Police Hospital in 1992; we decided to apply the Toyobo VAD. The boy recovered well with support, but weaning was difficult because of the advanced stage of the disease. We attempted to locate a donor heart, but this was far beyond realistic. I called Dr. “Bud” Frazier of Houston, TX, about the possibility of HTx in the US. His first answer was that it seemed like a “bridge to nowhere.” Nevertheless, he accepted the patient if we could transfer him to Houston. From the great support provided by Toyobo Co. and Dr. Y. Nosé of Houston, the boy was transferred via a chartered jet and underwent successful HTx at Texas Heart Institute.48 The patient, Mr. Ozaki, has been followed up over a 30-year period, and Dr. Frazier was very satisfied with his good status when visiting Japan (Figure 8).
FIGURE 8
6.2 Preparation for restart of HTx
In the First Department of Surgery at OU, my mentors, Prof. Hisao Manabe and Prof. Yasunaru Kawashima, started to work toward HTx in the 1980s. During the 1990s, leading cardiac surgeons, Dr. Kawashima, Dr. Koyanagi, and Dr. A. Taira (Professor of Kagoshima University) had worked intensely to promote HTx, which they believed should be resumed without delay. They had organized the Japanese Society for HTx in 1983 and made great efforts to the government and to medical professional societies in order to prepare the circumstances suitable for a restart. Our department obtained approval from the Ethics Committee at the Medical School for heart, liver, and kidney transplantations from brain-dead donors in 1992, which pushed us to promote HTx.
The real restart of HTx was delayed until the legislation was settled in 1997 after many years of nationwide controversies about brain death which was difficult to be understood as human death by the politicians in Parliament. Along with the preparation of organ transplantation law, the professional preparation of HTx was put under the control of the government and cardiology professionals. Furthermore, approval of the institute was limited into two teams, separated into east and west Japan. TWMU Team (Prof. Koyanagi) for the east and combined team of OU (H. Matsuda) and NCVC (Dr. S. Kitamura, Director of NCVC Hospital) as the west team. This was a government-controlled scheme that resembled a convoy system, which was very unusual in medical and academic activities. This was because the shadow of previous drawbacks, known as the “Curse of Wada Transplant,” remained limiting the transplant surgeon’s professional and academic activities.
6.3 Heart transplantation resumed in 1999
In 1999, the restart of HTx was realized after three HTx procedures; 1st case at Osaka University Hospital,49, 50 and the 2nd and 3rd at the NCVC.51 The first case was of a male patient aged 43 years who presented with the dilated phase of hypertrophic cardiomyopathy and underwent HTx using the conventional Lower-Shumway technique. The patient was on the waiting list for 16 months, last 4 months supported by a Novacor VAD, permitted for compassionate use by courtesy of Medtronic Co. because the official trial had already finished.
At the time of first case, we set up a conference room in the next building of the hospital to exclusively gather the media to keep a quiet environment in the hospital area. Dr. R. Shirakura, one of my important partners, explained the process in the operating room through the monitor (Figure 9). This was one of the attempts to provide open and transparent information on the transplantation. The operative procedure was smoothly performed with a support of the OU-NCVC team. Dr. Goro Matsumiya, returned from Cleveland Clinic some months before, joined the operation (Figure 10). Prof. Kawashima had moved to NCVC in 1990 and resigned before this HTx, and we sincerely appreciate his great dedication to restarting the HTx in Japan.
