Cardiomyopathy and heart transplantation in children

W. Robert Morrow, MD

Cardiomyopathy is one of the most common causes of death

in children with heart disease. Increasingly, dilated cardiomyopathy is recognized to be familial, and specific gene products
related to the myocyte cytoskeleton and contractile proteins
have been identified. Other associations with metabolic
disease, dysmorphic syndromes, and neuromuscular disease
are important to establish, particularly in pediatric patients, to
guide therapy and patient selection for transplantation. Survival
in children with dilated cardiomyopathy depends on accurate
diagnosis and aggressive therapy. Patients may respond to
conventional treatment for heart failure or may deteriorate,
requiring mechanical support. Extracorporeal membrane
oxygenation has been used effectively for mechanical support
in children until improvement occurs or as a bridge to transplantation. For those who are listed, the mortality rate while
waiting for a donor organ averages approximately 20%.
Survival after transplantation is good, with an intermediate
survival rate of approximately 70%. Late survival remains to be
determined in the current cyclosporin era but may in fact be
improving. However, increased organ donation or strategies to
increase the size of the organ donor pool, such as xenotransplantation, are needed to significantly reduce the rate of
mortality while waiting. Curr Opin Cardiol 2000, 15:216223 2000
Lippincott Williams & Wilkins, Inc.

From the Division of Pediatric Cardiology, Department of Pediatrics, University of

Arkansas for Medical Sciences and Arkansas Childrens Hospital, Little Rock,
Arkansas, USA
Correspondence to: W. Robert Morrow, MD, Division of Cardiology, Arkansas
Childrens Hospital, 800 Marshall Street, Little Rock, AR 72202, USA; e-mail:
morrowwilliamr@exchange.uams.edu

Current Opinion in Cardiology 2000, 15:216223

Abbreviations
ECMO
ISHLT
PHTS

extracorporeal membrane oxygenation

International Society for Heart and Lung Transplantation
Pediatric Heart Transplant Study

ISSN 02684705 2000 Lippincott Williams & Wilkins, Inc.

216

Cardiomyopathy and cardiac transplantation

in children
Cardiomyopathy is one of the leading causes of death in
infants and children with heart disease [1,2]. Yet
prospects for survival in this group of patients have
never been better, owing to progress in medical therapy
of heart failure, largely reported in adults, and improving
results of cardiac transplantation [3]. Increasing appreciation for genetic and metabolic etiologies has led to
earlier detection of cardiomyopathy in patients with
familial disease, specific therapy in some with metabolic
cardiomyopathy, and more selective use of cardiac transplantation in others [2,4]. However, despite the
rapidly increasing availability of genetic and metabolic
diagnosis, specific metabolic therapy is available, regrettably, in only rare instances, and hopes for specific gene
therapy for most cardiomyopathies are as yet unrealized.
Survival is good after cardiac transplantation, but on
average 20% of patients die waiting for a donor heart
[57,8]. There is also concern regarding long-term
survival in pediatric heart transplant recipients, an area
where expectations for greater longevity are clearly
justified. In this article we review recent developments
in the diagnosis and treatment of myocardial disease in
children, specifically dilated cardiomyopathy, and
discuss results of cardiac transplantation in pediatric
patients.
Classification of cardiomyopathy

For the purposes of this review, we define cardiomyopathy as diseases of heart muscle excluding ischemic and
hypertensive cardiomyopathy [2]. The World Health
Organization classification of cardiomyopathy is still
widely employed in the evaluation of children.
However, this classification of cardiomyopathy is only
loosely related to the major pathophysiologic alterations
found in patients with cardiomyopathy. These are
reduced systolic function, diastolic dysfunction, adrenergic dysfunction, and, in the case of hypertrophic
cardiomyopathy, obstruction. The understanding of
pathophysiology is of at least equal clinical importance
to the description of pathology, although the latter is
useful in understanding natural history and prognosis.
Most patients have mixed pathophysiology. Patients
with dilated cardiomyopathy typically have systolic and
diastolic dysfunction as well as alterations in adrenergic
tone. Also, a variety of etiologies account for similar if
not identical clinical pathophysiologic varieties of
cardiomyopathy, and different pathophysiologies may
be present in different patients with the same etiology.

Cardiomyopathy and heart transplantation in children Morrow 217

From a clinical perspective, the pathophysiologic classification of cardiomyopathy is currently most useful in
guiding treatment. However, cardiomyopathy in children may also be classified according to certain other
clinical associations, including the presence of biochemical abnormalities at diagnosis, encephalopathy (including developmental delay), associated dysmorphic
features, coexisting neuromuscular disease, or cardiomyopathy without other associations [4]. This classification
is useful in formulating an approach to diagnosis in
which associated metabolic disease, neuromuscular
disease, malformation syndromes, and familial associations may exist. Recognizing underlying neuromuscular,
metabolic, and genetic disease is key to guiding decisions regarding the use of selective therapy or cardiac
transplantation [1,2,4].

