From the Cardiovascular Surgery Research Department (T.J.M., O.H.F.) and
the Cardiopulmonary Transplantation Department (O.H.F.) of the Texas Heart
Institute, Houston; and the Division of Cardiovascular Medicine (S.A.H.),
Stanford University Medical Center, Palo Alto, Calif.
Congestive heart
failure is not a specific disease but rather a clinical syndrome of
diverse etiologies. This syndrome is characterized by
ventricular dysfunction leading to decreased cardiac
output; consequent neurohumoral activation leading to salt and water
retention, with congestion in the pulmonary and systemic
circulation; a "vicious circle" of blood-flow maldistribution; and
eventual hypoperfusion of vital organs. In North America, the most
common underlying cause of CHF is atherosclerosis
resulting in ischemic dysfunction of the
myocardium. A second important underlying cause is
valvular malfunction leading to pressure and/or volume
overloading of the ventricles. Other important causes of CHF include
primary myocardial disease (idiopathic, infiltrative, or inflammatory)
and congenital cardiac malformations.
The incidence of heart failure is increasing, probably not only because
of aging of the population, but also because effective palliative
therapies are extending the lives of many CHF victims. In addition,
many patients have undergone successful emergency intervention for
otherwise fatal acute coronary events only to develop CHF at a
later date. The American Heart Association estimates that at least
400 000 new cases of CHF are diagnosed each
year.1 In the United States, more than $34
billion is spent each year for the medical care of CHF
patients.2 Despite the advent of more effective
therapy, CHF is the principal cause of 40 000 deaths per year in the
United States and is a contributing factor in another 250 000
deaths.1
The short-term goal of CHF therapy is to improve the patient's quality
of life by relieving his or her symptoms. Current medical therapy is
highly successful in achieving this goal.3 Such
therapy has also had limited success in achieving the longer-term goal
of extending these patients' lives.4 5 Despite
these advances, however, most patients eventually succumb to CHF. Many
patients, because of their relative youth and lack of comorbid
conditions, become candidates for cardiac replacement therapy, which is
currently limited to allotransplantation. Transplant candidates whose
disease reaches its final stage before an appropriate donor heart
becomes available are considered eligible for temporary MCS. The
long-term MCS systems presently in clinical use serve as temporary
"bridges" to transplantation. In the future, such devices will
likely become viable alternatives for permanent nonbiological cardiac
replacement; indeed, the Institute of Medicine estimates that between
35 000 and 70 000 Americans each year could benefit from long-term
MCS.6 Genetically altered animal organs may also
eventually provide another alternative for biological replacement of
the heart.
Over the past 4 decades, MCS and cardiac transplantation have evolved,
somewhat in parallel, toward the goal of lowering the mortality and
morbidity associated with CHF. By combining these two surgical
interventions, physicians have improved the length and quality of many
lives, and additional patients are potentially treatable with these
methods. This review describes the current status of cardiac
transplantation and mechanical circulatory assistance, examines the
major persisting clinical problems in these fields, and discusses the
clinical advances to be expected during the coming years.
Mechanical Circulatory Support
Background
MCS Systems
HeartMate LVAS
The patient is on cardiopulmonary bypass when the HeartMate is
implanted. The pump is positioned below the left hemidiaphragm, either
within the peritoneal cavity17 or in a
preperitoneal pocket.18 The inflow tube crosses
the diaphragm and is inserted in the apex of the left ventricle; a
20-mm Dacron outflow graft exits from the pump, crosses the diaphragm,
and is anastomosed to the ascending aorta. After it has been
externalized through the right or left abdominal wall, the driveline is
connected to the external power and control unit. The maximum blood
flow possible is 11.6 L/min for the IP-LVAS and 9.6 L/min for the
VE-LVAS. An automatic mode may be used to maximize pump flow, or a
fixed-rate mode may be used to provide a preset flow rate. During
normal operation, the pump completely unloads the left ventricle and
supports cardiac output at physiological levels.
Because of the portability and ease of operation of the HeartMate,
patients can be discharged to await heart transplantation outside the
hospital.19
The HeartMate IP-LVAS is approved by the FDA for use as a bridge to
transplantation. As of April 1998, it had been used for this purpose in
944 patients worldwide. Owing to the unique lining and flow
characteristics of this pump, only minimal anticoagulation (with
aspirin or other platelet inhibitors) is required.
Patients can be supported for extended periods with a relatively low
risk of thromboembolism or mechanical failure.
Novacor LVAS
The Novacor pump is surgically placed in a preperitoneal pocket just
anterior to the posterior rectus sheath, between the left costal margin
and the iliac crest.22 Cardiopulmonary
bypass is necessary during implantation, and the surgical inflow and
outflow connections are similar to those described for the HeartMate. A
percutaneous driveline is brought out through the right
abdominal wall and attached to the external control unit or drive
console. The synchronous and fill-to-empty modes provide sufficient and
variable cardiac output by responding to increased
physiological demands. During device use,
anticoagulation with heparin and later with warfarin and
antiplatelet agents is necessary to prevent thromboembolism. During
long-term support, ambulatory patients can be discharged and live
outside the hospital while awaiting a suitable donor
heart.23
Thoratec VAS
The Thoratec VAS is implanted through a median sternotomy, but
cardiopulmonary bypass is not required in all
cases.25 For left ventricular
support, the pump inflow cannula can be placed in the left
ventricular apex or the left atrium, and the pump outflow
conduit is anastomosed to the ascending aorta. For right
ventricular support, a large-bore cannula is placed in the
right atrium, and the outflow conduit is sewn to the main
pulmonary artery. After they have been externalized
subcostally, the inflow and outflow cannulas are connected to the
pump(s), which reside(s) externally on the anterior surface of the
abdomen. During the support period, anticoagulation with dextran,
heparin, warfarin, and dipyridamole is required.
