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AHA Medical/Scientific Statement
Position Statement
Cardiac Transplantation: Recipient Selection,
Donor Procurement, and Medical Follow-up
A Statement for Health Professionals From the Committee on
Cardiac Transplantation of the Council on Clinical
Cardiology, American Heart Association
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John B. O'Connell, MD, Chairman; Robert C. Bourge, MD; Maria Rosa Costanzo-Nordin, MD;
David J. Driscoll, MD (Liaison, Council on Cardiovascular Disease in the Young);
James P. Morgan, MD, PhD (Liaison, Council on Basic Science); Eric A. Rose, MD
(Liaison, Council on Cardio-Thoracic and Vascular Surgery); Barry F. Uretsky, MD, Members
D uring the past decade heart transplantation has
evolved from an experimental procedure performed in selected centers to the treatment of
choice for patients with end-stage heart disease. The
rapid increase in the number of heart transplants performed worldwide is attributable to numerous advances
in surgery, tissue preservation, immunology, and infectious disease that have resulted in acceptable short- and
long-term patient and graft survival. The improved
outcome of heart transplantation is also due to the
highly specialized care provided by physicians and surgeons who have made a strong commitment to heart
transplantation and have acquired expertise in recipient
selection, donor procurement, and medical follow-up
before and after transplantation. Standardized criteria
help physicians and surgeons identify patients who will
likely benefit from heart transplantation. Unfortunately,
the limited availability of donor hearts makes it impossible to offer transplantation to all potential candidates.
The need for an equitable system of donor organ
allocation was a factor in the organization of a national
organ procurement and distribution network, the
United Network for Organ Sharing (UNOS),* which
distributes organs based on the severity of the recipient's illness, waiting time, donor and recipient's blood
types, and body-size match.
In addition to maximizing access to donors and
matching organs to specific recipients, other important
aspects of a donor procurement program are knowledge
of medical, ethical, and legal issues concerning brain
death, skill in hemodynamic management of potential
donors, and expertise in organ retrieval, preservation,
and transport.
*UNOS is responsible for maintaining the national computerized prioritization and allocation system and certifying transplant
centers and local organ procurement organizations.
"Cardiac Transplantation" was approved by the American
Heart Association Steering Committee on February 19, 1992.
Requests for reprints should be sent to the Office of Scientific
Affairs, American Heart Association, 7272 Greenville Avenue,
Dallas, TX 75231-4596.
Heart transplantation is not a cure; thus, competent
long-term treatment is essential for a successful outcome. Care of heart transplant recipients must focus on
evaluation of heart allograft function, which is affected
by denervation, donor-recipient size mismatch, rejection surveillance, and treatment of immunosuppression.
Complications occurring after transplantation affect
multiple organ systems and vary in type and frequency.
Because most complications are a result of adverse
effects of immunosuppression, successful outcome of
heart transplantation requires a delicate balance between adequate immunosuppression and control of
drug-related morbidity. This statement reviews recipient selection, donor procurement, and medical follow-up in heart transplantation.
Recipient Selection
Selection of heart transplant recipients is based on a
determination of which patients are likely to exhibit the
most pronounced improvement in symptoms, functional
capacity, and life expectancy after transplantation. The
donor organ shortage precludes transplantation for all
patients who may benefit from the surgery. Variation in
recipient selection criteria among transplant centers is
related to this dilemma. Therefore, an elaborate nationwide system, supervised by UNOS, has evolved. Equitable distribution of limited donor resources is based on
length of recipient waiting time, severity of illness,
blood type, and body size.
Deciding which patients should receive transplants
requires knowledge of both potential benefits and expectations and the natural history of the illness for
which transplantation is suggested. It should be understood that controlled trials have not compared the
results of transplantation with those of medical treatment. As such, the precision of patient selection is
limited.
Current Results in Transplantation
and Medical Management
After successful cardiac transplantation, most recipients will be without functional limitation (i.e., will be in
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New York Heart Association [NYHA] Functional Class
I) or have only mild limitations (NYHA Class II). The
expectation for 1-year and 5-year survival after cardiac
transplantation is 80-90% and 60-70%, respectively.'
Therefore, any patient with a cardiac condition that has
a lower survival rate could potentially benefit from
transplantation. The magnitude of expected improvement in survival, functional capacity, and symptoms
usually drives the decision-making process.
In uncontrolled trials, patients in NYHA Class IV
(symptoms at rest despite optimal medical therapy) with
congestive heart failure and systolic dysfunction have
annual survival rates of less than 50%.2-6 In a controlled
trial involving NYHA Class IV patients (CONSENSUS),
1-year survival with optimal medical therapy (digoxin,
diuretics, angiotensin-converting enzyme [ACE] inhibitors, and in many cases other vasodilators) was approximately 60%.2 Although the survival rate of patients who
respond inadequately to this medical therapy has not
been detailed, it is unlikely that this group will have a
1-year survival rate greater than 50%. Therefore, patients with severe impairment of cardiac function achieve
maximal survival and symptomatic benefit from cardiac
transplantation.
Results of uncontrolled studies suggest that 1-year
survival in patients with NYHA Class III symptoms of
congestive heart failure varies from 40% to 70%.3-7 The
Studies of Left Ventricular Dysfunction (SOLVD) trial,
in which investigators analyzed the effect of enalapril in
a large cohort of Class II and Class III patients, suggests
a better prognosis with medical treatment than previously noted in these patients.8 Although improvement
in survival and symptoms after transplantation is not
expected to be as great as for Class IV patients, selected
NYHA Class III patients may be acceptable candidates
for the procedure and should be referred to a transplant
center for further evaluation.
Selection of the Candidate for Transplantation
Because of the limited number of donors and the
subjectivity of categorizing functional impairment, several investigators have attempted to identify other determinants of survival and provide guidelines for candidate selection.3-5,9-$ Patients with severely impaired
left ventricular function (ejection fraction less than
20%) are at a higher risk than patients whose ejection
fraction is 20% or greater.9'1 Patients with extremely
poor left ventricular dysfunction, especially those requiring continuous intravenous inotropic support or
mechanical assist devices, are probably at highest risk of
mortality and therefore are most likely to benefit from
transplantation. In ambulatory NYHA Class III patients, impairment of exercise tolerance (Vo2max <14
ilill/kgiiiiii') is a poor prognostic sign.'0 Indexes of risk
should be obtained only after optimal medical therapy.
The long-term survival of patients with symptomatically
mild heart failure receiving optimal medical therapy
(Veterans Administration Cooperative VasodilatorHeart Failure Trial [V-HeFT] I and V-HeFT II and
SOLVD) is comparable to the results of transplantation, particularly in the initial 3-5 years.8"123 Transplantation should generally not be considered for this
group.
The most common illnesses leading to transplantation are dilated cardiomyopathy and ischemic heart
disease with left ventricular dysfunction. The symptoms of patients with refractory angina pectoris and
left ventricular dysfunction who cannot be treated
successfully with revascularization or medical therapy
improve or are eliminated after cardiac transplantation. Transplantation probably improves survival in
this group of patients, who usually have extensive
coronary artery disease.14 Patients with refractory
life-threatening arrhythmias not amenable to medical
therapy or the insertion of automatic implantable
cardioverter devices may benefit from transplantation,
as may those with valvular and congenital heart disease. Less common cardiac problems may also be
improved by cardiac transplantation: for example,
restrictive cardiomyopathy, sarcoidosis, amyloidosis,
hypertrophic cardiomyopathy, myocarditis, and cardiac tumors.' 5'6 Sarcoidosis is a relatively rare indication for transplantation and very few cases with longterm follow-up have been reported.'5 Although some
benefit may be derived from cardiac transplantation if
amyloidosis appears to be limited to the heart, progression of the systemic manifestations of this disease
may limit the long-term efficacy of this procedure.16
Transplantation in patients with active myocarditis has
been successful. However, mortality and rejection
rates may be higher in this group than in patients who
do not have myocarditis.17 Patients with tumors limited to the heart that cannot be resected by conventional surgical techniques may be successfully treated
with transplantation.
Additional criteria have been established to identify
the best recipient candidates. Those who do not have
other conditions that might limit survival have the
highest selection priority. A typical evaluation for cardiac transplant patients, which should be tailored to the
specific clinical situation, is shown in Table 1. Infection
and malignancy, unless cured or controlled, are absolute
contraindications to transplantation. The immunosuppression required to prevent allograft rejection will
favor the progression of an active infection and may
accelerate growth of certain malignancies. Pulmonary
infarction is a relative contraindication to transplantation because secondary infection may occur postoperatively.'8 In many centers, patients with pulmonary infarction are treated with anticoagulant agents and
monitored for at least 6-12 weeks or until radiographic
improvement is documented before they are added to
the list for transplantation. Alternatively, resection of
the infarcted segments may be performed during the
transplant surgery.
One of the most problematic relative contraindications to transplantation is age. The upper age limit for
recipients in most transplant centers is between 55 and
65 years, although the benefits of transplantation in
carefully selected older patients are comparable to
those of a younger cohort.19,20 However, older patients
may have other conditions that preclude transplantation. Preferential selection of older donors for older
recipients has been the practice in some transplant
centers.
