Development of ventricular assist device and heart transplantation in Japan: How people worked

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). 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 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. 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. 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. 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. 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. 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. 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. 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. 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). 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, was the device used as support in cases of postcardiotomy heart In the early 1990s, this acute support using centrifugal we introduced a system of circulatory and support with a This support system was released as a of Since then, the system has been widely as a and support In to the NCVC Y. and Dr. OU and worked to Prof. S. Takatani, Tokyo Medical and University, has started the project introducing a centrifugal pump which has been in In research project, a left ventricular support system has been using a to the inflow cannula to the left for left ventricular support without In the field of continuous flow we are very proud to have two devices of Japanese the EVAHEART and the EVAHEART Medical Research Corp., was by Dr. K. at from to and the DuraHeart Corp., by Dr. Y. and Dr. C. we must that the development of both devices was supported by Prof. Koyanagi of Dr. began his project on a centrifugal pump at in The was on the system for and provided the flow with large to the of the This project was supported by the University M. and University of R. The group developed a centrifugal pump Figure in After the in at and of EVAHEART Medical in the use was performed in at The clinical trial to 2008 covering and the system obtained government approval as a medical device in and insurance reimbursement was obtained in In the report in a total of patients had this VAD between and The results showed the survival on the device were at 6 months and at 1 and 2 years. The inflow cannula of this device has been revised to in In the clinical trial project for BTT has started. the of total number of implants has reached of which had HTx and are a version, has been The of this project at Corp. to and Dr. who system at joined to this project with Co. (Osaka) in 1994. Dr. cardiac surgeon at joined this project after returning from was by Drs. and In Dr. moved to Medical Science Research Center as a research under the support of Dr. T. This project at Research Center developed the (Figure and in 2000, the of research was moved to the for further and Heart began the trial in The was obtained in 2007 supported by many cardiac In Japan, an clinical trial was started in and device obtained the government approval in and was to the in In the OU patients received this device without early death, and were from to days The Japan implants in have reached to in patients until the of when the DuraHeart was for Dr. passed away in 2015 at the of years, and we must which was to introducing the of implantable VADs of centrifugal Dr. has been as the of the total artificial heart and to develop the the USA), a continuous flow VAD mainly in I with him at such as for Heart and (Figure and had a about this role and its applications in I at the Hospital, He has been one of the chronic animal had a about of MCS (Figure in early in the of University Hospital, I received a from Dr. in at the time. He to introduce the to as the second in after the team worked and we had a chance to the under doctor’s license two patients in Dr. to support the and a left was applied without use of the the in both patients. was very and and both patients received a HTx This was intended to show the of MCS to the Japanese who only the of extracorporeal VADs in chronic heart failure. The clinical trial was started with the type device and later it was changed to the type which showed results with incidence of in the After long between Japanese and the the insurance reimbursement was obtained in the national registry data obtained from the Japanese for the and demonstrated results in a cohort of patients implanted with the device and The of and the of the pump to the left are well for Japanese patients. Medical (Tokyo) has as the company and I their Regarding the implantable the of the durable flow pump has changed the of The was introduced to Japan in and after period of clinical the insurance reimbursement for BTT was in the indication for was but the decision has not been made The number of implants of above-described implantable VADs up from the data of in is shown in restarting HTx, we a with cardiomyopathy who developed heart failure at Osaka in we to the Toyobo VAD. The well with but weaning was because of the advanced of the to a donor but this was I Dr. of Houston, about the of HTx in the first was that it like a to he the patient we could him to the great support provided by Toyobo Co. and Dr. Y. Nosé of Houston, the was a and HTx at Texas Heart The has been up over a period, and Dr. was very with his when Japan (Figure In the First Department of Surgery at OU, my Prof. Hisao Manabe and Prof. started to toward HTx in the 1980s. During the 1990s, cardiac surgeons, Dr. Dr. and Dr. of University) had worked to HTx, which be without had organized the Japanese for HTx in and made great efforts to the government and to medical in to the circumstances for a obtained approval from the at the Medical for and from brain-dead donors in which to HTx. The restart of HTx was until the legislation was in after many years of about brain death which was to be as death by the in with the of organ transplantation the of HTx was under the of the government and approval of the was limited two and for the and team of OU and NCVC S. of NCVC as the This was a scheme that a system, which was very in medical and academic This was because the of as the of Wada the and academic In 1999, the restart of HTx was after three HTx case at Osaka University and the and at the The first