FIGURE 9
FIGURE 10
The first 10 patients who received a HTx at OU are shown in Table 3. Among this initial phase of HTx, all in Status-1, 6 cases were BTT using VADs. The support periods were extremely long except one and thus the restart was undertaken under very critical patient management and complex surgery as a re-do. During these HTx, we were very encouraged to use implantable VADs which allowed the patients to be discharged particularly with the Novacor VAD. There was an adult case with complex congenital heart disease of single ventricle, heterotaxy and dextrocardia. The transplant procedure for this complex case was well-performed and the patient demonstrated an early recovery.53 The patient developed humoral rejection and expired from infection 4 months after transplantation – the only death among the first 10 cases.
| Patient | Disease | Age | Male | On the list | Status-1 | VAD | On VAD |
|---|---|---|---|---|---|---|---|
| Years | Female | Days | Days | Days | |||
| 1 | dHCM | 40s | M | 502 | 502 | Novacor | 125 |
| 2 | DCM | <10 | M | 182 | 163 | On inotrope | |
| 3 | dHCM | 40s | M | 878 | 355 | NCVC-TYB | 20 |
| 4 | dHCM | 40s | M | 977 | 977 | Novacor | 1087 |
| 5 | dHCM | 20s | F | 866 | 533 | HM-IP | 518 |
| 6 | PP-CM | 30s | F | 547 | 547 | HM-IP | 590 |
| 7 | DCM | 30s | M | 551 | 551 | On inotrope | |
| 8 | CHD | 40s | M | 1221 | 1221 | On inotrope | |
| 9 | DCM | 30s | M | 936 | 936 | On inotrope | |
| 10 | ICM | 50s | M | 1294 | 1294 | HM-IP | 1233 |
Abbreviations: CHD, congenital heart disease; DCM, dilated cardiomyopathy; dHCM, dilated phase of hypertrophic cardiomyopathy; HM, HeartMate; ICM, ischemic cardiomyopathy; PP-MC, postpartum cardiomyopathy; TYB, Toyobo.
Even after the successful launch of HTx, donations from brain-dead donors were critically limited, and during the next 10 years, the number of HTx performed was limited to 66 total.54 In the analysis as of September 2011, including the transplants after the revision of the law (described below), the total number has reached to around 100 and the long-term outcome was very acceptable even under the long waiting period.55
6.4 2010 law revision
After a very critical period of severe donor shortage, revision to the law was delayed to 2010, and the number of donations rapidly increased, and HTx increased to 70 per year in 2019. The cumulative number of HTx since 1997 has reached 500 in the year of 2019. The outcome of HTx procedures in Japan has been satisfactory with excellent early and late survival rates.56 However, donor shortage is still a huge problem, and the waiting period has exceeded 3 years. The authorized institutes for HTx has increased from 3 to 11 with eight new institutes. After the case at TWMU in 2001, other institutions have followed in the next 6 years; Saitama Medical College in 2004, Kyushu University and Tohoku University in 2005, and UT in 2006, respectively. In overall numbers, about 80% of the total HTx were undertaken at three institutes: NCVC, OU, and UT, with a cumulative number exceeding 100 in each.
7 BRIDGE TO TRANSPLANTATION WITH IMPLANTABLE VADs
The introduction of implantable VADs has had a great impact on supporting candidates for considerably long waiting periods.57 In the report from our program during 1992 to 2008, a total 121 patients were reviewed58; 77 with Toyobo and 44 with implantable VADs. In this cohort, BTT was successfully performed in a limited number of cases (17), and another 17 patients were on-going at the time of report as of 2008.
The total HTx cases have reached 476 at the end of August 2019, and 449 (94.3%) were BTT with VADs. The details of the devices are shown in Table 4 (from the registry of Japanese Society for Heart Transplantation58). The annual number of BTT reaching HTx is shown in Figure 11 with simultaneous trend of HTx. When looking at the J-MACS report,59 the number of newly implanted VADs, mostly BTT with implantable VAD, has been increasing to over 100 per year indicating the waiting periods to be further extended.
| Type of VAD | Number of BTT |
|---|---|
| Toyobo (Nipro) | 109 |
| HM-I | 5 |
| Novacor | 6 |
| EVAHEART | 79 |
| DuraHeart | 54 |
| Jarvik 2000 | 43 |
| HM-II | 123 |
| HVAD | 9 |
| EXCOR | 12 |
| Combined | 9 |
| Total of BTT | 449 |
| Total of HTx | 476 |
FIGURE 11
8 DONOR SHORTAGES, LONG WAITING TIMES, AND HIGH WAITING MORTALITY RATES
The newly settled law approved brain death as human death only when organ donation is committed. In other words, until now, double standards of death have remained as one of the key issues preventing widespread organ donation.60 Donor pool expansion is critically important, and recent data has shown that a significant number of deaths have occurred while on the waiting list.61 To reduce death of candidates on the waiting list, it is crucial to explore the risk analysis of waiting list mortality to revise the heart allocation system (eg, adding Status 1A).