Patients may be ambulatory,26 but their mobility
is limited by the size of the drive console and the paracorporeal
position of the pump(s).
The FDA has approved the Thoratec VAS for use as a bridge to heart
transplantation. In the future, use of this system may be extended to
include patients with acute heart failure, including postcardiotomy
cardiogenic shock. New system designs that are currently being tested
include a small, portable drive console and implantable blood
pumps.
CardioWest TAH
The TAH is surgically implanted in the mediastinal space after the
ventricles have been excised, with atrial cuffs retained. The pneumatic
drivelines are externalized percutaneously and attached
to the drive console. Anticoagulation with
dipyridamole, heparin, and warfarin is necessary to
prevent thrombus formation. Patients may be ambulatory, but their
mobility is greatly restricted by the large drive console.
The CardioWest TAH is currently undergoing an FDA-approved
clinical investigation at select institutions in the United States. In
other countries, this TAH is being used at some centers as a bridge to
heart transplantation. A small, portable drive console is being
developed for out-of-hospital use.
Major Differences Between MCS Systems
MCS: Clinical Results Summary
The only controlled study of the effects of LVAS support in
bridge-to-transplant patients was performed with the
IP-LVAS.32 The control group met all the criteria
for MCS, but because of logistical problems, no device was available
for them. These patients were compared with a similar cohort that
underwent MCS during the same period. Despite the added morbidity and
mortality associated with a major surgical intervention, the
device-supported patients had a significantly better survival rate than
did the control group (71% versus 36%, respectively, 90 days after
transplantation). Interestingly, the surviving control patients all
received a heart transplant within 12 days of becoming eligible for the
study.
Complications
Recovery and Rehabilitation
Patients who have significant improvement in their physical status
while undergoing MCS often have a similar degree of improvement in
their psychological status. However, those who are not rehabilitated
fully and who have frequent medical complications may experience
stress, major depression, organic mental syndromes, and adjustment
disorders.46 The required degree of psychosocial
support varies greatly between patients and changes with the duration
of MCS. Patients who remain hospitalized for extended periods become
more susceptible to stress and depression. Generally, patients readily
accept MCS because they strongly believe that it is lifesaving.
Patients and their family members rarely complain about the
inconvenience imposed by MCS and its associated equipment.
The anxiety of awaiting a suitable donor heart can be severe for
patients and their families. By returning to a relatively normal
lifestyle during the MCS period, patients have a greatly reduced level
of anxiety, stress, and depression. Presently, recipients of the
HeartMate and Novacor LVASs can live outside the hospital, in their own
homes, while awaiting heart transplantation. In many of these cases,
patients have been able to participate in social events and return to
employment. As a result, their quality of life has been greatly
enhanced.19 47
Cardiac Transplantation
Allocation of Donor Hearts
Because of the limited ischemic times allowed for heart
allografts (maximum,
Recipient Selection
Once the patient's therapy has been maximized, assessment of his or
her prognosis without transplantation can rely on the following
objective measurements: left ventricular ejection fraction
(the prognosis is markedly worse for patients with an ejection fraction
<20%54), level of exercise tolerance (the
prognosis is very poor for patients with a
The most common indications for transplantation are idiopathic dilated
cardiomyopathy and ischemic heart disease
with left ventricular dysfunction, each of which accounts
for nearly half of the transplant population in any given
year.49 Less common indications for
transplantation include congenital malformations, giant cell
myocarditis, unresectable cardiac tumors, isolated cardiac sarcoidosis,
and restrictive or hypertrophic cardiomyopathy.
Once a patient undergoing optimal medical management is deemed to have
an extremely poor prognosis, other criteria are applied to determine
whether the patient can be expected to benefit from cardiac
transplantation. Unfortunately, many patients with chronic heart
failure develop pulmonary hypertension. Early in the heart
transplant era, physicians discovered that a normal donor right
ventricle is not always able to increase its external workload acutely
in response to elevated pulmonary
pressures.57 There is no single specific level of
PVR beyond which the donated right ventricle will always undergo acute
failure, but most programs defer patients with a PVR in excess of 4 to
6 Wood units, and many programs limit the transpulmonary
gradient as well.58 59 In recent years,
physicians have accepted the concept that some reversibility of
elevated PVR is possible in patients with chronic heart failure, and
patients with reversible PVR elevation have done well after
transplantation.60 Therefore, those with an
elevated PVR during catheterization of the right side
of the heart should undergo pharmacological maneuvers with prostacyclin
or nitroprusside during catheterization in an attempt
to demonstrate reversibility of the PVR elevation. Patients whose PVR
can be reduced to the acceptable range without concomitant severe
systemic hypotension are suitable candidates for transplantation.