Excessive elevation of pulmonary vascular resistance
may cause right heart failure in the immediate postoperative period.21 The absolute level of pulmonary vascular resistance that will produce right heart failure is
unknown, but in most centers patients with pulmonary
vascular resistance of more than 4-6 Wood units (4-6
AHA Scientific Council Cardiac Transplantation
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TABLE 1. Studies Routinely Performed During the Heart Transplant Recipient Selection Process
Comprehensive history and physical examination
Liver and kidney function (bilirubin, SGOT, SGPT, alkaline
phosphatase, BUN, creatinine)
Complete blood cell count and differential
Platelet count
Prothrombin time
Partial thromboplastin time
Urinalysis
24-hour urine for measurement of glomerular filtration rate
Stool guaiac (three tests)
Electrocardiogram
Chest x-ray
Right heart catheterization
Left heart catheterization*
Coronary angiography*
Endomyocardial biopsy*
Echocardiogram
Radionuclide angiogram
Serologies for hepatitis A and B, human immunodeficiency
virus, cytomegalovirus (IgM) antibody, Toxoplasma gondii (IgG,
IgM) antibody, Epstein-Barr virus, varicella titers, syphilis, and
fluorescent titer antibody*
ABO blood typing and antibody screen
Histocompatibility leukocyte antigen typing (for retrospective
comparisons)
Panel reactive antibody
Consultation with social service, dental service, psychiatry*
Pulmonary function testing
Exercise testing with oxygen consumption*
Abdominal ultrasound*
Carotid and peripheral Doppler flow studies*
SGOT, serum glutamate oxaloacetate transaminase; SGPT, serum glutamate pyruvate transaminase; BUN, blood urea nitrogen.
*When appropriate.
mm Hg/i per minute) are not accepted as candidates for
transplantation. An elevated transpulmonary gradient
([mean pulmonary artery] - [pulmonary artery wedge
pressure] >15 mm Hg) may also predict postoperative
right ventricular failure and predispose patients to
perioperative mortality.22-26 In most cases, pulmonary
vascular resistance and transpulmonary gradient may be
reduced by pharmacological intervention, which should
be attempted before candidacy is denied.27 Agents most
successful in modulating the pulmonary vascular resistance include nitroprusside and prostaglandin E1.27 If
this treatment fails, prolonged intensified medical management, including chronic parenteral administration of
inotropic or vasodilator drugs may gradually reduce
pulmonary vascular resistance to an acceptable range.
Although patients with severe fixed pulmonary hypertension are usually excluded from orthotopic heart
transplantation, heterotopic ("piggyback") heart transplantation may be a viable alternative. "2
Increased pulmonary vascular resistance is particularly associated with decreased survival after cardiac
transplantation in the pediatric population.29 Because
of differences in lung size, body size, and absolute
cardiac output in children of different ages and sizes, it
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appears most appropriate to use pulmonary vascular
resistance measurements indexed by body surface area,
i.e., Wood units - m2 (u im2), when assessing relative
suitability for transplantation. The highest level of
pulmonary arteriolar resistance for successful cardiac
transplantation in children also has not been defined.
There are data to support a continuous positive relation, as determined by multivariate analysis, between
higher pretransplant pulmonary vascular resistance and
mortality after transplantation in both adults and children.30,31 In patients with congenital heart disease, the
risk of death is very significant when pulmonary vascular resistance is greater than 6-7 u - m2.30 Evidence of
reversibility of the pulmonary vascular resistance with
maximum treatment with inotropic and vasodilator
drugs may indicate that cardiac transplantation in infants and children can be successful.
There are concerns about transplantation in patients
with diabetes mellitus. Corticosteroids, frequently used
in immunosuppression, increase the difficulty of controlling blood sugar. Patients whose diabetes has been
controlled by diet or oral agents may require insulin
postoperatively. Diabetics tend to have an increased
frequency and severity of infections, and diabetics are at
increased risk for vascular complications that decrease
life expectancy.32 Therefore, end-organ damage (neuropathy, nephropathy, or retinopathy) must be carefully
excluded before the diabetic is accepted for transplantation. Intermediate-term (2-4-year) survival of some
diabetics is comparable to that of nondiabetics.32-34
Therefore, insulin-dependent diabetes mellitus is no
longer an absolute contraindication to transplantation.
Patients with irreversible moderate to severe liver or
kidney disease generally have been excluded from consideration31 because of the expectation of limited survival due to involvement of those organs and the additional damage induced by immunosuppression.
Moderate to severe chronic lung disease is a relative
contraindication. A higher incidence of immediate postoperative respiratory problems, decreased survival due
to the chronic lung disease itself, and the increased risk
of lung infections due to immunosuppression have been
noted. Generally an FVC (forced vital capacity) <50%
predicted, an FEV1.0 (forced expiratory volume in 1
second) of less than 1 liter, or an FEV,.,/FVC ratio of
less than 1 have been used as guidelines for predicting
risk. Consequently, whether an active smoker should be
considered a candidate for transplantation is highly
questionable.
Peripheral or cerebral vascular diseases are also
relative contraindications. Peripheral vascular disease
may rarely preclude the use of intra-aortic balloon
support and functional rehabilitation. A history of
cerebrovascular disease, including previous stroke, also
may limit long-term survival or rehabilitation. Asymptomatic carotid bruits are not absolute contraindications
for transplantation.
Hyperlipidemia, cholelithiasis, and complications of
diverticulosis are common after transplantation.35,36 Although their presence before transplantation is not a
contraindication per se, preoperative identification aids
in postoperative management. Previous cardiothoracic
surgery is not a contraindication to cardiac transplantation. However, such patients may be at higher risk for
bleeding and other complications in the immediate
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postoperative period.37 Because cachexia may retard
wound healing and increase the risk of postoperative
infection, one goal of pretransplant care is to maintain
adequate nutrition.38 Active peptic ulcer disease has
been considered a possible contraindication because the
use of corticosteroids may aggravate this condition;
however, aggressive medical treatment usually eliminates it. Morbid obesity has also been considered a
relative contraindication because it may increase postoperative morbidity, limit functional recovery, and
make the identification of a suitably large donor almost
impossible.
It is not unusual for the patient with chronic severe
heart failure to feel depressed. Psychiatric consultation
may be useful in determining whether the depression is
related to the chronic illness or is endogenous and
requires long-term treatment. The support of caring
family members or other persons should be enlisted
when possible. Commitment by the patient to a lifetime
of medical treatment is essential for acceptance into a
transplant program. Inability or unwillingness to comply
with long-term medical care precludes further consideration for transplantation. This aspect of the selection
process may be subjective and may be the focal point of
disagreement among physicians. Although an adequate
psychological instrument to test compliance has not
been universally accepted, compliance with a rigorous
treatment regimen for congestive heart failure may be
objective evidence of the patient's suitability for transplantation. It is also important that the patient, or in the
case of a child the parents or guardians, have the
intellectual skills necessary to cope with multidrug
therapy, frequent heart biopsies, and long-term medical
care. It is crucial to ascertain that the candidate is not
actively abusing drugs or alcohol. Postoperative recidivism in patients with a history of drug or alcohol abuse
may be a problem.39'40 However, data on this possibility
are limited and the decision must be made on an
individual basis.
In assessing a patient's candidacy, financial resources
must be evaluated. Most third-party carriers and government programs will pay for cardiac transplantation
for eligible patients.41 Nevertheless, the cost of medical
care and the patient's subsequent need for social support may still be formidable and review of finances
should be part of the preoperative evaluation.
Infants and Children as Transplant Recipients
There are two major categories of potential transplant recipients: patients with complex forms of congenital heart defects, and patients with dilated cardiomyopathy. Hypoplastic left heart syndrome is the most
common complex congenital heart defect for which
cardiac transplantation is a potentially useful treatment
in the neonate. In this condition the left ventricle and
ascending aorta are too small to support normal systemic blood flow. The three major strategies for initial
treatment of infants with hypoplastic left heart syndrome are supportive treatment with anticipation of
death, the Norwood procedure, and cardiac transplantation. It is unclear which is best. Until sufficient mid- to
long-term data are available, it is reasonable to offer
cardiac transplantation to these patients as a treatment
option.
Patients with other complex congenital cardiac or
end-stage defects that are not amenable to conventional
surgical repair or palliation may be acceptable candidates for cardiac transplantation. In general, the end
stage of congenital heart defects results from severe
ventricular failure. The guidelines for defining the end
stage are similar to those listed below for dilated
cardiomyopathy.
Cardiac transplantation is a reasonable treatment for
infants, children, and adolescents with end-stage dilated
cardiomyopathy. Unfortunately, the natural history of
dilated cardiomyopathy is not well defined for this age
group. This uncertainty is highlighted by a reported
range of 6-year survival from 20% to 84%.42-45
It is difficult to know when cardiac disease has
become end-stage and hence to know the optimum time
for cardiac transplantation. Though no guidelines are
absolute, the following can be helpful in identifying
end-stage cardiac disease:
1. Progressive deterioration of ventricular function
or functional status despite optimal medical care, including treatment with digitalis, diuretics, and angiotensin converting enzyme inhibitors
2. Growth failure secondary to severe congestive
heart failure unresponsive to conventional medical
treatment
3. Malignant arrhythmias, or survival of cardiac arrest, unresponsive to conventional medical treatment
and not likely to be successfully treated with an automatic implantable cardioverter/defibrillator
4. Need for ongoing intravenous inotropic support
5. Unacceptably poor quality of life
6. Progressive pulmonary hypertension that would
preclude transplantation at a later date
Patients with congenital cardiac defects in which both
ventricles are present are candidates for conventional
reparative operations even when their levels of pulmonary vascular resistance are higher than that considered
acceptable for low-risk cardiac transplantation. The
most definitive conventional repair for patients with
only one useful ventricle (i.e., tricuspid atresia and all
variants of univentricular heart) is the modified Fontan
operation. Pulmonary vascular resistance must be less
than 4 u m2 for a successful modified Fontan operation.