case was of a patient years who with the of cardiomyopathy and HTx using the The patient was on the waiting for 16 months supported by a Novacor VAD, permitted for use by of Medtronic Co. because the trial had already At the of first case, we set up a in the next of the to the media to a in the Dr. R. one of my important the in the through the (Figure This was one of the to and on the The was smoothly performed with a support of the Dr. from Cleveland some months joined the (Figure Prof. had moved to NCVC in 1990 and before this HTx, and we sincerely his great dedication to restarting the HTx in The results a significant to the the era of organ transplantation had As medical the introduced this that the HTx was carried out under stringent with a of donors and a of surgeons, but the was Prof. Koyanagi performed the case at in 2001 in a patient with The first 10 patients who received a HTx at OU are shown in this initial of HTx, in 6 cases were BTT using The support were long one and the restart was under very critical patient management and complex as a During these HTx, we were very to use implantable VADs which the patients to be particularly with the Novacor VAD. was an adult case with complex congenital heart disease of and The for this complex case was and the patient demonstrated an early The patient developed and from months after transplantation the only death among the first 10 after the of HTx, donations from brain-dead donors were and during the next 10 years, the number of HTx performed was limited to In the as of including the after the of the law the total number has reached to 100 and the long-term was very under the long waiting After a very critical period of donor to the law was to 2010, and the number of donations and HTx increased to per year in 2019. The cumulative number of HTx has reached 500 in the year of 2019. The of HTx in Japan has been with early and late survival However, donor is still a and the waiting period has exceeded years. The for HTx has increased from to with After the case at in have in the next 6 Saitama Medical College in 2004, University and University in and UT in 2006, In about of the total HTx were at three NCVC, OU, and with a cumulative number exceeding 100 in The introduction of implantable VADs has had a great on for long waiting In the report from during to a total patients were with Toyobo and with implantable In this cohort, BTT was performed in a limited number of cases and another patients were at the of report as of The total HTx cases have reached at the of and were BTT with The of the devices are shown in the registry of Japanese for Heart The number of BTT HTx is shown in Figure with trend of HTx. at the the number of newly implanted mostly BTT with implantable VAD, has been to over 100 per year the waiting to be further The newly law approved brain death as death only when organ donation is In until of death have as one of the organ is and recent data has shown that a significant number of have on the waiting death of on the waiting it is to the of waiting to the heart system In the the indication of implantable durable VADs has been to BTT. In Japan, the in implantable VAD therapy have been as BTT with long-term management over years which may be to The is how to the indication of implantable VAD to and the for Clinical of Ventricular Assist has the for in 2012, and we are waiting its The bridge to with VADs for patients with as well as is another important and some patients had been weaned only by the left ventricular are many important about in of and are with a very long period on VAD, and a strategy must be with therapeutic Regarding the reported therapy for heart failure, in my we must its to with very advanced The strategy for advanced heart failure from be with and HTx as the During the of we have for medical devices and organ which has the introduction of the device particularly in case of implantable with Prof. I worked to the of and 10 related academic to up the device review system during 2008 to This has led to of the VAD in first was Prof. under the support by and the Japanese Association of Surgery was the of the in to develop an academic to and support in MCS under academic and This scheme has organized to set the and to to the and to use implantable The number of to use VADs as to the HTx is and the number of implants has increased to over 100 in recent years in the report of This VAD is one of the valuable achievements we have made after much to the device in the field of MCS. to advanced for research and development to medical devices, the and the of and a to for newly MCS in The research was conducted by Prof. and the clinical trial was conducted by which is well in with the above the government has started the review for and medical devices, the and Medical in under the of by in collaboration with in the In to the particularly of the registry of advanced medical devices, the government and medical introduced a registry system as described below. The registry system has an registry the Japanese of started in and the first report from was published in the of the in I was to the of in 2001 as under the great support of the Japanese for Artificial Organs and of and Drs. R. Y. and Prof. S. Nitta of University, of The was published in Artificial Organs in as a HTx in Houston, was the (Figure from this are shown in In this article, two medical for advanced heart failure, HTx and were was on how these advanced therapeutic modalities developed in Japan in the of very limited of organ donors and medical devices with the and was a significant between the above two the use of VADs as BTT with the still limited HTx. In to much HTx and in collaboration with have provided very reliable and durable extracorporeal VADs and implantable must and to who their to this I this review further development of HTx and devices in MCS. The of the above described historical steps to VADs and HTx development is in I my to Prof. and Prof. Koyanagi for the support during my I to thank the of the First Department of Surgery at Osaka University Department of Cardiovascular and to the and of related medical for their dedication to this

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