A number of other contraindications to transplantation are generally
accepted, some being relative and others absolute. Most of these
factors have been discussed by the American Heart Association Committee
on Cardiac Transplantation61 62 and the American
College of Cardiology's Bethesda Conference on Cardiac
Transplantation.63 With time and increasing
experience, several of the original exclusion criteria, such as older
age64 65 and the presence of insulin-requiring
diabetes,66 67 68 have been challenged;
nevertheless, elderly or diabetic patients are carefully screened with
respect to physiological status and secondary organ
or vascular complications. Because of the limited donor supply, there
probably should be an upper age limit for transplant candidates, but
there is no consensus in the United States regarding what that limit
should be. Some experts have proposed that age be considered in organ
allocation, so that older organs would be given to older recipients. To
do so, however, would further complicate an already difficult medical
and ethical decision-making process.
Absolute contraindications to heart transplantation include other
medical conditions that would markedly and separately limit the
patient's survival, such as ongoing malignancy or irreversible
pulmonary, hepatic, or neurological disease. Active infection
is usually a temporary contraindication to transplantation because
immunosuppression would make any infection difficult to control.
Currently, HIV infection is probably the only infectious problem that
is a permanent contraindication. Relative contraindications include
severe obesity or osteoporosis, psychosocial instability or substance
abuse, active peptic ulcer disease, a history of malignancy with an
uncertain prognosis for recurrence, and severe
peripheral vascular disease.
Survival Rates
Rehabilitation Rates
Causes of Death
Major Clinical Problems
Newer drugs and modalities have been introduced to suppress the immune
system, but none has yet addressed the ultimate goal of transplantation
immunology: to induce specific immune tolerance of the grafted organ
without impairing the recipient's immune reactivity against infectious
organisms. Therefore, infection and malignancy remain ever-present
threats.
In addition, solid-organ grafts are prone to develop a unique form of
vasculopathy, which, for want of a better term, is called "chronic
rejection." In the cardiac allograft, this problem takes the form of
a diffuse, obliterative coronary vasculopathy, which eventually
produces all the sequelae of ordinary coronary artery disease,
including ischemic dysfunction and sudden death. This
coronary vasculopathy is analogous to obliterative
bronchiolitis in lung grafts,69 70 chronic
rejection in renal allografts,71 and (probably)
vanishing bile duct syndrome in liver
allografts.72 73 The underlying cause seems
complex and probably includes immune as well as nonimmune factors. This
vasculopathy currently constitutes the main limitation to truly
long-term survival in the majority of long-term heart transplant
recipients. Because of the diffuse, concentric, and longitudinal
distribution of the condition,74 angiography
provides only a gross underestimate of its severity. Nevertheless,
angiographic results have been correlated with an extremely poor
prognosis.75 Although several
measures76 77 have been shown to effectively
decrease the incidence of this vasculopathy, effective strategies for
treating or palliating established cases do not
exist,78 and retransplantation is the only
definitive therapy. Unfortunately, retransplantation is associated with
decidedly inferior graft and patient survival
rates.79 For this reason, experts have major
ethical reservations about using scarce donor organs for this
purpose.80
Future of Cardiac Transplantation
Issues and Controversies
MCS Use and Patient Selection
Patient selection is a complex process, and universal criteria do not
exist; experts generally agree, however, that the timing of device
implantation in transplant candidates is
crucial.30 32 44 For patients with acutely
exacerbated heart failure, hasty implantation may be as unwise as
waiting too long before implantation. For patients with a severely
deranged coagulation profile and/or renal failure and fluid overload,
the most prudent course is to resolve these conditions before
implantation. Heart transplantation is least likely to be successful in
CHF patients who have severely impaired renal, hepatic, and
pulmonary function perioperatively. However,
recovery from such secondary end-organ dysfunction occurs in many
patients during MCS, so failure of 1 or more organs is not necessarily
a contraindication to MCS.82 83 84 Risk factors
that may lessen the patient's chance of surviving to transplantation
include coagulopathy, previous cardiac surgery, pneumonia, and hepatic
dysfunction.85 86 No reliable predictors have
been found that can identify patients unlikely to survive MCS.
Ambulatory CHF patients at high risk of sudden death or acute
decompensation appear to be good candidates for
support.87 In fact, these patients may avoid
cardiac transplantation by undergoing long-term MCS followed by
eventual removal of the device. With this ambulatory population, the
greatest challenge is appropriate identification of candidates.
Alternatives to Cardiac Transplantation
Xenotransplantation involves the replacement of a human heart with a
nonhuman one.88 Strong immunologic barriers
currently limit the use of nonhuman hearts, but pioneering genetic
researchers are producing transgenic animals whose genetic materials
incorporate important human epitopes. When expressed, several of these
epitopes may ameliorate or abrogate the intensity of hyperacute
xenograft rejection. Because rejection depends on the activation of
complement, one current approach is to insert regulatory proteins for
human complement into the porcine genome; the altered pigs are unable
to activate complement and generate antibody-mediated
hyperacute rejection.89 Even after this
immunologic hurdle has been cleared, the cellular immune response and
subsequent development of graft vasculopathy will remain potential
problems. The extent to which these problems may be controlled by
conventional immunosuppression is uncertain. It also remains unclear
whether fundamental physiological incompatibilities
may preclude adequate functioning of a cardiac xenograft. Recently,
however, the Cambridge group90 documented
survival and normal function of a porcine orthotopic cardiac xenograft
in a nonhuman primate model for several months. Although
xenotransplantation may be a common clinical practice someday, it is
hard to predict when that day may be; when it does occur, organ
replacement will have taken a giant leap forward. Currently, concerns
about the epidemiological risks of xenosis, or the transfer of animal
infections to the human population, have led to calls for a moratorium
on human xenotransplantation until these ethical, societal, and medical
issues are resolved.