Whether cardiac transplantation should be offered to a
patient with tricuspid atresia or univentricular heart
whose pulmonary vascular resistance is greater than 4
u m2 but still within an acceptable range for cardiac
transplantation is problematic, because the natural history of these patients and the ultimate morbidity and
mortality for cardiac transplantation in children has not
been fully defined.
Infants, children, and adolescents have additional
unique psychosocial needs.., Adolescents in particular
may rebel against the strict regimen required after
cardiac transplantation. A parent or guardian may be
the primary care giver for an infant or child, so the
social, emotional, intellectual, and financial stability of
the care provider must be assessed in the preoperative
and postoperative periods. While a child should not be
deprived of the potential benefit of cardiac transplantation because of a situation beyond his or her control,
a precious donor organ should not be squandered if
failure is inevitable because of an adverse psychosocial
situation.
AHA Scientific Council Cardiac Transplantation
Strategies of Prioritization for Patient Selection and
Donor Allocation
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The availability of transplantable organs is limited.
The subjective and interdisciplinary nature of the process of patient selection mandates a committee structure to facilitate fair and equitable consideration. The
committees at most transplant centers include transplant surgeons, cardiologists, coordinators, social workers, and experts in relevant medical and ancillary
disciplines.
In the United States, all patients awaiting heart
transplantation are listed on the computerized system
maintained by UNOS. Donor hearts are initially offered
to compatible recipients on the waiting lists at local
institutions. If a local recipient is not identified, the
organ is then offered to candidates at more distant
locations on the basis of severity of illness.
Many systems for fair, equitable prioritization of
transplant candidates on the waiting list have been used.
In the United States, UNOS mandates recipient prioritization based on time on the waiting list and two
classes of clinical severity. UNOS status 1 (high priority) is given to potential recipients who are intensivecare bound and require intravenous inotropes or mechanical circulatory assistance. Status 2 designates all
other recipients. This system requires continual reevaluation since patient status may change or the patient
may be removed from the active waiting list if his or her
condition improves. Although aspects of this system are
now arbitrary, future donor organ allocation may be
based on more objective determinants of successful
outcome.
The Cardiac Organ Donor
Ethical and Legal Concerns
Unlike bone, cornea, and skin, which may be harvested after circulatory arrest, solid vascularized organs
such as the heart must be harvested while still functioning after brain death is declared. In the United States,
criteria for brain death specify that death may only be
declared when all brain functions cease according to
reasonable medical standards (Table 2).4748 Variations
of the Uniform Anatomical Gift Act of 1968 establishing the framework for the consent for anatomical donations after death were passed in all states by 1972.47
Persons 18 years old or older may specify their preference about donating organs. In the absence of specific
objection from the potential donor, the next of kin may
consent to organ donation. The right to insist on organ
donation from a consenting individual, despite objections from the next of kin, was proposed in 1987 and
adopted in a few states.47 However, organ recovery
teams avoid creating such conflicts because of possible
negative influences on future organ donations.
Since 1986 hospitals receiving Medicare and Medicaid funds are required to establish protocols for documentation of donor status after all deaths. "Required
request" legislation, which mandates that hospitals offer
the option of organ donation to next of kin at the time
of brain death, has been adopted in most states.49
Presumed consent, whereby a brain-dead person is
assumed to be a donor unless the person had specified
otherwise, has been adopted in a few European countries and has substantially increased the number of
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TABLE 2. Brain Death Criteria
No cortex function
Cerebral unreceptivity and unresponsiveness
Absence of brainstem function
No pupillary reflex
No corneal reflex
No extraoccular reflex
No gag reflex
No cough reflex
No spontaneous respirations (apnea test)
Irreversibility
Etiology of central nervous system catastrophe known
No hypothermia, drug intoxication or shock
Persistance over time*
6 hours with confirmatory tests
12 hours without confirmatory tests
24 hours in anoxic brain injury
Ancillary confirmatory tests (not required)
Electroencephalogram
Radionuclide imaging
Cerebral angiography
*For adults. Observation period for infants aged 7 days to 2
months is 48 hours and for those aged 2 months to 1 year is 24
hours; observation period for children aged 1-5 years is 12 hours.
organs transplanted. In general, however, recovery
teams in these countries do not harvest organs if there
are strong objections from the next of kin.
In most cases, the declaration of brain death is made
by the patient's attending physician, and options for
disposition of the patient's remains, including organ
donation, are presented to the family if they are available. A trained member of an organ procurement
organization (OPO)* should explain the organ donation
option to the family and obtain consent.50 If next of kin
are not available, appropriate hospital or government
personnel may authorize organ donation. Questions
about a person's suitability as an organ donor or
whether brain death criteria have been met should be
referred to the regional OPO.
Donor Availability
Surveys in the United States have documented a
gradual increase in both donor awareness and willingness to donate one's or a relative's organs.51 Despite this
changing attitude, families frequently do not consider
organ donation and occasionally refuse to donate the
heart because of religious or cultural beliefs or inadequate knowledge of transplantation. It is estimated that
only 10-20% of brain-dead patients with suitable hearts
become actual donors.50 The failure of medical professionals to pursue organ donation with a brain-dead
patient's next of kin remains a major obstacle to transplantation.52 While the number of cadaveric donors has
increased significantly since 1985, the number of cardiac
transplants has peaked and leveled off at approximately
2,000 per year in the United States.' The lack of cardiac
*Local and regional organ procurement organizations are responsible for donor management and organ procurement and
distribution. All OPOs in the United States are members of and
agree to abide by the rules of UNOS.
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donors remains a major problem. On April 30, 1992,
2,486 people were on heart transplant waiting lists in the
United States.53 The donor shortage is grimly illustrated
by the fact that at major transplant centers in the United
States, 10-40% of patients die while awaiting transplantation.5154 Inadequate organ availability is certain to
remain the major factor limiting the number of cardiac
transplantation procedures performed.55 The number of
donors available per year in the United States has
recently been estimated to be no more than 6,90010,700.56
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Medical Treatment of Donors
Potential cardiac donors are best treated in an intensive care unit, cared for by OPO-provided trained
personnel using continuous hemodynamic monitoring,
because multiple hemodynamic, hormonal, metabolic,
pulmonary, and thermal changes accompany brain
death. After brain death is declared, efforts should be
shifted immediately from minimizing brain injury to
maximizing perfusion and performance of transplantable organs.52,57-61
The hemodynamic alterations that accompany brain
death may include early transient severe hypertension
and tachycardia due to excessive sympathetic tone. This
hyperdynamic state is best treated by afterload reduction (using a vasodilator such as intravenous nitroprusside) and reduction of heart rate with a short-acting
13-blocker (i.e., esmolol). A loss of vasomotor tone and
resultant hypertension usually follow, typically exacerbated by inadequate intravascular volume due to traumatic blood loss, diabetes insipidus (see below), and
therapeutic interventions before brain death. Hypotension is initially treated with fluid replacement to maintain central venous pressure between 8 mm Hg and 12
mm Hg. If volume replacement fails to restore the
systemic systolic blood pressure to 100 mm Hg, dopamine should be administered at less than 10 gg/kg per
minute.60,61 Phenylephrine may also be used to maintain
systemic vasomotor tone. Prolonged high doses of catecholamines should be avoided because early cardiac
allograft dysfunction with decreased blood flow to the
kidneys and liver may result.61,62
Central diabetes insipidus occurs in 38-87% of braindead patients and may induce massive diuresis.61 Adequate but not excessive crystalloid fluid replacement
and correction of electrolyte abnormalities are needed
to maintain blood pressure and avoid cardiac arrhythmias. Fluid replacement should be monitored carefully
by determination of pulmonary capillary wedge pressure to ensure adequate hydration; overhydration may
result in sudden cardiac chamber distention and pulmonary edema that may render the organ unsuitable for
transplantation, and cardiac chamber overdistention
may contribute to early allograft dysfunction after transplantation. Low-dose continuous vasopressin infusion
will reduce the urine output to 100-300 ml/hr, but bolus
or high-dose continuous infusion should be avoided
because of the severe vasoconstriction that may result,
causing increased afterload and decreased cardiac output. Vasoconstriction also directly affects the renal and
splanchnic vasculature, potentially damaging transplantable organs.
Clinical and experimental evidence suggest that abnormalities in thyroid function occurring at brain death
may contribute to donor heart dysfunction.52 Controlled
studies of the use of triiodothyronine in the cardiac
organ donor and recipient are in progress. Other metabolic abnormalities associated with brain death include
hypernatremia, hypokalemia, and hypomagnesemia,
electrolyte abnormalities related to diabetes insipidus.
Mechanical hyperventilation used to lessen cerebral
edema often leads to severe hypophosphatemia.63 Volume and crystalloid replacement, adjusted for these
abnormalities, should be given with frequent serum
electrolyte measurements.