Etiology of cardiomyopathy
Dilated cardiomyopathy has also been termed idiopathic, a designation that may no longer be relevant.
Cardiomyopathy may have a variety of causes, including
genetic, infectious, metabolic, and toxic, among others.
Exhaustive lists of possible etiologies have been
published elsewhere [1,4]. Table 1 summarizes the
more common etiologies encountered in clinical practice
and some of the most important uncommon diagnoses.
Table 1. Dilated cardiomyopathy: etiology
Viral
Coxsackievirus A and B
Echovirus
Adenovirus
Mumps
Metabolic
Thyrotoxicosis
Hypothyroidism
Carnitine deficiency syndrome
Leigh disease
Barth syndrome
*MELAS syndrome

MERRF syndrome
Kearn-Sayre syndrome
Sengers syndrome
Toxic
Anthracycline toxicity
Hemachromatosis
Alcohol
Neuro/Muscular
Friedreich ataxia
Duchenne muscular dystrophy
Becker muscular dystrophy
Familial/Genetic
X-linked
Autosomal dominant
Autosomal recessive
Autosomal dominant dilated cardiomyopathy with conduction
defects
Other
Isolated ventricular noncompaction
Tachyarrhythmia induced
*Mitochondrial encephalopathy, lactic acidosis, and stroke-like
episodes

Myoclonic epilepsy, ragged red fibers

Dilated cardiomyopathy has often been thought of as a

sequela of viral myocarditis. It is indeed clear that viral
myocarditis may lead to sustained cardiac dysfunction
[9,10]. The presence of viral genome and inflammatory
infiltrate on biopsy in patients with chronic ventricular
dilatation and dysfunction also supports this view
[9,10,11]. In the clinical setting of an acutely deteriorating patient, the distinction between viral myocarditis
and dilated cardiomyopathy may be difficult.
Familial dilated cardiomyopathy

Increasingly, dilated cardiomyopathy is being recognized to be familial because of a history of affected

parents or siblings [2]. From 20% to 65% of dilated
cardiomyopathy cases may be familial [2,11].
Mestroni et al. [11] found a number of presentations
among those patients with familial dilated cardiomyopathy and distinguished five subtypes. These
included patients with autosomal dominant inheritance
and isolated dilated cardiomyopathy, X-linked inheritance with defects of the dystrophin gene, autosomal
dominant inheritance with subclinical skeletal muscle
disease, dilated cardiomyopathy with conduction
defects, and other rare forms. X-linked dilated
cardiomyopathy, also involving a dystrophin gene
defect isolated to myocardium, has been well described
[12]. This progressive cardiomyopathy typically occurs
in adolescent males and follows an X-linked transmission pattern. In the series by Mestrioni et al. [11],
autosomal dominant transmission of dilated cardiomyopathy is the most common pattern, followed by autosomal recessive and X-linked inheritance. Currently, at
least 10 genes have been mapped to loci in families
with autosomal dominant dilated cardiomyopathy
[2,11], although not all have identified gene products (Table 2). In addition to the dystrophinopathies,
defects of other cytoskeletal proteins and of contractile
proteins have been demonstrated to cause dilated
cardiomyopathy [11,1215].
Several genetic syndromes of importance are seen in
children and illustrate the genetic complexity of
dilated cardiomyopathy. Barth syndrome, 3-methylglucatonic aciduria, is characterized by dilated cardiomyopathy, skeletal myopathy, neutropenia, and mitochondrial abnormalities and is rapidly progressive. with
death in infancy and X-linked inheritance[4].
Duchenne muscular dystrophy and Becker muscular
dystrophy, both of which affect children with skeletal
muscle weakness, are associated with cardiomyopathy
and defects of the dystrophin gene. Although X-linked
inheritance has been clearly demonstrated, carriers of
Duchenne muscular dystrophy have also been demonstrated to have evidence of cardiomyopathy by
echocardiography, and there are reports of carriers
presenting with severe symptoms [1618]. In addition,

218 Pediatrics

Diagnostic evaluation

Table 2. Dilated cardiomyopathy: genetics

Syndrome

Loci

Gene/Product

X-linked DCM
Duchene MD
Becker MD
Barth syndrome
Isolated ventricular
noncompaction
Cardiomyopathy with MD
Familial DCM
(autosomal dominant)

Xp21
Xp21
Xp21
Xq28
Xq28

Dystrophin
Dystrophin
Dystrophin
Tafazzin (G4.5)
G4.5

17q12-21
15q4

1q21
1q32
2q31
2q35
2q14-22
3p25-22
9q13-22
10q21-23
1p1-q1

Alpha sarcoglycan
Cardiac actin
Metavinculin
Lamin A/C

desmin

22q

Carnitine palmityl
transferase

Familial DCM with

conduction defects
Systemic carnitine
deficiency

DCM, dilated cardiomyopathy; MD, muscular dystrophy.

other familial dilated cardiomyopathies have been

described with defects of the G4.5 gene of chromosome Xq28, including left ventricular noncompaction
and cardiomyopathy [19]. Ichida et al. [20] recently
reviewed the clinical features of isolated noncompaction of the ventricular myocardium in the Japanese
population. This entity is characterized by ventricular
dysfunction, systemic embolization, ventricular
arrhythmia, and prominent left ventricular trabeculations. Although X-linked transmission has been
proposed, the equal representation of females among
affected family members in this series suggests other
potential inheritance patterns.
Other causes of dilated cardiomyopathy

Cardiomyopathy may also be caused by toxic exposure

and may be preceded by viral infection. The most
common toxic cardiomyopathy commonly encountered
in children is the cardiomyopathy caused by anthracycline toxicity following treatment for childhood cancer.
Viral etiologies have been established as the major
source of the cardiomopathy in patients with HIV infection [21]. Cardiomyopathy may be associated with neuromuscular disease and metabolic disease [4,22]. Patients
with neuromuscular disease or metabolic disease usually
have some form of recognizable encephalopathy or
muscle weakness at presentation. These entities have
been thoroughly reviewed, and an in depth discussion of
these is beyond the scope of this report [4,22]. It is
particularly important to identify metabolic disease that
may be treatable, such as some forms of carnitine deficiency and 3-hydroxyacyl coenzyme A dehydrogenase
deficiency, or diseases that may recur in patients who
undergo cardiac transplantation (storage disease).