Cardiomyoplasty is a surgical procedure that involves translocation and
wrapping of the latissimus dorsi muscle pedicle around the heart to
assist the cardiac pumping action. The "trained" latissimus dorsi
muscle is electronically paced and contracts synchronously with the
heart to augment systolic function. Postoperatively, there is a
3-week delay before the latissimus dorsi begins to augment blood flow
in response to increased work. Therefore, there is a functional delay
in circulatory assistance when this approach is used. Cardiomyoplasty
has been shown to improve the patient's symptoms and quality of life
but does not appear to improve survival.91 The
improvement in symptoms may relate not only to improved
systolic function but also to a reduction of
ventricular wall stress owing to diastolic
"girdling." Cardio-myoplasty does not appear to have a lasting
effect on primary myocardial disease, and progressive heart failure
limits postoperative survival. During the first year after surgery,
survival rates range from 75% to 80%. During the subsequent 2 or 3
years, however, there is a consistent decrease in survival
rate. Outcomes are affected by the severity of heart failure at the
time of the cardiomyoplasty. Determination of the appropriate role of
this procedure awaits the results of randomized prospective
studies.
Partial left ventricular reduction (the Batista procedure)
entails removing a segment of the left ventricular
myocardium and repairing the mitral
valve.92 The objective of the operation is to
reduce the diameter of the left ventricular cavity and to
decrease mitral regurgitation. Ventricular
pressure and wall stress are decreased after this operation, and
patients with dilated cardiomyopathy have
significantly increased left ventricular ejection fraction
and cardiac index and improved NYHA status in the short
term.93 In Brazil, where this procedure was
devised, the operative mortality is 15%92; in
the United States, however, the operative mortality seems lower,
probably because of the availability of MCS and transplantation as
"rescue" modalities after failed
procedures.94 Controlled studies involving
sufficient patients to allow a critical assessment of this operation
are lacking. Before left ventricular reduction can become a
routine treatment for CHF, long-term follow-up studies are needed to
determine the clinical utility of the procedure and the appropriate
criteria for patient selection.
There are 2 possible approaches to the use of MCS as an alternative to
cardiac transplantation. In the first approach, a long-term implantable
system may be used to support patients for an indefinite period.
Patients who are discharged from the hospital and return home will have
an enhanced quality of life and will possibly live longer than with
medical therapy alone. Over the past 15 years, experience with the
bridge-to-transplant population has allowed investigators to gain
considerable confidence with regard to MCS. Two systems, the HeartMate
and Thoratec, have proved safe and efficacious by FDA standards.
Because the HeartMate was originally envisioned as a permanent system,
a randomized, multicenter clinical trial is under way to evaluate the
VE-LVAS for long-term use in NYHA class IV patients who are not
transplant candidates.95 96 The REMATCH
(Randomized Evaluation of Mechanical Assistance for the Treatment of
Congestive Heart Failure) Trial, initiated in 1996, is designed to
compare medical management and VE-LVAS support with respect to
mortality, quality of life, and cost. On the basis of a pilot series, a
revised REMATCH protocol was approved by the FDA, and enrollment has
recently begun. The results, which are unlikely to be known until after
the year 2000, should reveal the long-term capabilities of the VE-LVAS
and similar MCS systems.
The second potential approach for using MCS systems as alternatives to
transplantation involves bridging to recovery of myocardial function in
CHF patients. Long-term MCS is known to improve the clinical and
histological signs of CHF.97 98 99 100
Chronic unloading of the left ventricle decreases cardiac dimensions,
enhances ejection fraction, and lowers pulmonary capillary
wedge pressure and pulmonary vascular
resistance.101 102 Myocytolysis is
consistently reduced in patients with idiopathic
cardiomyopathy who are supported by an LVAS for
prolonged periods. So far, reports concerning LVAS removal after
prolonged support have been anecdotal.102 103 In
1 series,102 5 patients who had significant
cardiac recovery and underwent LVAS removal were all doing well many
months later. However, redilation, with exacerbated CHF symptoms, and
death have also been observed after MCS
removal.99
In the authors' experience, 2 young patients, 1 with idiopathic
cardiomyopathy and the other with peripartum
cardiomyopathy, were supported for 16 months and 5
months, respectively, before VE-LVAS removal. Both patients were in
NYHA class I 18 and 15 months, respectively, after device explantation.
They represent a population likely to benefit from bridging to
recovery. Indeed, young patients with severe CHF have a limited life
expectancy even with cardiac transplantation and may have a better
long-term prognosis and quality of life without transplantation.
Nevertheless, many questions remain: Which patients are most likely to
have sufficient cardiac remodeling to allow removal of the MCS system?
How long will adequate cardiac function be maintained? Do practical
measures of myocardial recovery exist, and can the degree of recovery
be assessed? Controlled trials designed to answer these questions are
urgently needed.