Brain death is accompanied by thermoregulatory
abnormalities. Initial hyperthermia followed by hypothermia is often observed. Fever may be mistaken for a
sign of systemic infection. Hypothermia may be aggravated by unwarmed fluid replacement and may lead to
cardiac arrhythmias and decreased cardiac output. In
general, a body temperature below 35°C should be
corrected by heating blankets.
Pulmonary dysfunction after brain death may be
aggravated by underlying lung trauma, infection, aspiration pneumonia, atelectasis, and neurogenic pulmonary edema. These problems should be prevented or
treated and the lungs should be considered for
donation.
Medical Evaluation of Donor
An evaluation of the cardiac donor must be performed (Table 3). Echocardiography may be used to
evaluate left and right ventricular function, and coronary angiography may be required to rule out obstructive disease suspected because of the donor's age or
atherosclerosis risk factor profile. Invasive hemodynamic monitoring allows serial assessment of cardiac
output and volume status. Positive serologies for hepatitis B surface antigen and human immunodeficiency
virus remain absolute contraindications for donation to
serologically negative recipients. Hepatitis C titers
should not necessarily exclude donation. Other viral
serologies and blood typing are performed to help
match the donor heart with a compatible recipient.5052,5461 Although not currently feasible, HLA typing may be useful in assessing compatibility of the donor
and recipient.
Donor Selection Criteria and
Donor-Recipient Matching
There are several suggested cardiac donor criteria for
cardiac transplantation (Table 4). Donor organ allocation is also based on ABO blood group compatibility,
donor-recipient weight match, severity of recipient
illness, and waiting time.54
Preformed anti-human lymphocyte antigen IgG antibodies with donor specificity may cause potentially fatal
hyperacute rejection. Before transplantation the potential recipient is screened for circulating antibodies to
various human lymphocyte antigens with a panel of
blood cells representing diverse human lymphocyte antigen specifications (percent, or panel, reactive antibody
[PRA]). Exposure to foreign HLA antigens, due to
previous blood transfusions or pregnancy, results in
higher probability of a reactive PRA. If the PRA is
greater than 5-15%, most cardiac transplant centers
require a negative prospective crossmatch between donor and recipient sera.54 63, The requirement for a
AHA Scientific Council Cardiac Transplantation
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TABLE 3. Cardiac Donor Evaluation
Cardiology or Internal Medicine Consultant Evaluation
Past medical history (obtained from family and/or medical records) specifically cardiac disease history, risk factors for early coronary
artery disease, and evidence of systemic illness such as infection, diabetes mellitus, or malignancy
Physical examination, especially thorax inspection and palpation and cardiovascular auscultation; weight should be determined
Electrocardiogram (pathological Q waves or arrhythmias, ST changes may be present secondary to brain death)
Chest x-ray (for cardiac size or evidence of congenital heart disease or trauma)
Central venous pressure (preferably invasive direct measurement); Swan-Ganz catheter placement to aid in donor management or
cardiac output determination; ongoing inotropic support should be considered when evaluating cardiac function
Echocardiography (if possible) to evaluate for unsuspected congenital heart disease or cardiac trauma and for ventricular function
evaluation
Coronary arteriography may be requested if donor is likely to have coronary artery disease (older age, risk factors by history)
Organ Procurement Organization Coordinator Evaluation
Confirm or obtain consent for organ donation, confirm declaration of brain death
Review, and assist in obtaining, past medical history; review and confirm physical examination findings (document age, height, weight,
cause of injury or death, any extracranial injuries, length of hospitalization, hemodynamic support, infection status, urine output,
condition of other organs)
Obtain and review social history (including tobacco, alcohol, or drug use; assess risk factors for human immunodeficiency virus
infection)
Obtain and review laboratory evaluation (ABO blood type, histocompatibility leukocyte antigen type, arterial blood gases, rapid
plasma reagin, serologies for human immunodeficiency virus, cytomegalovirus, hepatitis A, B, and C, Toxoplasma gondii, herpes
simplex)
prospective crossmatch, which delays organ harvesting,
at many cardiac transplant centers.66'69 However, early
markedly prolong a recipient's waiting time.54
Data for donor-recipient weight matching are limited. It has been suggested that oversizing of donor
hearts, compared with recipient's hearts, may actually
have a negative effect on survival, and that a donor-torecipient weight ratio as low as 0.5 does not negatively
affect survival.65 Additional issues in donor-recipient
matching include recipient heart size, and therefore the
size of the pericardial space; conditions indicating scar
tissue and adhesions, such as prior sternotomy or radiation therapy to the thorax; and the prolonged use of
intrathoracic ventricular support devices.
To increase the cardiac donor pool, the criteria for
acceptability has been expanded at many centers. The
use of organs from older donors has specifically been
advocated.66-70 In one institution, short-term survival
did not seem to be affected by transplantation of older
donors' hearts with simple analysis of variance.70 However, a multicenter multivariate analysis of data from
911 patients identified older donor age as a risk factor
for death after cardiac transplantation when donor age
was analyzed as a continuous variable.31 Extending
allograft ischemic time (time from procurement to
reperfusion of the heart in the recipient) to more than
4 hours has been attempted under special circumstances
allograft function and survival is significantly poorer
when ischemic times are more than 4-5 hours.31
may
Cardiac Size Matching in Pediatric
Cardiac Transplantation
The selection of a donor heart of appropriate size is
particularly important in pediatric patients, who range
in size from that of a newborn to that of an adult-sized
adolescent. Although there is not uniform agreement
about size matching, the following guidelines may be
helpful.
The limiting factor for use of an oversized donor
heart is the heart size the recipient's chest will accommodate. There are few data to indicate that an oversized donor heart will adversely affect outcome in the
pediatric population. For infant recipients, the body
weight of the donor should be no more than three times
the body weight of the recipient. For recipients more
than 18 months old, the body weight of the donor should
be no more than 25-50% of the recipient's weight.
In general, a heart from a donor who weighs less than
the recipient should not be used. For children and
adolescents the donor's body weight should be no less
than 75% of the recipient's weight. The transplanted
heart will grow with the recipient.71
TABLE 4. Suggested Criteria for Cardiac Donors and Guidelines for Recipient Matching
Age less than 40 years (may be extended by certain centers under certain circumstances)
Negative serologies for human immunodeficiency virus and hepatitis B
No active severe infection or malignancy with possibility of metastases (i.e., most extracranial malignancies disqualify person as donor)
No evidence of significant cardiac disease or trauma
Very low probability of coronary artery disease (coronary angiograms may be required to ascertain its absence)
Normal or acceptable ventricular function after intravascular volume normalization; dopamine less than 10 mcg/kg per minute
Blood type (ABO) compatibility with recipient
Donor body weight usually between 80% and 120% of recipient's body weight
If required (see text), negative prospective cytotoxic T cell crossmatch. A retrospective crossmatch is performed in most centers
Anticipated allograft ischemic time less than 4-5 hours
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Organ Retrieval and Transport
Several organs are now procured from most donors,
requiring cooperation and timing among the heart,
kidney, liver, pancreas, and lung procurement teams.
Coordination of these activities is the responsibility of
the OPO. The final acceptance of a donor heart is made
after physical inspection of the heart by the procuring
surgeon. Precise heart dissection, rapid cardioplegia
administration, cardiectomy, and placement of the
heart in a cold transport container requires an experienced and knowledgeable heart procurement team. In
certain circumstances multiorgan procurement can be
safely performed after the donor has been placed on
cardiopulmonary bypass. Rapid ground and air transport must be prearranged by the OPO. Occasionally, the
procurement is performed by a team from one medical
center and the heart is then transported by OPO
coordinators to another center for implantation. Unlike
kidneys, hearts cannot be kept viable on a perfusion
device that would allow delayed implantation. Transplantation is timed to synchronize cardiectomy with
arrival of the donor organ.5052,72
Postoperative and Long-term Medical Follow-up
Expert long-term management is essential for a successful outcome. Patients must accept a lifelong commitment to medical care, because complications may
occur at any time. In addition, patients must assume an
active role in their health care by learning to monitor
vital signs, recognize and promptly report symptoms of
rejection and infection, and make appropriate changes
in medications upon instructions from the physician.
Cardiologists dedicated to transplantation must be
knowledgeable in immunology and infectious diseases,
areas that traditionally are not included in subspecialty
training in cardiovascular disease. Because complications after heart transplantation involve multiple-organ
systems, medical care requires a multidisciplinary approach with the input of specialists in the areas of
infectious disease, nephrology, gastroenterology, neurology, endocrinology, pulmonology, gynecology, oncology, pathology, social work, and nursing.
After heart transplantation cardiovascular physiology
is affected by denervation, donor-recipient size mismatch, rejection, and immunosuppression. Allograft
rejection remains the major life-threatening complication, yet immunosuppression is the major source of
morbidity. Therefore, the follow-up of heart transplant
recipients must be focused on evaluation of heart
allograft function, rejection surveillance, management
of immunosuppression, and diagnosis and treatment of
immunosuppression-induced adverse effects.