Infants and children with cardiomyopathy present with

symptoms and signs of congestive heart failure or with
arrhythmia, syncope, or sudden death. Myocarditis may
be present in 2 to 15% of children who present with
congestive failure but may be more common in infants
[1]. The diagnosis of myocarditis may be established
with endomyocardial biopsy by standard histologic criteria or by demonstration of viral genome in cardiac tissue
[2,9,10,11,23]. In fact, many patients with familial
dilated cardiomyopathy may have associated cellular
infiltrate [11]. A careful history often reveals symptoms of chronicity, which favor a diagnosis of cardiomyopathy over myocarditis (poor feeding, exertional
fatigue). Often a diagnosis of cardiomyopathy is made
by exclusion of myocarditis on biopsy and lack of
improvement of cardiac function over months following
a presentation with acute failure.
Schwartz et al. [4] reviewed the diagnostic evaluation of
cardiomyopathy in infants and children. History and
physical examination will direct the nature of the evaluation to be undertaken. Clearly, family history and evaluation of first-degree relatives for cardiomyopathy is
important in patients with isolated cardiomyopathy.
First-degree relatives should undergo electrocardiographic and echocardiographic studies, since many
affected individuals are asymptomatic. In all patients,
routine electrolytes, creatinine, blood urea nitrogen,
magnesium, calcium, and glucose measurements should
be obtained. An electrocardiogram may give specific
indications of hypertrophic cardiomyopathy, storage
disease, and certain familial forms of cardiomyopathy,
and may exclude an anomalous left coronary artery.
When the clinical presentation with dilated cardiomyopathy in an infant in the first 3 months of life is
compatible with anomalous left coronary artery, echocardiography and angiography should be performed to
make or exclude the diagnosis. When metabolic acidosis
is present or the patient is hypoglycemic or hyperammonemic, a more thorough metabolic evaluation is indicated [4]. This is also true in patients with encephalopathy. Urine for amino acids and organic acids, serum
lactate and pyruvate, quantitative ketones, blood for
acyl carnitine, T4 and thyroid-stimulating hormone, and
creatine kinase should be obtained. For patients with
dysmorphic features, developmental delay, or failure to
thrive, a karyotype is also indicated. Endomyocardial
biopsy, although not without risk, has been shown to be
safe and efficacious in infants and children [24] and
should be performed if other diagnostic studies fail to
reveal a definitive diagnosis. As noted earlier, biopsy
may be useful in excluding acute myocarditis, but cellular infiltrates may be seen in patients with cardiomyopathy. Although routine histology usually demonstrates
myocyte hypertrophy and variable degrees of fibrosis,

Cardiomyopathy and heart transplantation in children Morrow 219

myocardial biopsy is necessary for the diagnosis of

cardiac phosphorylase kinase deficiency. Skeletal
muscle biopsy, nerve conduction velocity studies, and
electromyography are useful in patients with suspected
neuromuscular disease.

Treatment of myocardial disease

Stabilization

Infants and children with dilated cardiomyopathy often

present with congestive heart failure and are frequently
profoundly ill, requiring aggressive medical management to achieve stabilization. In addition to supplemental oxygen and diuretic therapy, these children require
inotropic support with dobutamine and dopamine, and
many require mechanical ventilation. The addition of
myocardial phosphodiesterase inhibitors, such as milrinone, may be very useful in providing additional
inotropic support and afterload reduction. Correction of
acidosis with sodium bicarbonate is important, provided
the patient has adequate ventilation. Arrhythmia
management is key and may require the use of intravenous therapy for those with intractable ventricular
arrhythmia.
Recent studies have demonstrated the usefulness of
examining tissue for viral genome and may establish the
etiology of myocarditis [9,10,11]. However, polymerase chain reaction studies are seldom useful in the
management of acutely ill children. Frequently, patients
who present with a clinical presentation compatible with
myocarditis are often treated empirically with either globulin or corticosteroids. Some evidence exists
suggesting that -globulin may be useful in reducing
morbidity and mortality of myocarditis in children [25].
More aggressive treatment of myocarditis with other
immunosuppressants and cytolytics has also been
proposed [26]. Patients with cardiac failure who fail to
respond to therapy and continue to deteriorate, whether
due to myocarditis or cardiomyopathy, should be considered for mechanical support and are potential candidates
for cardiac transplantation.
Mechanical support in children