Comments
In the absence of a definitive cure for the primary diseases that
lead to CHF, combined medical and surgical therapy will continue to be
the standard of care. Cardiac transplantation and MCS will continue to
evolve in parallel, and ongoing refinements in these modalities will
improve patient survival and quality of life. Other future therapies
may be based on gene therapy, new pharmaceutical agents, and improved
biomaterials. Because cardiac transplantation is limited by the
insufficient supply of human donor organs, better immunologic
manipulation is needed to enhance graft survival and possibly expand
the donor pool to include other species. Future blood pumps must be
smaller and totally implantable, as well as more efficient,
biocompatible, and reliable. In this era of rapid technological
progress, the main obstacles to major advancement are societal,
financial, and regulatory barriers. Fortunately, these barriers are not
insurmountable, and there is every reason to believe that they will
eventually be overcome.
Selected Abbreviations and Acronyms
Footnotes
Reprint requests to O.H. Frazier, MD, Texas Heart Institute, PO Box 20345, MC 3–147, Houston, TX 77225-0345.
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© 1998 American Heart Association, Inc.
Clinical Cardiology: New Frontiers
Mechanical Circulatory Support and Cardiac Transplantation
Key Words: transplantation • heart-assist device • survival
MCS was first used clinically in 1953 with the implementation of
cardiopulmonary bypass.7 This
breakthrough led to numerous surgical treatments for a variety of
cardiac disorders. The success of cardiopulmonary bypass
stimulated research into other innovative techniques for supporting the
circulation. Counterpulsation with the intra-aortic balloon pump was
first applied clinically in 1967 to support patients with acute heart
failure.8 In the 1960s, CHF patients occasionally
were temporarily supported by cardiopulmonary
bypass,9 10 an implantable
VAS,11 or a TAH.12 Although
the overall success rate was limited, this early experience did prove
that MCS could adequately sustain a patient's circulation until
cardiac function recovered or a donor heart could be obtained. During
the 1970s, major hurdles related to immunosuppression prevented heart
transplantation from becoming a reasonable treatment option. During
this time, research efforts, made possible by support from the NHLBI,
were directed toward producing MCS systems for long-term use or for
permanent cardiac replacement. In the early 1980s, the introduction of
cyclosporine-based immunosuppression allowed heart
transplantation to become a widely accepted therapeutic alternative.
During that same decade, clinical trials were initiated to evaluate the
safety and efficacy of MCS systems in supporting terminally ill
transplant candidates until a suitable donor heart could be found.
Today, after nearly 30 years of research and development, MCS systems
are in widespread clinical use as bridges to transplantation or
myocardial recovery. Despite numerous design modifications and
refinements, an ideal system has not yet evolved; nevertheless, current
systems can adequately support many heart failure patients.
The MCS systems currently being used as bridges to transplantation
resulted from the NHLBI program for the development of long-term
circulatory support initiated in the 1970s. Two of these systems, the
HeartMate (Thermo Cardiosystems Inc) and the Novacor (Baxter Healthcare
Corp), are fully implantable LVASs, which permit mechanical
"bypass" of the left ventricle without removal of the native heart.
The Thoratec VAS (Thoratec Laboratories, Inc) is a paracorporeal system
that can provide univentricular or
biventricular support. The implantable CardioWest TAH
replaces the entire native heart during the support period. All 4 of
these systems can provide physiological circulatory
support for extended periods, yet each has unique advantages and
disadvantages. As the waiting time for donor hearts has lengthened,
physicians have gained increased experience with the long-term benefits
and problems of MCS.
The HeartMate is an implantable, pulsatile LVAS designed to be
portable and easy to operate. The blood-contacting surfaces that line
the blood pumps are textured to encourage the deposition of circulating
cells. A uniform autologous tissue lining is established on all the
blood-contacting surfaces of the pump, minimizing thrombus formation
and bacterial colonization.13 14 The inflow and
outflow conduits each contain a 25-mm porcine valve to ensure
unidirectional blood flow. Presently, 2 versions of the HeartMate
(Figures 1
and 2) are in clinical use: an implantable
pneumatic version (IP-LVAS) and a vented electric version
(VE-LVAS).15 16 The 2 models use the same blood
pump and differ primarily in their method of actuation. With the
IP-LVAS, an external drive console sends pulses of air that cause the
pump's flexible diaphragm to move upward, pressurizing the blood
chamber and causing the ejection of blood into the aorta. In contrast,
with the VE-LVAS, diaphragm movement and blood ejection depend on an
electric motor positioned below the diaphragm. An external vent
equalizes the air pressure and permits emergency pneumatic actuation.
The external system controller and batteries in the VE-LVAS are small
and lightweight, allowing the patient nearly unlimited mobility.
View larger version (26K):
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Figure 1. The HeartMate Implantable Pneumatic Left
Ventricular Assist System.
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[in a new window]
Figure 2. The HeartMate Vented Electric Left
Ventricular Assist System.
The Novacor LVAS is a portable, implantable pump designed for
long-term use (Figure 3).20 It differs
significantly from the HeartMate in its method of pump actuation and
use of a smooth blood-contacting surface. During pump systole, 2
opposing pusher plates compress a seamless polyurethane blood sac,
causing ejection of blood. Unidirectional flow is achieved with 21-mm
bioprosthetic valved conduits. A percutaneous
lead contains the necessary electrical wires and a vent. Transducers
within the pump send signals to the external control unit to regulate
the pumping rate and to display the pumping parameters. The
system can be operated in either fixed-rate, synchronous, or
fill-to-empty mode. In 1993, the Novacor LVAS was converted from a
console-operated system into a wearable or portable system. The
wearable system eliminates the need for a bulky console by
incorporating a compact controller and rechargeable power packs that
are worn on the patient's belt.21 The wearable
system is designed for out-of-hospital use and can be monitored with a
bedside monitor.