9 DESTINATION THERAPY AND BRIDGE TO RECOVERY
In the US, the indication of implantable durable VADs has been shifted to DT rather than BTT. In Japan, the advances in implantable VAD therapy have been remarkable as BTT with long-term management over 3-4 years now, which may be comparable to DT.62 The key issue is how to extend the official indication of implantable VAD to DT, and the Council for Clinical Use of Ventricular Assist Device Related Academic Societies (VAD Council, http://j-vad.jp/) has admitted the preparation for DT in 2012, and we are waiting its real start.
The bridge to recovery (BTR) with VADs for patients with ischemic as well as idiopathic myopathies is another important issue, and some patients had been weaned only by the left ventricular unloading scheme. There are many important reports about BTR in terms of mechanism and treatment strategies.63–66 We are faced with a very long supporting period on VAD, and a new BTR strategy must be explored more aggressively combined with other therapeutic methods.67
Regarding the current enthusiastically reported regenerative therapy for heart failure, in my opinion, we must understand its limitation to those with very advanced myocardial derangement. The strategy for advanced heart failure from now should be collaborated with BTR and DT supporting HTx as the core.
10 JAPANESE GOVERNMENT REGULATORY SYSTEM FOR MEDICAL DEVICES AND THE NATIONAL REGISTRY FOR MCS
10.1 VAD Council and guidelines
During the last couple of decades, we have faced old-style regulatory systems for medical devices and organ transplantation, which has inhibited the timely introduction of internationally accepted modalities.68 To overcome the device lag particularly in case of implantable VADs, with Prof. Shun-ei Kyo (UT), I worked to the Ministry of Health, Labor and Welfare (MHLW) representing 10 related academic organizations to speed up the device review system during 2008 to 2010. This action has led to organization of the abovementioned VAD Council in 2010 (the first Director was Prof. Kyo) under the support by MHLW and the Japanese Association of Thoracic Surgery (Matsuda was the Director of the Board) in order to develop an academic organization to regulate and support professional activities in MCS under academic and professional autonomy. This scheme has organized to set the guidelines and to give certifications to the institute and surgeons to use implantable VADs. The number of institutions certified to use VADs as affiliate institutions to the designated HTx institutions is now 36, and the annual number of implants has increased significantly to over 100 in recent years in the report of J-MACS. This VAD Council is one of the valuable achievements we have made after spending much time to solve the device lag in the field of MCS.
Also, to make advanced guidelines for research and development relating to medical devices, the MHLW and the Ministry of Economy, Trade and Industry founded a joint committee to establish guidance for newly emerging MCS technologies in 2005. The research requirement was conducted by Prof. Kyo and the clinical trial requirement was conducted by me, which is well illustrated in Yamane’s report.69
10.2 PHARMACEUTICAL AND MEDICAL DEVICES AGENCY
Along with the above movements, the government has started the new review board for drugs and medical devices, establishing the Pharmaceuticals and Medical Devices Agency (PMDA) in 2004 under the concept of international harmonization (Harmonization by Doing) in collaboration with FDA in the US.70 In connection to the PMDA matter, particularly of the registry of advanced medical devices, the government and medical professionals introduced a nationwide registry system as described below.
10.3 THE JAPANESE REGISTRY FOR MECHANICALLY ASSISTED CIRCULATORY SUPPORT
The abovementioned registry system has grown into an internationally accepted registry system; the Japanese Registry of Mechanically Assisted Circulatory Support (J-MACS).71 started in 2010 and the first report from J-MACS was published in the journal of the ISHLT in 201759.
