История трансплантации и механической поддержки сердца человека: 50 лет инноваций и применения
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 (firstname.lastname@example.org) и никогда не публиковалась до 13 июля 2017 г.
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
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)  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
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 .
Thus, within a single decade, the core group of early
pioneers in this amazing medical and surgical miracle
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 . 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
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) . Over the first
5 years post-transplant, the leading causes of death
are graft failure, infection, and multi-organ failure
(Fig. 2). 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) .
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,
Fig. 2. Cumulative incidence of leading cause of death (adult heart
2009 - June 3, 2014)
CAV - cardiac allograft vasculopathy; CMV - cytomegalovirus;
PTLD - post-transplant
Reproduced with permission,
Lund et al. and designated
co-author Joseph Stehlik, email@example.com 
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 . Approximately 50% of institutions employ an induction immunosuppression strategy, most commonly with antithymocyte globulin or basiliximab .
The most commonly reported complications during the first 5 years following cardiac transplantation
include hypertension, hyperlipidemia, renal dysfunction, diabetes, and allograft vasculopathy . 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) . 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
(transplants: January 1982
to June 2014)
permission, Rosanno et al.
and designated co-author
Mechanical circulatory support
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 . 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
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 . 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  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) , 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 . 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) .
Fig. 4. Kaplan-Meier
depiction for survival
of a durable LVAD,
stratified by therapeutic
Reproduced with permission,
Kirklin et al. James K. Kirklin,
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 .
The major adverse events after MCS are bleeding,
infection, neurologic events, pump thrombosis,
and right heart failure . 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
This work was supported in part by National Heart,
Lung, and Blood Institute (NHLBI), USA: Contract
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