Evaluation and Management of
Heart Allograft Function
Effective management requires a working knowledge
of the unique physiological responses to transplantation, the effects of cardiovascular drugs on the denervated heart, and the effects of rejection on allograft
function. Because the heart is denervated for at least
the first year after transplantation, resting heart rate is
higher than that of an innervated heart and increases
only gradually with exercise.65 7374 Partial or complete
denervation prevents perception of cardiac ischemic
TABLE 5. Effects of Cardiovascular Drugs in the Denervated
Heart
Effects
Drug
No atrioventricular nodal effect
Digoxin
No chronotropic effect
Atropine
No vagolytic effect
Quinidine
No reflex tachycardia
Nifedipine
No reflex tachycardia
Hydralazine
pain in most patients, so the diagnosis of cardiac
allograft vasculopathy depends on surveillance coronary angiography. Knowledge of the physiology of
denervation is essential to understanding of the effects
of commonly used cardiovascular drugs on heart transplant recipients (Table 5). Drugs with a direct effect on
the atrioventricular node, such as verapamil and
,B-blockers, may be used to treat supraventricular arrhythmias; adenosine, though effective, should be used
at a much lower dose because the denervated human
heart is supersensitive to the effects of adenosine.75
Drugs that act indirectly via autonomic stimulation are
not generally effective in these patients.
Restrictive hemodynamics detected in some patients
are attributed to rejection, cyclosporine, and donorrecipient weight mismatch.76 Pericardial effusion is common early after transplant but a late effusion suggests
rejection.
Heart Allograft Rejection
Acute rejection. The clinical manifestations of acute
rejection are highly variable. Rejection is usually detected by routine outpatient surveillance endomyocardial biopsy before the appearance of any symptoms.
Occasionally, however, acute rejection produces malaise, reduced exercise tolerance, low-grade fever, or
reduction in blood pressure. The physical examination
may reveal increased jugular venous pressure and the
appearance of a third heart sound. Even with close
follow-up acute rejection may, rarely, appear to be
severe cardiac dysfunction or shock. Supraventricular
arrhythmias may also be a manifestation of rejection.
Acute rejection is more common in occasionally noncompliant patients who consider themselves cured and
discontinue or reduce immunosuppressive therapy. Although noninvasive techniques for diagnosis of rejection
have been proposed, endomyocardial biopsy remains
the procedure of choice in patients older than 6 months
or heavier than 5 kg. Typically, endomyocardial biopsy is
performed weekly for the first 4-8 weeks after transplantation. Endomyocardial biopsy frequency is reduced progressively over subsequent months to 3-4
times per year. If acute rejection is detected, endomyocardial biopsy is usually repeated within 2 weeks.
The indication and timing of endomyocardial biopsy
in infants differs from that of adults, children, or
adolescents. For children younger than 6 months or
smaller than 5 kg, myocardial biopsies are performed
only selectively because of the morbidity associated with
the procedure. Use of this technique is based on the
need to confirm noninvasive indications of possible
cardiac rejection.29
The diagnosis of rejection is made by histologic
changes observed on endomyocardial biopsy samples.
AII4 Scientific Council Cardiac Transplantation
TABLE 6. Standardized Cardiac Biopsy Grading
Grade
New nomenclature
No rejection
0
1
A, focal (perivascular) or infiltrate without necrosis
B, diffuse but sparse infiltrate without necrosis
2
One focus only with aggressive infiltration or focal myocyte damage
3
A, multifocal aggressive infiltrates or myocyte damage
B, diffuse inflammatory process with necrosis
4
Diffuse aggressive polymorphous infiltrate, with necrosis, with or
without edema, hemorrhage, or vasculitis
From Billingham et al.77
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The optimal frequency of biopsy sampling is unknown.
A standardized endomyocardial biopsy rejection grading system has recently been established by the International Society for Heart and Lung Transplantation
(Table 6).77 Mild rejection characterized by a mononuclear inflammatory infiltrate without myocyte necrosis
often reverses spontaneously in patients given therapeutic doses of corticosteroids, cyclosporine, and azathioprine. In some centers mild rejection either remains
untreated, especially if the transplantation was long ago
and the patient is clinically stable, or is treated only if
persistent or progressive. In other transplant centers
mild rejection is treated with an increased dosage of
cyclosporine or oral prednisone. If myocyte necrosis
(indicating moderate or severe rejection) accompanies
mononuclear cell infiltration, immunosuppression is
generally intensified by administration of high-dose oral
or intravenous corticosteroids and/or antilymphocyte
antibodies.78,79 Because rejection indicates the failure of
maintenance immunosuppression to prevent activation
of the immune effector cells that produce allograft
injury, clinicians should always attempt to identify
possible precipitating factors. These may include noncompliance, a fall in cyclosporine levels due to excessive
dose reduction or drug interaction, discontinuation of
azathioprine because of leukopenia, or reduction in
immunosuppression necessitated by infection. In many
or most instances, however, no precipitating factor is
readily apparent.
Cardiac allograft vasculopathy. Cardiac allograft vasculopathy, a unique form of coronary artery disease, is
the major factor limiting long-term survival of heart
transplant recipients.3' The prevalence of this complication is approximately 10-15% by 1 year, 15-25% by 2
years, and 35-50% by 5 years after transplantation.80-82
Although the immunopathogenesis of cardiac allograft
vasculopathy remains largely unknown, evidence suggests that the lesion results from an immune-mediated
injury.80,83-85 Conventional risk factors for atherosclerosis that are also risk factors for cardiac allograft vasculopathy include older (donor) age and hyperlipidemia.86
Differences in immunosuppressive protocols, such as
the use or avoidance of immunosuppressive prophylaxis,
anti-T cell antibody type (monoclonal or polyclonal),
long-term use of or withdrawal from corticosteroids,
have not been shown to affect the incidence and severity
of cardiac allograft vasculopathy.82
There are many important differences between cardiac allograft vasculopathy and coronary atherosclerosis
in the nontransplanted heart. Cardiac allograft vasculopathy is usually diffuse, involving epicardial, myocar-
1069
Old nomenclature
No rejection
Mild rejection
Focal moderate rejection
Low moderate rejection
Borderline/severe
Severe acute rejection
dial, and microscopic vessels. Its most striking histological features are intimal proliferation, mononuclear cell
infiltration, and presence of lipid-laden macrophages
throughout the vessel wall.86 These abnormalities may
be detected, though rarely, on endomyocardial biopsy
samples.87
Cardiac allograft vasculopathy is usually not suspected clinically since patients may not experience
angina because of heart denervation. Its first manifestation may be congestive heart failure or sudden death
due to ischemia or infarction. Noninvasive screening
tests such as exercise electrocardiography, thallium scintigraphy, exercise radionuclide ventriculography, and
ambulatory electrocardiography are sometimes helpful
in making a diagnosis, but generally are not sensitive or
specific enough to be considered reliable screening
tests.88 Coronary angiography is the only technique for
establishing the diagnosis of cardiac allograft vasculopathy and should be performed when cardiac symptoms
occur in the absence of histopathological evidence of
rejection. Use of coronary angiography may lead to
underestimation of the severity of cardiac allograft
vasculopathy because of diffuse and concentric luminal
narrowing89; severe cardiac allograft vasculopathy has
been found at autopsy in patients whose coronary
angiography, performed shortly before death,89 was
normal. Intracoronary ultrasound may improve the sensitivity of diagnostic techniques, but the utility and
safety of this technique remains to be defined. Baseline
and follow-up angiography is used in most centers to
guide therapy.
The efficacy of measures to prevent cardiac allograft
vasculopathy, including anticoagulation therapy, administration of antiplatelet agents, weight reduction, and
low-fat, low-cholesterol diets is unestablished.90 A preliminary analysis of an ongoing trial suggests the calcium-channel blocker diltiazem may be of prophylactic
value.91 For cases of established cardiac allograft vasculopathy retransplantation is common but is associated
with a significantly lower 1-year survival than the first
heart transplant (55% comnpared with >80%).92 Coronary angioplasty may be used to treat patients if discrete lesions of the proximal coronary arteries are
present.89,93 Coronary artery bypass grafting has been
used but is generally avoided due to the diffuse nature
(often undetected by coronary angiograms) of cardiac
allograft vasculopathy.94 Medical therapy for established cardiac allograft vasculopathy is empiric and
should be directed at preventing ischemia. The lack of
effective prophylaxis or therapy is the rationale for an
ongoing broad-based research effort.
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Immunosuppression
Insufficient immunosuppression may result in rejection that threatens allograft and patient survival, and
excessive immunosuppression increases the risk of
infection and malignancy. The variability of patients'
responses, due to individual characteristics, multiple
environmental influences, drug-induced complications, drug interactions, and patient compliance, calls
for constant monitoring and adjustments of the immunosuppressive regimen. In addition, conditions such as
acute infection, malnutrition, and surgical complications may require a reduction in the immunosuppression regimen. Not all adverse effects of immunosuppression should prompt dosage reduction, because
maintenance of adequate immunosuppression is crucial to long-term allograft and patient survival. Immunological maturation and senescence can positively or
negatively affect the amount of immunosuppression
required. Females reject transplanted organs more
frequently than do males and thus require more
intensive immunosuppression.95 Immunosuppression
in growing children should be designed to minimize
adverse affects on growth.