A number of investigators have demonstrated the efficacy of providing mechanical support of the circulation,
principally by extracorporeal membrane oxygenation
(ECMO) in children with refractory heart failure
[2732]. Patients with myocarditis or cardiomyopathy
who progress to cardiogenic shock despite maximal
inotropic support should be placed on mechanical
support, provided contraindications do not exist. In children, the primary modality for mechanical support
continues to be ECMO. Left ventricular assist devices
are applicable only in some adolescent patients,
although devices for smaller children are currently being
evaluated [3032]. When patients with left ventricular

failure are placed on ECMO, left ventricular ejection

may cease, leading to left atrial hypertension and
pulmonary venous congestion. Adequate decompression
of the left atrium is essential in reducing left ventricular
wall stress and preventing pulmonary complications of
pulmonary venous congestion. Seib et al. [33] has
described the technique for blade and balloon atrial
septostomy in patients requiring ECMO and demonstrated the superiority of this technique to surgical
decompression. Patients with myocarditis may improve
and be weaned from support. It is clear that a majority of
patients with acute cardiac failure can either be weaned
from support or are successfully transplanted, although
the rate of mortality while waiting is certainly significant
[27,28]. It is most important to progress to mechanical
support prior to cardiac arrest or onset of generalized
organ failure. The prognosis for full recovery with or
without transplant is much poorer if cardiac arrest has
occurred prior to instituting mechanical support.
Chronic heart failure management

Studies in adults with heart failure have shown substantial benefit for aggressive treatment of heart failure. In
addition to the beneficial effects of digoxin and diuretics, therapy directed at the pathophysiology of the activation of the sympathetic axis have proven benefit.
Children with heart failure should receive digoxin,
diuretics including spironolactone, and angiotensinconverting enzyme inhibitors. Studies of heart failure
treatment directed at reducing the effects of adrenergic
activation have been limited in children. The benefit of
metoprolol in the treatment of heart failure [34] and
initial studies with carvedilol have shown encouraging
results [35]. However, owing to the small number of
pediatric patients with heart failure at any individual
center, these studies have had low statistical power.
Also, the pathophysiology of heart failure in children
may be different. Children characteristically present
with fewer symptoms for any given degree of left
ventricular dysfunction and have worse ventricular function at presentation. Therefore, the end points for
improvement in children may in fact be different from
those in studies in adults. Prospective multicenter trials
are currently underway to evaluate the effect of betablockade in pediatric cardiomyopathy patients. The use
of beta-blockade should be undertaken cautiously until
further evidence of efficacy is forthcoming.
Patients with severe systolic dysfunction and severe left
ventricular dilatation should be treated with anticoagulants, preferably coumadin, to prevent the development
of intracardiac thrombus and systemic embolization.
Arrhythmia should be treated aggressively, as sudden
death is a common cause of death for patients with
dilated cardiomyopathy. Predictors of sudden death in
dilated cardiomyopathy are few. Clearly preexisting

220 Pediatrics

arrhythmia is a risk factor for sudden death in children

[36]. QT dispersion may be associated with greater
arrhythmia and therefore be a risk factor for sudden
death [37]. Patients with more severe cardiomyopathy,
such as greater degrees of ventricular dilatation and
worse systolic dysfunction, as well as patients with
pulmonary hypertension, may be more likely to die
suddenly. Since many anti-arrhythmic agents have negative inotropic effects, treatment may lead to a deterioration in cardiac function. Amiodarone may be the best
agent for treating arrhythmia, particularly in patients
listed for cardiac transplantation. Although experience is
limited, the use of implantable defibrillators has been
effective in pediatric patients large enough for these
devices [38]. Patients who continue to deteriorate
should be considered for mechanical support [2732].

Cardiac transplantation
Indications for listing

The registry of the International Society for Heart and

Lung Transplantation (ISHLT) records 4178 cardiac
transplant procedures in children, ranging from 147 in
1987 to 324 in 1998 [3], although the frequency of transplantation has declined slightly since a peak of 395 in
1993. The indications for cardiac transplantation in children were recently reviewed by Fricker et al. [39].
Patients with refractory symptomatic heart failure are
candidates for listing for transplantation provided
contraindications do not exist. Serious central nervous
system, renal, hepatic, and pulmonary dysfunction are
contraindications in children as in adults. Patients with
Becker muscular dystrophy may be successfully transplanted depending on the severity of their skeletal
myopathy.
Pulmonary hypertension may be a contraindication to
transplant in some patients with dilated cardiomyopathy. The upper limit of pulmonary resistance associated
with successful cardiac transplantation has not been
established [39,40,41,42,43]. Transplantation in
patients with pulmonary arteriolar hypertension in
excess of 5 Wood units or a transpulmonary gradient
greater than 15 mm Hg is potentially contraindicated.
However, if pulmonary resistance is reactive and
decreases with the administration of oxygen, nitric
oxide, or prostaglandin, transplantation is not necessarily
contraindicated. All patients with elevated pulmonary
resistance must undergo hemodynamic testing to establish both resting and best pulmonary arteriolar resistance
and transpulmonary gradient prior to transplantation or
exclusion from listing. Best values should always include
response to oxygen and nitric oxide, but the latter may
be omitted if resistance falls into an acceptable range
with other interventions (inotropic agents, intravenous
afterload reduction, prostaglandin)[43]. When the
response is marginal, repeat values after a 1- to 2-week

course of intravenous inotropic support, afterload reduction, and pulmonary vasodilatation may demonstrate
improvement. Patients known to have marginal values
should be tested at least every 6 months while waiting
for transplantation, since reactive pulmonary hypertension may worsen and become fixed. Patients with fixed
elevation of pulmonary resistance on the basis of cardiac
failure may be candidates for heart-lung transplantation.
Fricker et al. [39] discuss other potential contraindications to transplantation.