11 THE 13TH WORLD CONGRESS OF ISAO IN 2001 AT OSAKA
I was honored to organize the 13th World Congress of ISAO meeting in 2001 as Congress President under the great support of the Japanese Society for Artificial Organs and of international members and guests; Drs. R. Bartlett, J.T. Watson, Y. Nosé, and Prof. S. Nitta of Tohoku University, President of ISAO. The outline was published in Artificial Organs in 2003 as a Guest Editorial.72 Mr. Ozaki, 1992 HTx recipient in Houston, was granted the Burl Osborne Pioneer Organ Replacement Hero Award (Figure 12). Some other photographs from this Congress are shown in Figures 13-15–13-15.
FIGURE 12
FIGURE 13
FIGURE 14
FIGURE 15
12 SUMMARY
In this article, two main medical strategies for advanced heart failure, HTx and MCS, were reviewed. Focus was placed on how these advanced therapeutic modalities developed in Japan in the face of very limited availability of organ donors and new medical devices compared with the US and Europe. There was a significant imbalance between the above two options; the overwhelming use of VADs as BTT compared with the still limited HTx. In contrast to much delayed HTx development, outstanding engineers and researchers in collaboration with medically committed companies have provided very reliable and durable extracorporeal VADs and continuous-flow implantable VADs. We must give heartfelt respects and thanks to those who committed their careers to this challenging field. I hope this review can promote further development of HTx and devices in MCS.
The outline of the above described historical steps relating to VADs and HTx development is summarized in Table 5.
| Year | Remarks |
|---|---|
| 1967 | First human HTx done at Cape Town by C. Barnard |
| 1968 | Heart transplantation done at Sapporo by J. Wada |
| 1980 | First clinical implant of Zeon VAD at Mitsui Memorial Hospital |
| 1982 | Toyobo VAD applied to a postcardiotomy patient |
| 1983 | Japanese Society for HTx started |
| 1991 | Yamazaki started the development of centrifugal pump at Suwa, Nagano |
| 1992 | BTT by overseas transfer from Osaka to Houston |
| 1994 | Akamatsu started the project of new centrifugal pump at TWMU. |
| Toyobo and Zeon VADs approved for insurance reimbursement | |
| HeartMate-IP started by doctor’s license (Saitama MC, OU) | |
| 1996 | Novacor started clinical trial in Japan |
| 1997 | Settlement of organ transplantation law |
| 1999 | First HTx from brain death donor under legislation at OU (bridged by Novacor) |
| Second & 3rd HTx cases at NCVC (bridged by Toyobo) | |
| 2004 | DuraHeart started European pivotal study to 2007 (CE Mark obtained) |
| PMDA started to promote the approval steps for medical devices | |
| 2004 | NOVACOR approved for BTT in 2 institutions (retracted in 2006) |
| 2005 | EVAHEART first-in-human use at TWMU and started pivotal study |
| First implant of Jarvik 2000 at OU | |
| 2008 | DuraHeart started pivotal study in Japan after obtaining CE-Mark |
| 2009 | HeartMate XVE approved as medical device |
| 2010 | Organ transplantation law revised |
| EVAHEAT/DuraHeart approved for BTT, starting in 2011 | |
| Council for Clinical Use of VAD Related Academic Societies started (VAD Council) | |
| J-MACS started the national registry project | |
| 2012 | HM-II approved for BTT |
| 2013 | Jarvik 2000 approved for BTT |
| 2019 | Number of HTx reached to 500 in total |
Abbreviation: see text.
ACKNOWLEDGMENT
I express my sincere gratitude to Prof. Kawashima and Prof. Koyanagi for the continuing support during my career. Also, I want to thank all the members of the First Department of Surgery at Osaka University (currently Department of Cardiovascular Surgery) and to the leaders and friends of related professional medical societies for their dedication to this field.