История трансплантации и механической поддержки сердца человека: 50 лет инноваций и применения

Резюме

История, современность и вероятные перспективы в проблеме хирургического лечения терминальных дисфункций миокарда и сердечной недостаточности - вся эта информация представлена в настоящей статье. Инновации в этих двух методах лечения конечной стадии заболеваний сердца дали надежду на жизнь сотням тысяч обреченных пациентов. Проблемы ближайшего будущего - ксенотрансплантация сердца у детей, миниатюризация и создание новой генерации пульсирующих насосов вспомогательного кровообращения. 

Ключевые слова:трансплантация сердца, механическая поддержка, полное искусственное сердце

Клин. и эксперимент. хир. Журн. им. акад. Б.В. Петровского. 2017. № 3. С. 22-27.

Статья поступила в редакцию: 13.07.2017. Принята в печать: 16.07.2017. 

Это оригинальная статья была написана по просьбе Сергея Дземешкевича (sdzemeshkevich@gmail.com) и никогда не публиковалась до 13 июля 2017 г

Heart transplantation

Historical Note 

The year 2017 marks the 50th anniversary of one of the most dramatic moments in medical history, the first human-to-human heart transplant. On December 3, 1967, a handsome and charming South African surgeon named Christiaan Barnard electrified the world with the first human-to-human heart transplant. Barnard became an instant celebrity, traveling the world as an International hero. However, there were many heroes in these early days of heart transplantation. The first recipient was Louis Washkansky, a 53-year-old former athlete who was dying from the ravages of end stage ischemic heart disease. He survived for 18 days (dying from pneumonia) but paved the way for thousands of successful heart transplants over the next 50 years. The donor of that first heart was a young 24-year-old woman named Denise Darvall, who died from injuries suffered when she was struck by a drunk driver. During a time of intense competition among numerous surgical groups to perform the first heart transplant, Barnard was accompanied in this race by other eminent luminaries. Adrian Kantrowitz would perform the second human heart transplant and the first infant heart transplant on an 18-day-old infant with Ebstein’s malformation. The baby lived only 5 hours after the transplant procedure. Barnard soon performed the world’s third human heart transplant, and Dr. Philip Blaiberg, a 46-year-old Dental Surgeon, would become the first long term survivor (18 months).

Norman Shumway has been recognized as the true Father of Heart Transplantation, based on his years of experimental preparation and subsequent contributions to cardiac transplantation during his years at Stanford University. Shumway entered the fray with the world’s fourth heart transplant on January 6, 1968. His first patient died two weeks later. Unfortunately, this dramatic initial experience with transplantation of the human heart outpaced the development of effective immunosuppression. By the end of 1968, 102 patients in 50 different institutions from 17 countries had received a heart transplant, with generally miserable outcomes. The short survival (60% mortality by the 8th post-operative day and a mean survival of 29 days) [1] caused widespread disenchantment within the medical community and general public. However, Normal Shumway at Stanford, Richard Lower at the University of Virginia, and a handful of others persisted with efforts to improve the outcomes after heart transplantation during the early 1970’s. In 1983, cyclosporine was introduced into the armamentarium of transplant surgeons. This breakthrough, when combined with refinements in other immunosuppressive agents, generated rapidly improved outcomes and persuaded the medical community to acknowledge the lifesaving value of human heart transplantation.

By the early years of the new millennium, most of these pioneers of early heart transplantation and cardiac surgery had died. Barnard tragically died alone in September 2001. James Hardy, who unsuccessfully transplanted the heart of a chimpanzee into a human patient, died in February of 2003. John Kirklin, the cardiac surgical pioneer who performed the first successful series of open-heart operations using a pump oxygenator, passed away in April of 2004. Shumway would succumb from cancer in February in 2006. Richard Lower, Shumway’s research compatriot and transplant pioneer, succumbed from cancer in May 2008. Michael DeBakey, cardiac surgical icon from Houston, died 7 weeks after Lower, and Kantrowitz passed away in November 2008 [2].

Thus, within a single decade, the core group of early pioneers in this amazing medical and surgical miracle were lost.

But their work lived on, and others would drive the field forward, saving thousands of patients by improving preservation of the donor heart, refining surgical techniques, and advancing the science of immunology to control allograft rejection.