Outcome of listing for transplantation

Very few studies have addressed pretransplant mortality
in infants and children after listing for cardiac transplantation. However, death after listing is not the only
potential outcome of listing for transplantation. Any of
four potential outcomes may occur after listing, including death while waiting, transplantation, removal from
the list, or continuing on the list waiting for transplantation. Competing outcome analysis has been used to
describe outcome after listing for transplant in pediatric
patients in the Pediatric Heart Transplant Study
(PHTS)[57,8]. McGiffin et al. [5] reported outcome of
listing in 264 pediatric patients listed for transplantation
over a 1-year period. Patients ranged in age from 3 days
to 17.9 years, with a mean age of 4.7 years. In this initial
report from the PHTS, 60% of patients underwent
transplantation by 6 months after listing, 23% died while
waiting, 14% remained on the list awaiting transplantation, and 4% improved and were removed from the list.
In a separate analysis of infants (less than 6 months of
age) who were listed for transplantation [6], nearly one
third of infants died awaiting transplantation, although
60% did undergo transplantation by 6 months. Only 6%
remained on the list awaiting transplantation. The use
of blood type O donors (universal donor) in non-blood
type O recipients resulted in more deaths while waiting
among blood type O patients. In older children, death
was more likely to occur in Status 1 patients and
patients requiring mechanical ventilation [7]. UNOS
policy now prioritizes allocation of type O donor hearts
to type O recipients. In addition, under new urgency
status categories (Status 1a, Status 1b, and Status 2)
prostaglandin-dependent infants with greater than 50%
systemic pulmonary artery pressure (prostaglandindependent, single-ventricle physiology) are prioritized
to Status 1a, the most urgent status. Whether these
changes ultimately lead to more equitable organ distribution remains to be determined.
Survival after transplantation

A number of institutions have reported excellent early

and intermediate survival in both infants and children
[4454] following cardiac transplantation. When all age
groups and diagnoses are analyzed together, an actuarial
survival of at least 75 to 85% at 1 year and 65 to 75% at 5

Cardiomyopathy and heart transplantation in children Morrow 221

years is seen. Survival data reported by the Registry of

the ISHLT are more or less in keeping with other
multicenter studies and single-institution experiences
[3]. Shaddy et al. [55] and Canter et al. [56] have
reported survival in infants and older children in the
PHTS experience. Survival in the recent PHTS experience indicates some improvements over time [8]. Oneyear survival among infants less than 1 year of age at
transplant was 82% in the most recent analysis,
compared with 70% in the initial PHTS experience
[8,55,56]. Five-year survival in pediatric patients in the
PHTS study was also virtually identical to survival
among adults and was approximately 70% (Fig. 1).
There was no difference in survival between patients
with congenital heart disease and those with cardiomyopathy. A number of individual programs have recently
reported survival in excess of 90% (Morrow WR, Frazier
EA, unpublished data, 1999) [57,58]. Four-year survival
has improved at Arkansas Childrens Hospital from the
first to the second half of our transplant experience
(Morrow WR, Frazier EA, unpublished data, 1999). An
initial survival of 61% at 4 years is now 94% in the
current era. The most current analysis of data from the
ISHLT registry also demonstrates a generally improving
survival rate over the period of data collection. Factors
accounting for this apparently improving survival rate
have not yet been determined.
Late survival

Attention has recently turned to late survival in children

after cardiac transplantation. In particular, there is
concern about increasing attrition with age because of
late complications such as late rejection due to noncompliance and occurrence of graft atherosclerosis. Few data

are available regarding long-term survival in pediatric

heart transplant recipients. Late survival at Stanford was
disappointingly low, with a reported 10-year survival
rate of 60% [8]. Importantly, many patients underwent
transplantation prior to the cyclosporin era. The ISHLT
registry report gives an 8-year actuarial survival rate of
approximately 55% for all ages [3]. Long-term survival
among patients transplanted early in the pediatric heart
transplant experience of some institutions appears to be
less favorable than current survival [59]. Ultimately,
improvements in early survival will translate into better
late survival. Since most late deaths occur due to rejection or rejection-related complications such as graft
vasculopathy [60,61], the development of new immunosuppressive agents promises to lead to improving longterm survival as well. Death from myocardial infarction
remains decidedly uncommon within 5 years of transplantation in children, although a disturbing increase in
sudden deaths has been observed [61]. Data from the
recent Loma Linda experience indicate that late
survival in neonates may in fact be superior to that in
older infants [62]. With improved rejection surveillance
and treatment in these high-risk patients and with new,
more effective immunosuppressive regimens on the
horizon, mortality from rejection can potentially be
reduced. Likewise, since graft atherosclerosis is at least
in part a rejection phenomenon, improved treatment of
rejection could lead to a reduced incidence and severity
of graft coronary disease.

Conclusions
In the past, the diagnosis of dilated cardiomyopathy in
children was associated with a generally poor prognosis.
However, with improved diagnosis, hopefully before

Figure 1. Actuarial survival percentages

100

Actuarial survival in pediatric patients 0 to 18 years of age

who underwent primary cardiac transplantation between
January 1, 1993 and December 31, 1998 in centers of the
Pediatric Heart Transplant Study. Mortality after transplantation is characterized by an early phase of risk followed by
a constant phase of lower risk of death.