Immunosuppressive Drugs
Azathioprine. Azathioprine, a purine antimetabolite
converted in the liver to 6-mercaptopurine, is a potent
but nonspecific immunosuppressive agent that inhibits
lymphocyte proliferation.96 The dose of azathioprine
must be adjusted according to changes in patient weight,
and decreased if severe leukopenia, anemia, or thrombocytopenia occur.9798 Mild leukopenia (<4,000 white
blood cells/mm3) and anemia do not warrant changes in
azathioprine dose. High-dose trimethoprim-sulfamethoxazole increases the risk of thrombocytopenia in azathioprine-treated patients. Because the enzyme xanthine oxidase controls 6-mercaptopurine levels, to avoid
excessive bone marrow toxicity, azathioprine dosage
must be reduced by as much as 75% when allopurinol is
used.98
Corticosteroids. Corticosteroids inhibit gene transcription for cytokines, which affect nearly all immune responses.99 While the basic strategy is the same among
heart transplant centers, corticosteroid dose protocols
vary significantly. Most centers use high-dose methylprednisolone intravenously in the immediate perioperative period. Subsequently, prednisone administration
is initiated, and its dose is tapered. Withdrawal of
corticosteroids has successfully reduced long-term adverse effects in some heart transplant programs.'00 It
must be remembered that diabetics, children, and older
patients are more susceptible to the adverse effects of
corticosteroids and corticosteroid doses in these patients should be reduced more rapidly.
Cyclosporine. Cyclosporine is a cyclic endecapeptide
that inhibits immune responses by inhibiting T cell
lymphokine production.'01 Patients may receive cyclosporine perioperatively, and doses are adjusted frequently to maintain target plasma or whole blood levels
and avoid toxicity. Because of variability in dose requirement, precise manipulation of cyclosporine dosage
is required for maintenance of a target blood level.101"102
The absorption of this highly lipophilic drug is affected
by the fat content of meals and the release of bile acids
into the proximal jejunum.101 Thus, abnormalities in
gastrointestinal function caused by previous surgery,
diabetic enteropathy, ileus, malabsorption, or viral gastroenteritis may dramatically decrease drug absorption.
Plasma or serum levels of cyclosporine must be measured frequently and dosage altered appropriately.
Drug interactions with cyclosporine are common and
some drugs should be avoided if possible (Table 7).
Cyclosporine levels must be measured frequently when
new drugs are added to the treatment regimen. The
inhibition of cyclosporine metabolism by drugs such as
ketoconazole and diltiazem reduce cyclosporine dose
requirement and cost. If cyclosporine levels change
abruptly, the possible causes that must be considered
and carefully excluded include drug interactions, laboratory error, altered absorption, noncompliance, or an
intercurrent illness such as hepatitis or gastroenteritis.
If severe diarrhea or vomiting occurs and lasts for more
than 36-48 hours, an empiric dose increase or the use of
intravenous cyclosporine is warranted. The intravenous
dose, administered as a continuous infusion, is usually
one fourth to one third the oral dose.10y
The determination of cyclosporine levels is also difficult because of the use of several different assays, which
produce widely differing results.105-'08 Therefore, physicians caring for patients taking cyclosporine must know
which assay was used to correctly interpret the meaning
of the assay results and make appropriate dose changes.
Cyclosporine can have adverse effects (Table 8).
The effect of immunoprophylaxis, by routine administration of antilymphocyte preparations or monoclonal
antibodies early after transplant, on the required dose of
maintenance immunosuppressants, and thus on morbidity due to them, is not yet resolved. Clinical trials of
immunosuppression with FK506, mycophenolate mofetil
(RS-61443), and photopheresis have been started. These
agents may be incorporated into maintenance immunosuppression protocols within this decade and consequently, the morbidity of conventional immunosuppression will be reduced or eliminated by substitution of the
causative agent by a less toxic immunosuppressant.
Complications Related to Immunosuppression
Infection. The Registry of the International Society of
Heart Transplantation reports that infection is the most
common cause of postoperative death.' A multicenter
study of 24 very active transplant centers recently found
that infection was the major cause of perioperative and
postoperative mortality after cardiac transplantation. In
this study of 814 patients, during a mean follow-up of
8.1 months, 409 serious infections occurred, of which
46% were bacterial, 40% were viral, 7% were fungal,
and 5% were protozoal.109 Perioperative bacterial infections such as mediastinitis, pneumonia, urinary tract
infections, and intravenous catheter-induced sepsis are
treated conventionally.1"0"'11 Opportunistic infections
transmitted by the donor organ and blood products may
result from reactivation of latent viruses or may be
caused by air-, water-, or feces-borne organisms.1"2
HERPES VIRUSES. Cytomegalovirus, a member of the
herpesvirus group, is the infection most commonly
transmitted by the donor heart. Fifty percent to 80% of
adults have detectable IgG antibodies to cytomegalovirus. Transmission of cytomegalovirus from a cytomegalovirus-seropositive donor heart to a cytomegalovirus-
AISA Scientific Council Cardiac Transplantation
TABLE 7. Cyclosporine Drug Interactions
Drugs that increase cyclosporine levels
cimetidine
ciprofloxacin
diltiazem
erythromycin
ketoconazole
metoclopramide
nicardipine
ranitidine
verapamil
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seronegative recipient is common. Measures to prevent
transmission by blood products should be taken in all
patients. The illness caused by a primary cytomegalovirus infection is usually more severe than that caused by
endogenous reactivation."1 The clinical manifestations
of cytomegalovirus infection are highly variable. The
infection usually occurs 4-12 weeks after transplantation. It may be asymptomatic and manifested only by a
fourfold rise in antibody titer or be manifested as a
febrile illness, with positive blood or urine cultures.
Localization to the lungs (pneumonia with fever and
hypoxia), gastrointestinal tract (ulcerative disease), liver
(hepatitis), heart (myocarditis), or eye (chorioretinitis,
papillitis) may cause a lifethreatening or sight-threatening illness.114-16 When organ localization is suspected,
demonstration of cytomegalovirus nuclear inclusions
should be aggressively pursued with bronchoscopy and
bronchoalveolar lavage and, when appropriate, with
transbronchial biopsy, endoscopy, and gastric, liver, and
myocardial biopsies. Invasive cytomegalovirus infection
can be successfully treated with ganciclovir, a guanine
analogue that prevents viral replication by inhibiting
virus-induced DNA polymerase.117"18 In life-threatening illness, the therapeutic efficacy of ganciclovir is
increased by the administration of cytomegalovirusspecific hyperimmune or pooled immunoglobulins.119"120
Prophylactic cytomegalovirus immunoglobulins, highdose oral acyclovir (800-3,200 mg daily), and, more
TABLE 8. Adverse Effects of Cyclosporine
Hypertension
Sodium retention
Hyperkalemia
Renal tubular acidosis
Renal dysfunction
Hepatic dysfunction
Seizures
Tremor
Paresthesia
Anxiety
Insomnia
Conjunctivitis
Gingival hypertrophy
Hypertrichosis
Malignancy
1071
Drugs that lower cyclosporine levels
cholestyramine
diltiazem
ethambutol
ethanol
isoniazid
nafcillin
ocreotide
phenobarbital
phenytoin
rifampin
sulfamethoxazole
recently, ganciclovir have reduced the perioperative risk
of cytomegalovirus infection.'21-'23 Prophylaxis is often
used in centers where cytomegalovirus morbidity is
prevalent.
Reactivation of herpes simplex or zoster, a bothersome but usually not life-threatening problem, may be
prevented with oral low-dose acyclovir and treated with
oral or intravenous acyclovir.124
ToxoPL4ASMA GONDII. The incubation period, latency,
and pathogenesis of Toxoplasma gondii infections are
similar to those of cytomegalovirus.125 Common manifestations of the primary infection, usually more severe
than illness due to reactivation, include encephalitis,
myocarditis, and pneumonitis. When Toxoplasma gondii
infection is suspected, endomyocardial biopsy findings
of inflammation and necrosis should prompt careful
search for cysts.126 Central nervous system involvement
is frequent, so a lumbar puncture should be included in
the diagnostic evaluation.
Infection with Toxoplasmosis gondii is treated and
prevented by pyrimethamine and sulfadiazine, or clindamycin in patients allergic to sulfonamides.127128 Prophylaxis is recommended when a seropositive donor
organ is transplanted into a seronegative recipient.