Heart Transplantation in the Current Era

As of 2016, nearly 120,000 heart transplants had been entered into the International Society for Heart and Lung Transplantation (ISHLT) Registry [3]. International transplant activity peaked in 1993, with nearly 5,000 heart transplants world-wide. After a decrease in transplant numbers in 2003-2004 (slightly over 4,000 heart transplants recorded world-wide), international activity has progressively increased over the last decade. In 2014, approximately 4700 heart transplants were entered into the ISHLT Database.

The largest age group for heart transplantation is patients aged 40-59 years, though patients at both ends of the age spectrum (0-9 years and 60-70 years) have progressively increased in numbers over the past 3 decades. Pediatric heart transplantation accounts for approximately 15% of overall heart transplant activity [3].

Survival after heart transplantation has progressively increased over the past 4 decades, with most recent 1 year survival approaching 90%. The median survival is now 12 years (Fig. 1) [3]. Over the first 5 years post-transplant, the leading causes of death are graft failure, infection, and multi-organ failure (Fig. 2)[3]. Among diagnostic categories, the risk of death within 10 years is highest for restrictive cardiomyopathy (hazard ratio 1.33) and congenital heart disease (HR 1.21) followed by ischemic cardiomyopathy (HR 1.16) [3].

Fig. 1. Kaplan-Meier long-term survival after adult heart transplantation by era

 NA - not available. Reproduced with permission, Lund et al. and designated co-author Joseph Stehlik, josef.stehlik@hsc.utah.edu [3]

  

Fig. 2. Cumulative incidence of leading cause of death (adult heart transplant: January 2009 - June 3, 2014)

 CAV - cardiac allograft vasculopathy; CMV - cytomegalovirus; PTLD - post-transplant lymphoproliferative disorder. Reproduced with permission, Lund et al. and designated co-author Joseph Stehlik, josef.stehlik@hsc.utah.edu [3]

 The current general immunosuppression strategy is to employ 3 immunosuppressive agents, at least early following heart transplantation. Tacrolimus is the preferred calcineurin inhibitor, and mycophenolate mofetil is the most commonly employed cell cycle inhibitor. Daily steroid therapy is often tapered off completely during the first year [3]. Approximately 50% of institutions employ an induction immunosuppression strategy, most commonly with antithymocyte globulin or basiliximab [4].

The most commonly reported complications during the first 5 years following cardiac transplantation include hypertension, hyperlipidemia, renal dysfunction, diabetes, and allograft vasculopathy [3]. Severe renal dysfunction (creatinine greater than 2.5 mg/dl, dialysis, or renal transplant) occurs in over 30% of patients by 10 years following transplantation, and is more common in patients with ischemic cardiomyopathy than with idiopathic dilated cardiomyopathy.

Pediatric heart transplant activity has remained relatively stable over the past 20 years, with only about 110 to 120 centers reporting pediatric heart transplants yearly to the ISHLT. Early mortality (first year) continues to be the greatest challenge among patients in the first 5 years of life, but later survival after 20 years is highest in the youngest patients (Fig. 3) [5]. The median survival by age group ranges from 13 years in patients age 11-17 up to 20 years for patients transplanted in the first year of life. The leading causes of death in pediatric patients include graft failure, allograft vasculopathy, infection, and acute rejection. Congenital heart disease is the most common indication for transplantation in the first year of life, but in all other age groups, dilated cardiomyopathy is the major indication. In contrast to adult programs, more than 60% of pediatric patients (70% of patients with congenital heart disease) receive induction immunosuppression. Nearly 60% pediatric patients remain on prednisone during the first year.

Fig. 3. Kaplan-Meier survival following pediatric heart transplantation (transplants: January 1982 to June 2014)

Reproduced with permission, Rosanno et al. and designated co-author Joseph Stehlik, josef.stehlik@hsc.utah.edu [3] 

Mechanical circulatory support

Historical Note

In 1969, 2 years after Barnard’s first heart transplant, Denton Cooley performed the first clinical implant of a total artificial heart (TAH) in a 47-year-old man dying of heart failure. The artificial pump kept the patient alive for 3 days until cardiac transplantation could be performed. Unfortunately, he succumbed less than 2 days later from overwhelming infection.