PHTS: Jan 1993Dec 1998

All institutions
Event: death after transplantation

90
80

Survival, %

70
60
50
Primary transplants: (n = 847)
Years Survival, %
1/12
92
1/2
86
1
84
2
81
3
78
4
75
5
73

40
30
20
10
0

3
4
Years after transplant

222 Pediatrics

symptoms become severe, and with improved medical

therapy, it is likely that many children will survive without
transplantation. The promise of specific therapy for most
patients with dilated cardiomyopathy is as yet unrealized.
However, when medical therapy fails, heart transplantation is effective and can provide good intermediate-term
survival. Lack of availability of donors results in significant
mortality while waiting among pediatric patients awaiting
heart transplantation, although most eventually undergo
successful transplantation. In fact, this mortality rate is
virtually equal to the 5-year mortality rate after transplant.
Survival after transplantation in infants and children is
equal to if not better than survival in adults. Despite late
survival estimates of 50% at 10 years, early and intermediate survival rate may be improving, based on recent
studies at individual institutions (Morrow WR, Frazier EA,
unpublished data, 1999) [57,58] and multicenter studies
[3,8]. The recent development of new immunosuppressive agents may also significantly affect long-term survival
by reducing the incidence and severity of acute and
chronic rejection. However, increased organ donation or
strategies to increase the size of the organ donor pool, such
as xenotransplantation [63], are needed to significantly
reduce overall mortality.

infants younger than six months: predictors of death and interval to transplantation. J Heart Lung Transplant 1997, 16:12551266.
7

Addonizio L, Naftel D, Fricker J, et al., and the Pediatric Heart Transplant

Study Group: Risk factors for pretransplant outcome in children listed for
cardiac transplantation: a multi-institutional study (abstract). J Heart Lung
Transplant 1995, 14:S48.

Morrow WR, Frazier EA, Naftel DC: Survival after listing for cardiac transplantation in children. Prog Pediatr Cardiol 2000, 11:99105.

Griffin LD, Kearney D, Ni J, et al.: Analysis of formalin-fixed and frozen

myocardial autopsy samples for viral genome in childhood myocarditis and
dilated cardiomyopathy with endocardial fibroelastosis using polymerase
chain reaction (PCR). Cardiovasc Pathol 1995, 4:311.

10

Bowles NE, Richardson PJ, Olsen EGJ, et al.: Detection of coxsackie-Bvirus specific RNA sequences in myocardial biopsy samples from patients
with myocarditis and dilated cardiomyopathy. Lancet 1986, 1:11201122.

11

Mestroni L, Rocco C, Gregori D, et al.: Familial dilated cardiomyopathy:

evidence for genetic and phenotypic heterogeneity. J Am Coll Cardiol
1999, 34:181190.
In this article, data are presented from an impressive series of patients with
dilated cardiomyopathy. The authors define subtypes of familial cardiomyopathy
and in doing so propose a useful framework for classification. The paper
includes an informative discussion on the genetics of dilated cardiomyopathy.
12

Towbin JA, Hejtmancik F, Brink P, et al.: X-linked cardiomyopathy (XLCM):

molecular genetic evidence of linkage to the Duchenne muscular dystrophy
(dystrophin) gene at the Xp21 locus. Circulation 1993, 87:18541865.

13

Fadic R, Sunada Y, Waclawik, et al.: Brief report: deficiency of a

dystrophin-associated glycoprotein (adhalin) in a patient with muscular
dystrophy and cardiomyopathy. N Engl J Med 1996, 334:362366.

14

Maeda M, Holder E, Lowes B, Bies RD: Dilated cardiomyopathy associated

with deficiency of the cytoskeletal protein metavinculin. Circulation 1997,
95:1720.

15

Olson TM, Michels VV, Thibodeau SN, et al.: Actin mutation in dilated
cardiomyopathy, a heritable form of heart failure. Science 1998,
280:750752.

16

Politano L, Nigro V, Nigro G, et al.: Development of cardiomyopathy in

female carriers of Duchenne and Becker muscular dystrophies. JAMA
1996, 275(17):13351338.

17

Hoogerwaard EM, Bakker E, Ippel PF, et al.: Signs and symptoms of

Duchenne muscular dystrophy and Becker muscular dystrophy among
carriers in The Netherlands: a cohort study. Lancet 1999,
353(9170):21162119.

Denfield SW, Gajarski RJ, Towbin JA: Cardiomyopathies. In: The Science
and Practice of Pediatric Cardiology. Edited by Garson A, Bricker JT,
Fisher DJ, Neish SR. New York: Williams & Wilkins, 1998.

18

Melacini P, Fanin M, Angelini A, et al.: Cardiac transplantation in a

Duchenne muscular dystrophy carrier. Neuromuscular Disorders 1998,
8:585590.

2
Towbin JA: Pediatric myocardial disease. Pediatr Clin North Am 1999,
46(2):289309.

This review deals with etiology, diagnosis, and treatment issues in a comprehesive fashion. The author is expert in both the genetics of cardiomyopathy and
treatment by cardiac transplantation.

19

Bleyl SB, Mumford BR, Brown-Harrison MC, et al.: Xq28-linked noncompaction of the left ventricular myocardium: prenatal diagnosis and pathologic analysis of affected individuals. Am J Med Genet 1997, 72:257265.