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Figure 3. The Novacor Wearable Left Ventricular
Assist System.
The Thoratec VAS is a paracorporeal, pneumatically powered system
configured for univentricular or biventricular
support (Figure 4).24 It features a
seamless polyurethane blood sac within a rigid polycarbonate housing.
An external drive console sends pressurized air to the pump, which
compresses the blood sac and causes blood to be ejected. Bjork-Shiley
concavo-convex tilting-disk valves within the inflow and outflow
conduits ensure unidirectional blood flow. The Thoratec VAS can be
operated in fixed-rate, volume, or synchronous mode. Volume mode is
preferred because it maximizes support of the cardiac output.
Synchronous mode is intended for weaning patients from support.
Although the console can function automatically to achieve maximum pump
flows, the operator must adjust the systolic driving pressure
and diastolic vacuum pressure. The pump has a maximum
stroke volume of 65 mL and a maximum flow of 6.5 L/min.
View larger version (32K):
[in a new window]
Figure 4. The Thoratec Ventricular Assist System
in the biventricular support configuration. RVAD indicates
right ventricular assist device; LVAD, left
ventricular assist device.
The CardioWest TAH, formerly called the Jarvik or Symbion TAH, is
a pulsatile biventricular cardiac replacement system
(Figure 5).27 Its
rigid polyurethane pump contains a smooth, flexible polyurethane
diaphragm that separates the blood and air chambers. Two Medtronic-Hall
mechanical valves provide unidirectional blood flow. Compressed air
from the external drive console moves the diaphragm upward,
pressurizing the blood chamber and causing ejection of blood. The pump
has a maximum stroke volume of 70 mL and a maximum flow rate of 15
L/min, although the average flow rate is <8
L/min.28 The operator can adjust the pump rate,
duration of systole, and driving pressure to achieve optimal flow
conditions.
View larger version (27K):
[in a new window]
Figure 5. The CardioWest Total Artificial Heart.
The Novacor and HeartMate systems are very similar with respect to
function, implantation techniques, and intended use. The HeartMate is
different in that it uses textured blood-contacting surfaces to allow
the development of a "pseudoneointimal" lining that
enhances biocompatibility. All the other MCS pumps have smooth
blood-contacting surfaces that necessitate anticoagulant therapy.
During prolonged HeartMate support, patient care can be managed safely
with minimal or no anticoagulation.13 29 Another
important difference concerns the availability of these systems in the
United States. The FDA has approved the Thoratec VAS and HeartMate
IP-LVAS for commercial use in bridge-to-transplant cases only. The
Novacor LVAS, HeartMate VE-LVAS, and CardioWest TAH currently remain in
clinical trials under an investigational device exemption, which limits
their use to selected centers. Whereas the Novacor and HeartMate
provide left ventricular support, the Thoratec and
CardioWest systems offer biventricular support. The most
important difference between the Thoratec VAS and the CardioWest TAH
involves pump position and the need for removal of the native heart
when the TAH is used. The Thoratec pump(s) reside(s) extracorporeally,
and the CardioWest TAH is placed within the mediastinal space.
Moreover, the Thoratec system can be used for
right-ventricular, left-ventricular, or
biventricular support, but the CardioWest TAH offers only
biventricular support.
Over the past 15 years, extensive clinical experience has been
gained with the above-described bridge-to-transplant systems in the
United States and Europe (Table 1). The
European30 and
international31 voluntary registries have
reported similar results with numerous systems. The overall
bridge-to-transplant population is supported by a wide variety of MCS
systems. The transplantation rate, or percentage of patients who
eventually undergo transplantation, ranges from 62% to 69%, and the
rate of hospital discharge after transplantation is 65% to 69%. In a
subset of patients supported by systems designed specifically as
bridging devices, the transplantation rate is similar (60%), but the
hospital discharge rate is 89%.28 Patients who
require only isolated left ventricular assistance rather
than biventricular assistance have much better rates of
transplantation and discharge. Those who require isolated right heart
support or biventricular support with hybrid MCS systems
have transplantation rates of 30% to 40% and hospital discharge rates
of 0% to 60%. For patients with the 4 systems described above (except
those undergoing biventricular support with the Thoratec
VAS), the hospital discharge rate after cardiac transplantation ranges
from 89% to 93%. This rate is comparable to that seen in the general
cardiac transplant population not requiring preoperative MCS. The
primary reason for the better survival rate with the implantable LVAS
is that patients can be safely supported for longer durations, allowing
complete physical rehabilitation before heart
transplantation.32 33 In 1 series, LVAS
recipients in NYHA functional class I at the time of transplantation
had survival rates of 100% at 2 years.34
View this table:
[in a new window]
Table 1. Summary of Experience With MCS Systems in
Bridge-to-Transplant
Patients
In the bridge-to-transplant population, the most frequent
complications are bleeding, infection, thromboembolism, renal failure,
hemolysis, technical problems, and neurological
dysfunction.30 31 The most prevalent and
important complications are bleeding and infection. Bleeding rates,
which are as high as 60%,30 31 35 are related to
coagulopathy due to hepatic dysfunction, the extensive surgical
procedures required for MCS, and the combined effects of
cardiopulmonary bypass and blood-pump rheology on platelet
activation. Patients who require biventricular assistance
are more susceptible to bleeding complications than those who need
univentricular assistance.9 Infection
rates generally range from 30% to 40%35 36 37 and
contribute to significant morbidity.38 Although
infections can be frequent and severe during MCS, they do not preclude
successful cardiac transplantation.39 40 41 Severe
infections typically occur in patients with comorbidities such as
bleeding and multiple organ failure.42 43