The Utah Group headed by Robert Jarvik and surgeon William DeVries gained International attention with the first implant of a “permanent total artificial heart” in December of 1982 [6]. Despite the notoriety, all 5 patients supported by the Jarvik 7 TAH died from multiple pump-related complications, and serious applications of the TAH would await another 20 years.

The development of TAH technology and long term LVAD devices were largely made possible by ongoing funding programs from the National Institutes of Health (NIH) and the National Heart, Lung, and Blood Institute (NHLBI) within the Devices and Technology Branch, directed by John Watson. Initial funding for the development of a clinical LVAD included research groups in Everett, Massachusetts; Berkley, California; Cleveland, Ohio; and Houston, Texas [7]. Although long-term support was always the goal, clinical opportunities arose primarily on patients who were desperately ill from circulatory failure while awaiting heart transplantation. In 1984, Philip Oyer of Stanford University performed the first successful bridge to transplantation with a Norvacor LVAD developed by Peer Portner and colleagues. This was followed by a successful implant by Don Hill using a Pierce-Donachey pneumatic LVAD. These early successes ushered in an era of rapid expansion of mechanical support as bridge-to-transplant (BTT) therapy. Jack Copeland and colleagues performed the first successful implant of a total artificial heart as BTT in 1985.

Victor Poirier worked with O.H.“Bud” Frazier and others at the Texas Heart Institute to develop portable battery system that would allow untethered existence outside the hospital setting. The efforts of this group and others culminated in the first patient to be discharged from the hospital with a ventricular assist device in 1991.

The concept of non-pulsatile continuous flow in an LVAD has been attributed to the pioneering work of Richard Wampler and his team, who developed the Hemopump continuous flow device. Frazier performed the first successful clinical implantation of this device in 1986. Robert Jarvik, a pioneer of the total artificial heart, developed an early durable continuous flow LVAD [7] which was suitable for support in the outpatient setting.

The effort to employ mechanical circulatory support for long-term therapy was brought to fruition with the REMATCH trial (Principle Investigator Eric Rose) [8], which concluded in 2001, resulting in US Food and Drug Administration (FDA) approval for an intracorporeal pulsatile LVAD as permanent MCS therapy. With increased interest and the potential expense of long-term MCS devices, the NHLBI focused on obtaining long-term scientific data on clinical application of these devices. This effort translated into a 10-year NHLBI-funded project to create a national database for durable circulatory devices. This database, called INTERMACS (Principal Investigator James Kirklin), provided seminal studies to identify risk factors for patients and devices, to provide long-term outcomes including adverse events, and to facilitate the introduction of new devices in the field.

During the first decade of the millennium, multiple continuous flow devices were introduced worldwide. In the United States, the HeartMate II (Abbott Laboratories, Abbott Park, IL) axial flow pump was approved for BTT therapy in 2008 and Destination Therapy (DT) in 2010. The HeartWare HVAD (Metronic Corp., Minneapolis, MN) centrifugal flow pump received FDA approval for BTT in 2012, and approval for Destination Therapy is imminent. The Abbott HeartMate III centrifugal flow pump with a magnetically levitated rotor, has completed pivotal clinical trials in the USA.

Mechanical Circulatory Support in the Current Era

In 1999, the ISHLT (President Robert Kormos) established a scientific council on mechanical circulatory support. Following the creation of INTERMACS in the United States, international interest in a multi-national MCS database culminated in the creation of IMACS, the ISHLT International MCS Registry, in April 2011. This registry has chronicled the world-wide application of MCS therapy [9]. During the past decade continuous flow technology has dominated the clinical field of MCS, accounting for greater than 95% of device implants. In the current era, overall survival with MCS therapy is 80% at 1 year and 70% at 2 years. Survival among patients with DT continues to be somewhat less good than for patients implanted as BTT (Fig. 4) The primary causes of death have been multi-system organ failure, right heart failure, and neurologic events. A risk factor analysis of over 5,000 patients has highlighted demographic and clinical risk factors for early and late mortality. (Table 1) [9].