20

Ichida F, Hamamichi Y, Miyawaki T, et al.: Clinical features of isolated

noncompaction of the ventricular myocardium. J Am Coll Cardiol 1999,
34:233240.

21

Bowles NE, Kearney DL, et al.: The detection of viral genomes by polymerase chain reaction in the myocardium of pediatric patients with
advanced HIV disease. J Am Coll Cardiol 1999, 34(3):857865.

22

Burton BK: Inborn errors of metabolism in infancy: a guide to diagnosis.

Pediatrics 1998, 102(6):1471.

23

Arola A, Kallajoki M, Ruuskanen O, et al.: Detection of enteroviral RNA in

end-stage dilated cardiomyopathy in children and adolescents. J Med Virol
1998, 56(4):364371.

24

Shaddy RE, Bullock EA: Efficacy of 100 consecutive right ventricular

endomyocardial biopsies in pediatric patients using the right internal
jugular venous approach. Pediatr Cardiol 1993, 14:58.

Acknowledgment
The author is indebted to the members of the Pediatric Heart Transplant Study
Group for their dedication and support.

References and recommended reading

Papers of particular interest, published within the annual period of review,
have been highlighted as:

Of special interest
Of outstanding interest

Boucek MM, Faro A, Novick RJ, et al.: The Registry of the International
Society of Heart and Lung Transplantation: Third Official Pediatric Report
1999. J Heart Lung Transplant 1999, 18(12):11511172.
The annual report of the ISHLT Registry provides an excellent overview of
survival of transplantation in children. In addition to cardiac transplantation, the
Registry Report provides information on heart-lung and lung transplantation.

4
Schwartz ML, Cox GF, Lin AE, et al.: Clinical approach to genetic
cardiomyopathy in children. Circulation 1996, 94(8):20212038.

This summary is truly excellent and deals with the genetics of cardiomyopathy in
a comprehensive way. The authors also give useful insight into associated
disease states and the management of pediatric patients presenting with
cardiomyopathy.
5

McGiffin DC, Naftel DC, Kirklin JK, et al., and the Pediatric Heart
Transplant Study Group: Predicting outcome after listing for heart transplantation in childen: comparison of Kaplan-Meier and parametric competing risk analysis. J Heart Lung Transplant 1997, 16:713722.
This report from the Pediatric Heart Transplant Study is the first to emphasize
the need for competing outcomes analysis to correctly analyze outcome after
listing for transplantation. It sets the standard for statistical analysis in the setting
of multiple, potentially mutually exclusive, outcomes.

25

26

Morrow WR, Naftel DC, Chinnock R, et al., and the Pediatric Heart
Transplant Study Group: Outcome of listing for heart transplantation in

Drucker NA, Colan SD, Lewis AB, et al.: Gamma-globulin treatment of

acute myocarditis in the pediatric population. Circulation 1994,
89(1):252257.
Although not a controlled study, this report provides useful and encouraging
data in pediatric patients with myocarditis.
Ahdoot J, Galindo A, Alejos JC, et al.: Use of OKT3 for acute myocarditis in
infants and children. J Heart Lung Transplant, in press.

Cardiomyopathy and heart transplantation in children Morrow 223

27

Frazier EA, Faulkner SC, Seib PM, et al.: Prolonged extracorporeal life
support for bridging to transplant: technical and mechanical considerations. Perfusion 1997, 12:9398.

44

Bailey LL, Razzouk AJ, Wang N, et al.: Bless the babies: one hundred
fifteen late survivors of heart transplantation during the first year of life. J
Thorac Cardiovasc Surg 1993, 105: 805815.

28

del Nido PJ, Armitage JM, Fricker FJ, et al.: Extracorporeal membrane
oxygenation support as a bridge to pediatric heart transplantation.
Circulation 1994, 90(5):6669.

45

Canter CE, Moorhead S, Huddleston CB, Spray TL: Restrictive atrial

communication as a determinant of outcome of cardiac transplantation for
hypoplastic left heart syndrome. Circulation 1993, 88:II-456II-460.

29

Galantowicz ME, Stolar CJ: Extracorporeal membrane oxygenation for perioperative support in pediatric heart transplantation. J Thorac Cardiovasc
Surg 1991, 102:148152.

46

Merrill WH, Frist WH, Stewart JR, et al.: Heart transplantation in children.
Ann Surg 1991, 213:393398.

47

30

Weyend M, Kececioglu D, Kehl HG, et al.: Neonatal mechanical bridging to

total orthotopic heart transplantation. Ann Thorac Surg 1998,
66:519522.

Backer CL, Zales VR, Idriss FS, et al.: Heart transplantation in neonates
and in children. J Heart Lung Transplant. 1992, 11:311319.

48

Bailey LL, Wood M, Razzouk A, et al.: Heart Transplantation during the first
12 years of life. Arch Surg 1989, 124:12211226.

31

Hetzer R, Loebe M, Potapov EV, et al.: Circulatory support with pneumatic

paracorporeal ventricular assist device in infants and children. Ann Thorac
Surg 1998, 66:14981506.

49

Armitage JM, Fricker FJ, del Nido P, et al.: A decade (1982992) of pediatric cardiac transplantation and the impact of FK506 immunosuppression.
J Thorac Cardiovasc Surg 1993, 105:464472.