Over the past decade, the duration of pretransplant MCS has
lengthened considerably because, as a whole, transplant candidates are
waiting longer for donor organs. Moreover, experienced physicians have
gained confidence in the reliability of MCS systems; with these systems
and improved medical management, patients can safely wait for many
months until a donor heart becomes available. For those with multiple
organ dysfunction secondary to prolonged heart failure, complete
recovery of secondary organ function may necessitate weeks to months of
MCS.32 33 The duration of circulatory assistance
required for end-organ recovery and physical rehabilitation varies
greatly from 1 patient to another and is somewhat dependent on the
duration and severity of CHF. Patients who return to NYHA class I
during MCS may await a suitable heart donor while living outside the
hospital.19 23 In these cases, hospital discharge
improves the patient's psychosocial status, reduces costs, and
decreases the incidence of certain serious complications such as
nosocomial infections.44 45
Although, as noted above, potentially 40 000 patients per year
die of heart disease that might otherwise have been treatable with
transplantation,48 only 
2500 donor hearts
become available annually.49 Because of this
disparity between demand and supply, recipient selection criteria and
donor allocation decisions are crucial medical, ethical, and societal
issues. The need for a fair, consistent, and ethical system of
donor allocation was the main factor that led to establishment of a
national organ procurement and distribution network, UNOS. Since 1986,
this private organization has had a federal contract within the United
States to maintain an organ procurement and transplantation network and
a scientific registry for organ transplantation. The organization's
policies are under direct review by the US Department of Health and
Human Services and are administered by that department's Division of
Organ Transplantation. UNOS maintains a national computerized list of
patients awaiting various organs, and it coordinates organ allocation
according to established, consistent, frequently reviewed
criteria. Policy decisions are made in public forums, with input from a
variety of medical, legal, and patient constituencies. Currently,
allocation of available donor hearts is based on the severity of the
recipient's illness, the recipient's length of time on the waiting
list, ABO blood-type compatibility between donor and recipient, and an
overall body-size match between donor and recipient. Priority is given
to those who require significant inotropic support or MCS; all others
are accorded secondary consideration, on an equal basis. 6 hours), a truly national donor-heart
distribution scheme is impossible in a country as large as the United
States. Instead, allocation is prioritized geographically, with
preference given to local recipients or, when no local recipients
exist, to those within areas in succeeding 500-mile radii from the
donor hospital. Because of time limitations, as well as the relatively
small numbers of organs involved, many nuances of donor/recipient
screening (such as matching for human lymphocyte antigens and
cytomegaloviral status) are not practical.
Owing to the lack of suitable donor hearts and the improving
survival prospects for CHF patients, it has become increasingly
important to stratify the risk of patients referred for heart
transplantation. For critically ill patients who require prolonged
hospitalization for inotropic support or MCS, eligibility is limited
only by contraindications to transplantation. For patients who are less
severely ill, greater selectivity is needed, and a variety of
guidelines have been proposed. In deciding to place a patient on the
waiting list for heart transplantation, the physician must weigh the
magnitude of the patient's need against the potential benefits of
transplantation. When a patient is first considered for heart
transplantation, the initial consideration is to exclude (or treat) any
potentially reversible causes of heart failure. Treatment options may
include high-risk revascularization for
ischemic heart disease in patients with a viable
myocardium,50 surgery for severe
valvular lesions that may be causing ventricular
dysfunction, or medical therapy for inflammatory or primary myocardial
disease.51 52 In patients with
nonischemic cardiomyopathy, an
endomyocardial biopsy may confirm or exclude other
potentially reversible causes of myocardial dysfunction, such as
hemochromatosis or sarcoidosis; the biopsy can also diagnose conditions
that may preclude heart transplantation, such as amyloidosis, which
recurs frequently in allograft recipients and may be rapidly
fatal.53 
O2max <14 mL ·
kg-1 · min-1
during formal exercise testing55),
hemodynamic data, and parameters of
neurohumoral activation.56 No single test or
measurement can identify end-stage heart failure involving an extremely
poor short-term prognosis. In assessing ambulatory transplant
candidates, physicians generally rely on several or all of the
above-mentioned factors.
As of 1982, meaningful numbers of cardiac transplant procedures
began to be accrued into the registry of the International Society of
Heart Transplantation. Since that time, these numbers have been updated
annually. According to the most recent data, based on >40 000
patients treated over a 15-year period, 1-year survival rates after
orthotopic heart transplantation have averaged
79%.49 Figure 6
shows the actuarial survival rates for the overall patient population
of 34 180 persons. The survival rate markedly improved for patients
undergoing transplantation after 1986, but no further increase in
survival rate has been seen in the more recent cohorts, here defined as
patients operated on after 1991. Figure 7
shows similar actuarial survival curves for the pediatric population,
which is divided into subsets according to age at the time of
transplantation. The highest mortality occurred in the youngest
patients; older children (5 to 16 years of age) had survival rates
almost identical to those of adults. Figure 8 shows actuarial survival curves for the
adult population, which is subdivided according to age. The survival
rate decreased for each succeeding decade of life, and the cohort over
age 65 years had a highly significant decrease in survival.