Fig. 4. Kaplan-Meier depiction for survival following implantation of a durable LVAD, stratified by therapeutic strategy

Reproduced with permission, Kirklin et al. James K. Kirklin, jkirklin@uabmc.edu [10] 

Despite the tremendous advances in survival during MCS therapy, the ultimate goal is long-term extension of this technology to ambulatory patients with advanced heart failure. Currently, patients in INTERMACS Profiles 4-6 (ambulatory NYHA Class IV) constitute only 13% of durable VAD implants [10]. The major adverse events after MCS are bleeding, infection, neurologic events, pump thrombosis, and right heart failure [11]. With the exception of right heart failure, all other major adverse events are as likely to occur in patients with ambulatory heart failure as in more critically ill patients. These potentially devastating adverse events constitute the major barrier to wider applications of MCS therapy.

The Future of Heart Transplantation and Mechanical Circulatory Support

The past 50 years have witnessed remarkable innovations in the surgical care of patients with end-stage heart disease. The combination of heart transplantation and MCS has revolutionized the options for hundreds of thousands of patients who otherwise were destined to die from terminal heart failure. In the coming few years, xenotransplantation will almost certainly achieve clinical reality for kidney transplants. The next logical extension will be infant cardiac xenotransplantation. In the realm of mechanical circulatory support, miniaturization of device technology will evolve as efforts coalesce to reduce the magnitude and frequency of serious adverse events. In this process, the favorable impact of pulsatility may re-emerge in the design of next generation devices.

This work was supported in part by National Heart, Lung, and Blood Institute (NHLBI), USA: Contract Grant#HHSN268201100025C. 

Литература

1. Cooley D.A., Bloodwell R.D., Hallman G.L., Nora J.J., et al. Organ transplantation for advanced cardiopulmonary disease. Ann Thorac Surg. 1969; 8 (1): 30-46.

2. McRae D.G. Early history of heart transplantation. In: J.K. Kirklin, M. Mehra, L.J. West (eds). Elsevier, 2010. ISHLT Mono- graph Series; 4 (1): 1-36.

3. Lund L.H., Edwards L.B., Dipchand A.I., Goldfarb S., et al. The registry of the International Society for Heart and Lung Transplantation: thirty-third adult heart transplantation report - 2016; focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant. 2016; 35 (10): 1158-69.

4. Ansari D., Lund L.H., Stehlik J., Andersson B., et al. Induction with anti-thymocyte globulin in heart transplantation is associated with better long-term survival compared with basiliximab. J Heart Lung Transplant. 2015; 34 (10): 1283-91.

5. Rossano J.W., Dipchand A.I., Edwards L.B., Goldfarb S., et al. The Registry of the International Society for Heart and Lung Transplantation: nineteenth pediatric heart transplantation report - 2016; Focus theme: Primary diagnostic indications for transplant. J Heart Lung Transplant. 2016; 35 (10): 1185-95.

6. DeVries W.C., Anderson J.L., Joyce L.D., Anderson F.L., et al. Clinical use of the total artificial heart. N Engl J Med. 1984; 310 (5): 273-8.

7. Copeland J.G., Frazier O.H., Holman W.L. Early history of heart transplantation / In: J.K. Kirklin, M. Mehra, L.J. West (eds). Elsevier, 2010. ISHLT Monograph Series; 4 (5): 112-62.

8. Rose E.A., Gelijns A.C., Moskowitz A.J., Heitjan D.F., et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001; 345 (20): 1435-43.

9. Kirklin J.K., Cantor R., Mohacsi P., Gummert J., et al. First annual IMACS report: a global international society for heart and lung transplantation registry for mechanical circulatory support. J Heart Lung Transplant. 2016; 35 (4): 407-12.

10. Kirklin J.K., Pagani F.D., Kormos R.L., Stevenson L.W., et al. Eighth Annual INTERMACS report: Special Focus on Framing the Impact of Adverse Events. J Heart Lung Transplant. 2016 (in press).

11. Kirklin J.K., Naftel D.C., Pagani F.D., Kormos R.L., et al. Seventh INTERMACS annual report: 15,000 patients and counting. J Heart Lung Transplant. 2015; 34 (12): 1495-504.