32

Sidiropoulos A, Hotz H, Konertz W: Pediatric circulatory support. J Heart

Lung Transplant 1998, 17:11721176.

50

Radley-Smith RC, Yacoub MH: Long-term results of pediatric heart transplantation. J Heart Lung Transplant 1992, 11:s227281.

33

Seib PM, Faulkner SC, Erickson CC, et al.: Blade and balloon atrial
septostomy for left heart decompression in patients with severe ventricular
dysfunction on extracorporeal membrane oxygenation. Cathet Cardiovasc
Intervent 1999, 46(2):179186.

51

Baum D, Bernstein D, Starnes VA, et al.: Pediatric heart transplantation at

Stanford: results of a 15-year experience. Pediatrics 1991, 88:203214.

52

34

Shaddy RE, Tani LY, Gidding SS, et al.: Beta-blocker treatment of dilated
cardiomyopathy with congestive heart failure in children: a MultiInstitutional Experience. J Heart Lung Transplant 1999, 18(3):269274.

Starnes VA, Bernstein D, Oyer PE, et al.: Heart transplantation in children. J

Heart Lung Transplant 1989, 8:2026.

53

Brune L, Kichuk MR, Lamour JM, et al.: Carvedilol as therapy in pediatric

heart failure: an initial multi-center experience. Circulation 1999, 100(18):I530.

Slaughter MS, Braunlin E, Bolman RM, et al.: Pediatric heart transplantation: results of 2- and 5-year follow-up. J Heart Lung Transplant 1992,
11:311319.

54

Turrentine MW, Kesler KA, Caldwell R, et al.: Cardiac transplantation in

infants and children. Ann Thorac Surg 1994, 57:546554.

55

Shaddy RE, Naftel DC, Kirklin JK, et al., for the Pediatric Heart Transplant
Study: Outcome of cardiac transplantation in children: Survival in a
contemporary multi-institutional experience. Circulation 1996, 94(suppl
II):II-69II-73.

56

Canter C, Naftel DC, Caldwell R, et al., and the Pediatric Heart Transplant
Study Group: Survival and risk factors for death after cardiac transplantation in infants: a multi-institutional study. Circulation 1997, 96:227231.

57

Fullerton DA, Campbell DN, Jones SD, et al.: Heart transplantation in children and young adults: early and intermediate-term results. Ann Thorac
Surg 1995, 59:804812.

58

Livi U, Luciani GB, Boffa GM, et al.: Clinical results of steroid-free induction
immunosuppression after heart transplantation. Ann Thorac Surg 1993,
55:11601165.

59

Webber SA: 15 years of pediatric heart transplantation at the University of

Pittsburgh: lessons learned and future prospects. Pediatric Transplantation
1997, 1:821.

60

Pahl E:. Transplant coronary artery disease in children. Progr Pediatr

Cardiol 2000, 11:137143.

61

Frazier EA, Naftel DC, Canter CE, et al., and the Pediatric Heart Transplant
Study Group: Death after cardiac transplantation in children: who dies,
when, and why [abstract]. J Heart Lung Transplant 1999, 18:6970.
Chinnock RE: Clinical outcome 10 years after infant heart transplantation.
Progr Pediatr Cardiol, in press 2000, 11:165169.

35

36

Wiles HB, McArthur PD, Taylor AB, et al.: Prognostic features of children
with idiopathic dilated cardiomyopathy. Am J Cardiol 1991,
68:13721376.

37

Dubin AM, Rosenthal DN, Chin C, et al.: QT dispersion predicts ventricular

arrhythmia in pediatric cardiomyopathy patients referred for heart transplantation. J Heart Lung Transplant 1999, 18(8):781785.

38

Silka MJ: Implantable cardioverter-defibrillators in children: a perspective

on current and future uses. J Electrocardiol 1996, 29(Suppl):223225.

39

Fricker FJ, Addonizio L, Bernstein D, et al.: Heart transplantation in children: indications. Report of the Ad Hoc Subcommittee of the Pediatric
Committee of the American Society of Transplantation (AST). Pediatric
Transplantation 1999, 3(4):333342.
This is an important review of the current indications for cardiac transplantation
in children authored by leaders in the field. The group also considers a number
of controversial issues with regard to transplantation and provides insight on
managing patients with potential contraindications.
40

Gajarski RJ, Towbin JA, Bricker JT, et al.: Intermediate follow-up of pediatric
heart transplant recipients with elevated vascular resistance index. J Am
Coll Cardiol 1994, 23:1682.

41

Shaddy RE: Pulmonary hypertension in pediatric heart transplantation.

Progr Pediatr Cardiol 2000, 11:131136.

42

Zales V, Pahl E, Backer C, et al.: Pharmacologic reduction of pretransplant

pulmonary vascular resistance predicts outcome after pediatric heart transplantation. J Heart Lung Transplant 1993, 12:965973.

62

Kieler-Jensen N, Ricksten S, Stenqvist O, et al.: Inhaled nitric oxide in the

evaluation of heart transplant candidates with elevated pulmonary vascular
resistance. J Heart Lung Transplant 1994, 13(3):366375.

63 Platt JL: Prospects for xenotransplantation. Pediatr Transplantation 1999,

3:193200.

This is an excellent review of the state of the art of xenotransplantation research.

43