View larger version (30K):
[in a new window]
Figure 6. Actuarial survival curves for heart
transplant recipients, overall and divided into subsets according to
year of transplant. (Reproduced with permission from Hosenpud et
al.49)
View larger version (28K):
[in a new window]
Figure 7. Actuarial survival curves for pediatric heart
transplant recipients, divided into subsets according to age at time of
transplant. (Reproduced with permission from Hosenpud et
al.49)
View larger version (31K):
[in a new window]
Figure 8. Actuarial survival curves for adult heart
transplant recipients, divided into subsets according to age at time of
transplant. (Reproduced with permission from Hosenpud et
al.49)
Figure 9 shows data from the
registry of the International Society for Heart and Lung
Transplantation regarding rates of rehabilitation of heart transplant
recipients between 1994 and 1996. Most patients returned to NYHA class
I status and resumed their normal occupational, physical, and social
pursuits. Ninety percent had no limitations in activity at 1 and 2
years postoperatively. In the United States, however, the healthcare
system makes it hard for transplant recipients to obtain health
insurance, and such insurance is generally tied to employment.
Therefore, many able-bodied transplant recipients are virtually
unemployable, with only 30% working full-time 1 year after
transplantation and 34% working full-time at 2 years (Figure 10).
View larger version (26K):
[in a new window]
Figure 9. Heart transplant recipient functional status,
United States data reported to the Registry of the International
Society for Heart and Lung Transplantation between April 1994 and
December 1996. (Reproduced with permission from Hosenpud et
al.49)
View larger version (31K):
[in a new window]
Figure 10. Heart transplant recipient work status, United
States data reported to the Registry of the International Society for
Heart and Lung Transplantation between April 1994 and December 1996.
(Reproduced with permission from Hosenpud et al.49)
Causes of death after heart transplantation vary according to the
posttransplant interval. Most deaths during the first postoperative
month are due to acute rejection, nonspecific graft failure, or
multisystem organ failure. After the first month, infectious
complications emerge as a major cause of morbidity and mortality. After
the first postoperative year, malignancy and graft coronary
disease become the main causes of death. It is hoped that more specific
immunosuppressive modalities will soon become available to prevent
these conditions and permit much longer survival.
As is evident from the causes of death noted above, several major
clinical problems remain. The primary one, which resembles a
double-edged sword, is the fine line that exists between
underimmunosuppression and overimmunosuppression in any organ
transplant recipient. With underimmunosuppression, the graft may be
rejected, causing either the death of the recipient (in the case of
heart transplants) or a need for increased immunosuppression, which
takes its own clinical toll. On the other hand, overimmunosuppression
can lead to opportunistic infection or malignancy, which can be as
disabling as the original heart disease. Current attempts to walk this
fine line usually involve the use of surveillance
endomyocardial biopsies (Table 2) to detect early cardiac rejection and
guide immunosuppressive therapy.
View this table:
[in a new window]
Table 2. Typical Regimen for Surveillance Endomyocardial
Biopsies After Heart
Transplantation1
Two factors can be expected to influence the future of cardiac
transplantation. The first factor will be the advent of improved
methods for suppressing the immune system, preferably with drugs or
other less toxic modalities that entail less tendency toward graft
vascular disease or chronic rejection. Although once thought to be
unrealistic, induction of specific immune tolerance of a donor organ
may become possible as the immune response becomes better understood
and manipulated.81 The second influential factor
will be the development and validation of alternatives to cardiac
allotransplantation, as discussed below. Even if optimally utilized,
available human donor hearts will never meet the increasing demand for
cardiac replacement. For this reason, attention has become focused on
alternative possibilities, including genetically altered animal organs
and permanently implantable mechanical devices.
No current single MCS system is capable of treating the full
spectrum of heart failure. At this time, it is neither financially nor
technically feasible for all cardiovascular care
centers to use all the available MCS systems. Ideally, transplant
centers should have implantable systems for long-term support,
short-term systems for acute heart failure, and a system capable of
providing temporary right ventricular support. Other
considerations include anticoagulation (if any), device portability,
and the patient's ability to leave the hospital during the support
period.
Possible alternatives to cardiac allotransplantation include
xenotransplantation, cardiomyoplasty, left ventricular
reduction surgery, and long-term MCS. Another possibility is
"bridging to recovery," in which the MCS device would be electively
removed after months or years of support, when sufficient cardiac
function had been regained.
CHF
=
congestive heart failure
FDA
=
US Food and Drug Administration
IP-LVAS
=
implantable pneumatic left ventricular assist system
LVAS
=
left ventricular assist system
MCS
=
mechanical circulatory support
NHLBI
=
National Heart, Lung, and Blood Institute
NYHA
=
New York Heart Association
PVR
=
pulmonary vascular resistance
TAH
=
total artificial heart
UNOS
=
United Network for Organ Sharing
VAS
=
ventricular assist system
VE-LVAS
=
vented electric left ventricular assist system
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