PNEUMOCYSTIS CARINI. Pneumocystis carinii a protozoal infection, should be suspected in heart transplant
recipients who have fever, dyspnea, profound hypoxemia, and radiographic evidence of diffuse pulmonary
infiltrates.'29"130 Early diagnosis of Pneumocystis carinii
pneumonia with methenarnine silver stain of bronchial
secretions or lavage specimens and aggressive treatment
is lifesaving. Ventilatory assistance and hyperalimentation should be initiated early in patients with severe
disease. Specific treatment is high-dose trimethoprim
and sulfamethoxazole for at least 4 weeks. Because
cytomegalovirus pneumonia often occurs concomitantly
with Pneumocystis carinii, cytomegalovirus infection
should be suspected in patients with Pneumocystis carinii when hypoxemia persists despite institution of the
appropriate antimicrobial therapy.'3' Infection with
Pneumocystis carinii can be prevented by administering
inhaled pentamidine or oral low-dose trimethoprim and
sulfamethoxazole if the frequency of infection in a
transplant center is high.132
OTHER INFECTIONS. Occasionally pneumonia in heart
transplant recipients is due to Legionella pneumophila.33 The diagnosis is easily overlooked unless direct
fluorescent antibody stain of appropriate sampling is
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performed. High-dose intravenous erythromycin is the
treatment of choice. Because this antibiotic sharply
increases plasma cyclosporine levels, the dose of cyclosporine should be decreased appropriately and its
plasma levels determined regularly to prevent drug
toxicity. Fever and meningitis in heart transplant recipients may be caused by Listeria monocytogenes, which
can usually be cured by a 6-week course of high-dose
intravenous ampicillin.134 Mucocutaneous candidiasis is
not uncommon in heart transplant recipients and can be
prevented and treated with clotrimazole or nystatin.135
Solitary or multiple pulmonary nodules in immunosuppressed patients can be due to Nocardia asteroides,
which can also cause retinitis, meningitis, and epididymitis. A prolonged course of sulfa drugs is required for
treatment. Minocycline can be added when Nocardia
asteroides is resistant to sulfisoxazole.136 Debilitated
heart transplant recipients receiving intensified immunosuppression for refractory or recurrent rejection or
who have other opportunistic infections while taking
multiple antibiotics are at higher risk of contracting
aspergillosis. Infection may also occur in immunosuppressed patients exposed to high-density air-borne fungus and particularly to dust generated by construction.
A solitary pulmonary lesion is treatable with antifungal
drugs or surgical excision. Disseminated aspergillosis is
usually fatal. The success of treatment with amphotericin B is limited by renal and bone marrow toxicity;
however, the toxicity of a liposome-encapsulated formulation of amphotericin B is significantly lower than that
of other formulations.137"138 Itraconazole shows promise
as an orally administered treatment for this infection.
Infection will be a frequent postoperative complication after heart transplantation until more specific im-
munosuppressive regimens are developed. Therefore,
fever is one of the most common clinical problems
facing transplant physicians. Because the febrile response is blunted by corticosteroids, even mild elevations of body temperature should not be disregarded
and the etiology of the fever should be aggressively
investigated. A thorough history and physical examination may identify the location of the infection. Whether
or not these are present, a complete blood count with
differential, chest x-ray, and bacterial, viral, and fungal
cultures of blood, urine, and sputum should be performed in dyspneic patients. Unexplained hypoxemia
(greater than 10% reduction in baseline arterial P02) or
a new pulmonary infiltrate must be investigated with
bronchoscopy, bronchoalveolar lavage, and transbronchial biopsy. It is rarely necessary to perform open lung
biopsy to make a definitive diagnosis. The evaluation of
patients with fever and gastrointestinal symptoms
should include endoscopy, with brushing and biopsy for
culture as well as staining to identify CMV inclusions
bodies. Computerized axial tomography and lumbar
puncture should be performed immediately in patients
with neurological abnormalities. Because infections in
immunosuppressed patients may have an insidious onset and become rapidly fatal, the input of pulmonologists, infectious disease specialists, gastroenterologists,
and neurologists is imperative.
Infective endocarditis is a rarely reported complication after cardiac transplantation. Although its efficacy
is not supported by trials, endocarditis prophylaxis is
frequently recommended before dental, upper respira-
genitourinary tract procedures that are likely to cause bacteremia.
Immunizations. After cardiac transplantation, the immunosuppressed recipient should not be given live viral
vaccines, which include MMR (mumps, measles, rubella) and Sabin oral polio vaccines. Diphtheria, pertussis, tetanus, and Salk vaccines do not contain live viruses
and can be administered safely. In addition, pneumococcus and Haemophilus infiuenzae vaccines can be
tory, gastrointestinal, and
administered.29'139
The immunization status of infants and children who
are potential cardiac transplant recipients should be as
up to date as possible. However, two factors may limit the
physician's ability to update the patient's immunization
status. Because it cannot be known exactly when a
patient on an active transplant waiting list will undergo
transplantation, one cannot administer live vaccine to
patients on an active transplant list, because shedding of
live virus can occur for many months after administration
of the vaccine, the period of shedding could potentially
extend into the period of immunosuppression.29"39
Immunologically normal siblings and other household
contacts of immunosuppressed recipients should not
receive oral poliovirus immunization because the virus
is transmissible. However, these siblings and household
contacts can and should receive measles, mumps, and
rubella immunization because transmission of these
viruses does not occur.29'39 Also, these siblings and
other household contacts should receive Salk polio
immunization.139 Immunization of the recipient with
influenza vaccine is controversial.
Hypertension. Most heart transplant recipients develop cyclosporine-induced hypertension. Their highest
daily blood pressures will be in the morning because of
increased salt retention at night.140-44 Morning blood
pressure values should therefore be used to guide
antihypertensive therapy. Cyclosporine-induced hypertension is rarely controlled by diuretics alone. Nifedipine and perhaps the other dihydropyridine calciumchannel blockers are effective and appear to be better
tolerated in the sustained-released preparation, which
is less likely to cause wide fluctuations of blood pressure. Another calcium antagonist, diltiazem, may also
be effective, but it significantly decreases cyclosporine
requirements by increasing plasma levels.145146 Other
calcium antagonists (nicardipine, verapamil), direct vasodilators (hydralazine) and pl-blockers have been used
to treat posttransplant hypertension with variable success. ,l-blockers should be used with caution because
the denervated transplanted heart relies on catecholamines to augment systolic performance, and the negative inotropic effect of these agents may be enhanced in
the allograft. Angiotensin-converting enzyme inhibitors
may also reduce blood pressure in cyclosporine-treated
patients.147 The use of multiple antihypertensive agents
frequently becomes necessary in most transplant recipients for adequate blood pressure control.
Renal Effects. When cyclosporine is administered
perioperatively, renal dysfunction may occur as a result
of cyclosporine-induced renal vasoconstriction superimposed on the effects of chronic renal hypoperfusion
(due to congestive heart failure), third space loss of
albumin and fluids (due to the use of extracorporeal
circulation), and maldistribution of blood flow (due to
anesthetic and inotropic drugs).146 The incidence of
AH4 Scientific Council Cardiac Transplantation
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acute cyclosporine nephrotoxicity may be decreased by
delaying initiation of cyclosporine until 5-7 days after
operation while antilymphocyte preparations are routinely administered or by reducing cyclosporine loading
doses.'48
Chronic cyclosporine nephrotoxicity is characterized
by irreversible interstitial fibrosis.149 Creatinine clearance will be reduced and serum creatinine elevated by 1
year after transplantation in virtually all cyclosporinetreated patients.150 Cyclosporine levels, endomyocardial
biopsy findings, and intensity of adverse effects are
considerations in selecting a cyclosporine dose that
minimizes renal dysfunction but prevents rejection. Cyclosporine nephrotoxicity does not generally progress
after 1 year, partly because cyclosporine serum levels
required to prevent rejection may be reduced.
To minimize chronic nephrotoxicity, cyclosporine
doses should be adjusted when drugs that raise cyclosporine levels are administered. In addition, fluid loss
due to fever, vomiting, or excessive diuresis should be
corrected promptly. Decreases in intravascular volume
are poorly tolerated by the kidneys of cyclosporinetreated patients and may result in a sharp increase in
serum creatinine.
Gastrointestinal Complications. Dysphagia in heart
transplant recipients suggests fungal or viral esophagitis
that is usually due to Candida albicans or Herpes simplex. Endoscopy and biopsy are required for diagnosis.
Herpes esophagitis is treated with intravenous acyclovir;
candida esophagitis is treated with oral nystatin, clotrimazole, or, in severe cases, intravenous amphotericin B.
Epigastric pain, abdominal bloating, and nausea may
result from gastritis or ulceration due to either peptic
ulcer disease induced by stress, corticosteroids and
antiplatelet agents, or cytomegalovirus infection. As in
the case of dysphagia, endoscopy and biopsy are required for diagnosis. Therapy should include H2-receptor blockers, antacids, and sucralfate. If cytomegalovirus
inclusions are demonstrated, a 14-day course of ganciclovir should be instituted. Infection with cytomegalovirus may result in ulcerations of the lower gastrointestinal tract that produce abdominal pain and rectal
bleeding. Another lower gastrointestinal complication is
perforation of preexisting diverticula.'5' Because symptoms and signs may be masked by corticosteroid treatment, this condition may remain unrecognized and
become lifethreatening.
Hepatocellular enzyme abnormalities after heart
transplantation may result from viral hepatitis due to
cytomegalovirus or hepatitis B or from the effects of
drugs such as cyclosporine and azathioprine. Cyclosporine hepatotoxicity is dose-dependent. The activation of
azathioprine, which is converted to 6-mercaptopurine in
the liver, is delayed in patients with hepatitis. Prednisone is converted to its active compound, prednisolone,
in the liver, and substitution should be considered if
liver function is severely impaired.
Corticosteroid therapy may cause or aggravate cholelithiasis. Pancreatitis, which occurs in approximately
10% of heart transplant recipients, may be related to
hypoperfusion, inotropic agents, cytomegalovirus infection, drugs (e.g., corticosteroid, azathioprine, cyclosporine), or cholelithiasis.152
Endocrine and Metabolic Abnormalities. Metabolic
abnormalities after heart transplantation are related
1073
primarily to corticosteroids and cyclosporine. Corticosteroid therapy may worsen glucose intolerance or
induce diabetes mellitus. In insulin-dependent diabetics, higher insulin doses may be needed, and in diabetics
treated with oral agents, insulin may be needed after
transplantation.
Corticosteroids accelerate osteoporosis by increasing
resorption and decreasing formation of bone. Older
patients and postmenopausal women are at highest risk.
Dietary calcium and vitamin D supplementation and
low-dose estrogen therapy are widely used for prevention, but their efficacy has not been established. Corticosteroid therapy may cause aseptic necrosis of hips,
knees, or shoulders. Accurate diagnosis can be made by
magnetic resonance imaging. Symptoms of osteonecrosis may improve with dose reduction or discontinuation
of corticosteroid, but joint replacement is frequently
necessary.153 The growth of most pediatric transplant
recipients is retarded by corticosteroids.154
Sexual or menstrual dysfunction is common early after
heart transplantation and often recurs when corticosteroid doses are increased. However, with resolution of the
changes of congestive heart failure and with clinical
stability, the loss of libido and sexual dysfunction so
common in patients in end-stage heart failure usually
resolves and fertility returns in most patients. There is no
reported evidence of teratogenicity in children of male
patients taking immunosuppressants.
An important minority of heart transplant recipients
are young women, and it is important to address the
advisability or safety of childbearing by such women.
There is little data on childbearing by heart transplant
recipients (five reported cases as of 1991); but, based on
data from renal allograft recipients on similar immunosuppressive regimens, pregnancy in an allograft recipient is associated with a high incidence of premature
births and of babies small for gestational age. However,
there are no data suggesting teratogenicity or any
long-term adverse sequalae in children of allograft
recipient mothers and no evidence of adverse affect of
pregnancy on the health of the mother.155 Thus, advice
to the individual patient must be based on review of
such data as well as on discussion of the personal beliefs
of the patient who understands that she may not survive
to raise the child to adulthood. Methotrexate and
cyclophosphamide may cause congenital anomalies,
while corticosteroids and azathioprine are said to be
safe in this regard. An increased incidence of spontaneous abortions, fetal anencephaly, and absence of the
corpus callosum have been reported with cyclosporine.
For the above reasons transplant recipients should be
discouraged from becoming pregnant and oral contraception or tubal ligation should be seriously considered.
The effects of immunosuppression drugs on male fertility and genetic damage is unknown.
Both corticosteroids and cyclosporine cause hypercholesterolemia, the latter by impairing hepatic clearance of low density lipoproteins.156"57 Serum cholesterol levels are significantly lower in patients no longer
taking corticosteroids.'58159 Treatment includes dietary
restriction of fat and cholesterol, weight loss, and lipidlowering agents. Lovastatin and other HMG CoA (3hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors are associated with an increased risk of
rhabdomyolysis and renal injury when used by cyclo-
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sporine-treated heart transplant recipients.160 Concomitant gemfibrozil administration increases the likelihood
of this adverse reaction. Lovastatin should be started at
low doses (10-20 mg/day) and discontinued immediately if liver dysfunction or elevation of skeletal muscle
enzymes are detected.161 Bile acid-binding agents may
be effective but they are poorly tolerated and impair
cyclosporine absorption.
Neurological Complications. Seizures may occur after
cardiac transplantation.162 The multifactorial etiology of
these seizures includes embolic, metabolic, and electrolyte disturbances, wide fluctuations in blood pressure,
and arrhythmias. Cyclosporine increases the likelihood
of seizures. Diagnostic evaluation should include computerized axial tomography and lumbar puncture to
exclude clinically silent neurological lesions or infections. Anticonvulsant therapy should be initiated and, if
phenytoin is used, close attention should be paid to its
potential interaction with cyclosporine.
Malignancy. Transplant recipients have up to a 6%
risk of developing cancer, an age-controlled frequency
100 times greater than that of the general population.'63
Because skin cancer is the most common posttransplant
malignancy, dermatological evaluation and protection
from solar injury should be practiced routinely. In
lymphoproliferative disorders there is a spectrum of
abnormal B lymphocyte proliferation. The incidence of
such disorders approaches 5% in recipients of thoracic
organs'6"; risk is correlated with the degree of total
immunosuppression'65 and is believed to result from
inadequate T cell control over Epstein-Barr virusdriven B cell proliferation.'64
Reactive lymphoid tissue or highly malignant tumors
such as large cell non-Hodgkin's lymphomas may be
detected histologically.'66 Both polyclonal and monoclonal proliferation have been identified by cell-surface
immunoglobulin phenotype and immunoglobulin rearrangement.'67-173 Lymphoma should be suspected when
transplant recipients have fever of undetermined etiology, lymphadenopathy, and elevated Epstein-Barr virus
titers. Some of the lymphoproliferative disorders may
have a fulminant clinical course with widespread tumor
dissemination, organ failure, and sepsis.'64 Because
early diagnosis and intervention are believed to improve
outcome, all heart transplant recipients should be carefully screened for early signs of posttransplantation
lymphoproliferative disorder. Thorough evaluation
should include assessment of the gastrointestinal tract
and central nervous system in patients in whom lymphoma is suspected. Tissue should be obtained from any
suspicious lesion for histology and lymphocyte phenotyping. Bone marrow aspiration and biopsy should be
done to exclude bone marrow involvement. For initial
treatment of lymphoproliferative disorders, immunosuppression should be reduced where feasible.174 In addition, administration of high-dose intravenous acyclovir
may be warranted if the lymphoproliferative disorder is
polyclonal. If it is monoclonal, chemotherapy and radiation therapy should be considered. Surgical resection of
malignant lesions has been helpful.'68"17",174-'77
In summary, complications following heart transplantation affect several organ systems and vary in type and
frequency over time. Because most are due to the effects
of immunosuppression, the successful outcome of heart
transplantation requires a delicate balance between
adequate immunosuppression and control of drugrelated adverse effects.
Conclusion
Heart transplantation is a widely accepted treatment
for end-stage heart disease. Standard recipient selection
criteria exist, but questions requiring further in-depth
investigation remain. Controlled trials comparing outcome after transplantation versus medical therapy
should be performed. The critical shortage of donors
makes it imperative to improve stratification of potential candidates according to preoperative risk.
The high mortality rate of patients awaiting heart
transplantation underscores the crucial need to intensify efforts to increase organ donation. Optimal use of
donor organs that do become available requires improvement in tissue preservation techniques, identification of ways to optimize donor organ function, and
organ allocation based on histocompatibility. Ultimately, heart replacement alternatives such as xenografts (nonhuman transplanted organs), mechanical
left ventricular assistance, and dynamic cardiomyoplasty may reduce the number of recipients requiring
transplantation of a human heart.
Medical follow-up requires expertise in diagnosis,
grading, and treatment of allograft rejection. Appropriate treatment also requires familiarity with individual
patients' histories of organ rejection. Overly aggressive
immunosuppression of a rejection episode that is likely
to resolve spontaneously as well as excessive reduction
of the immunosuppressive drug dosage should be
avoided. Prescribing a regimen of multiple powerful
immunosuppressive drugs while managing their adverse
effects is one of the greatest challenges facing transplant
physicians. The variable response of individual patients,
drug-induced complications, drug interactions, and patient compliance requires constant monitoring and adjustment of the immunosuppressive drug regimen. Cardiologists caring for heart transplant recipients must
now be familiar with the pharmacology, drug interactions, and drug toxicity of both agents extensively used
in clinical practice (cyclosporine, prednisone, azathioprine, polyclonal and monoclonal anti-T cell agents)
and newer treatments (methotrexate, FK-506, rapamycin, mycophenolate mofetil [RS61443], deoxyspergualin, anti-CD4 monoclonal antibodies, total lymphoid
irradiation, and photopheresis). Another important aspect of medical follow-up is the detection, differential
diagnosis, and treatment of allograft dysfunction. Donor
heart physiology is affected by denervation, donorrecipient size and age match, rejection, drug toxicities,
and infections. Hemodynamic abnormalities that occur
as a result of rejection or a direct drug effect must be
differentiated from seemingly physiological changes.
Cardiac allograft vasculopathy is the primary impediment to the long-term survival of heart transplant
recipients. Although experimental and clinical evidence
suggest that the lesion results from an immune-mediated injury, the pathogenesis of this disorder remains
largely unknown. Currently available diagnostic and
therapeutic approaches are inadequate. Immunopathogenesis, prevention, early detection, and treatment of
allograft vasculopathy should be the major focus of
heart transplantation research.
AISA Scientific Council Cardiac Transplantation
Heart transplantation has achieved an extraordinary
degree of success that in the individual patient depends
on a high level of effort at the transplant center and
close communication with the physician responsible for
long-term treatment.
Acknowledgments
The authors thank Sharon Hunt, MD, liaison from the
American College of Cardiology, and Sharon Augustine, MS,
RN, liaison from the AHA's Council on Cardiovascular Nursing, for their helpful comments during the preparation of this
manuscript.
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Cardiac transplantation: recipient selection, donor procurement, and medical follow-up.
A statement for health professionals from the Committee on Cardiac Transplantation of
the Council on Clinical Cardiology, American Heart Association.
J B O'Connell, R C Bourge, M R Costanzo-Nordin, D J Driscoll, J P Morgan, E A Rose and B
F Uretsky
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Circulation. 1992;86:1061-1079
doi: 10.1161/01.CIR.86.3.1061
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