Cardiomyopathy is one of the most common causes of deathin children with heart disease. Increasingly, dilated cardiomy-opathy is recognized to be familial, and specific gene productsrelated to the myocyte cytoskeleton and contractile proteinshave been identified. Other associations with metabolicdisease, dysmorphic syndromes, and neuromuscular diseaseare important to establish, particularly in pediatric patients, toguide therapy and patient selection for transplantation. Survivalin children with dilated cardiomyopathy depends on accuratediagnosis and aggressive therapy. Patients may respond toconventional treatment for heart failure or may deteriorate,requiring mechanical support. Extracorporeal membraneoxygenation has been used effectively for mechanical supportin children until improvement occurs or as a bridge to trans-plantation. For those who are listed, the mortality rate whilewaiting for a donor organ averages approximately 20%.Survival after transplantation is good, with an intermediatesurvival rate of approximately 70%. Late survival remains to bedetermined in the current cyclosporin era but may in fact beimproving. However, increased organ donation or strategies toincrease the size of the organ donor pool, such as xenotrans-plantation, are needed to significantly reduce the rate ofmortality while waiting. Curr Opin Cardiol 2000, 15:216223 2000Lippincott Williams & Wilkins, Inc.

From the Division of Pediatric Cardiology, Department of Pediatrics, University ofArkansas for Medical Sciences and Arkansas Childrens Hospital, Little Rock,Arkansas, USA

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

Current Opinion in Cardiology 2000, 15:216223

Abbreviations

ECMO extracorporeal membrane oxygenationISHLT International Society for Heart and Lung TransplantationPHTS Pediatric Heart Transplant Study

ISSN 02684705 2000 Lippincott Williams & Wilkins, Inc.

Cardiomyopathy and cardiac transplantationin childrenCardiomyopathy is one of the leading causes of death ininfants and children with heart disease [1,2]. Yetprospects for survival in this group of patients havenever been better, owing to progress in medical therapyof heart failure, largely reported in adults, and improvingresults of cardiac transplantation [3]. Increasing appre-ciation for genetic and metabolic etiologies has led toearlier detection of cardiomyopathy in patients withfamilial disease, specific therapy in some with metaboliccardiomyopathy, and more selective use of cardiac trans-plantation in others [2,4]. However, despite therapidly increasing availability of genetic and metabolicdiagnosis, specific metabolic therapy is available, regret-tably, in only rare instances, and hopes for specific genetherapy for most cardiomyopathies are as yet unrealized.Survival is good after cardiac transplantation, but onaverage 20% of patients die waiting for a donor heart[57,8]. There is also concern regarding long-termsurvival in pediatric heart transplant recipients, an areawhere expectations for greater longevity are clearlyjustified. In this article we review recent developmentsin the diagnosis and treatment of myocardial disease inchildren, specifically dilated cardiomyopathy, anddiscuss results of cardiac transplantation in pediatricpatients.

Classification of cardiomyopathyFor the purposes of this review, we define cardiomyopa-thy as diseases of heart muscle excluding ischemic andhypertensive cardiomyopathy [2]. The World HealthOrganization classification of cardiomyopathy is stillwidely employed in the evaluation of children.However, this classification of cardiomyopathy is onlyloosely related to the major pathophysiologic alterationsfound in patients with cardiomyopathy. These arereduced systolic function, diastolic dysfunction, adrener-gic dysfunction, and, in the case of hypertrophiccardiomyopathy, obstruction. The understanding ofpathophysiology is of at least equal clinical importanceto the description of pathology, although the latter isuseful in understanding natural history and prognosis.Most patients have mixed pathophysiology. Patientswith dilated cardiomyopathy typically have systolic anddiastolic dysfunction as well as alterations in adrenergictone. Also, a variety of etiologies account for similar ifnot identical clinical pathophysiologic varieties ofcardiomyopathy, and different pathophysiologies maybe present in different patients with the same etiology.

216

Cardiomyopathy and heart transplantation in childrenW. Robert Morrow, MD

From a clinical perspective, the pathophysiologic classi-fication of cardiomyopathy is currently most useful inguiding treatment. However, cardiomyopathy in chil-dren may also be classified according to certain otherclinical associations, including the presence of biochem-ical abnormalities at diagnosis, encephalopathy (includ-ing developmental delay), associated dysmorphicfeatures, coexisting neuromuscular disease, or cardiomy-opathy without other associations [4]. This classificationis useful in formulating an approach to diagnosis inwhich associated metabolic disease, neuromusculardisease, malformation syndromes, and familial associa-tions may exist. Recognizing underlying neuromuscular,metabolic, and genetic disease is key to guiding deci-sions regarding the use of selective therapy or cardiactransplantation [1,2,4].

Etiology of cardiomyopathyDilated cardiomyopathy has also been termed idio-pathic, a designation that may no longer be relevant.Cardiomyopathy may have a variety of causes, includinggenetic, infectious, metabolic, and toxic, among others.Exhaustive lists of possible etiologies have beenpublished elsewhere [1,4]. Table 1 summarizes themore common etiologies encountered in clinical practiceand some of the most important uncommon diagnoses.

Dilated cardiomyopathy has often been thought of as asequela of viral myocarditis. It is indeed clear that viralmyocarditis may lead to sustained cardiac dysfunction[9,10]. The presence of viral genome and inflammatoryinfiltrate on biopsy in patients with chronic ventriculardilatation and dysfunction also supports this view[9,10,11]. In the clinical setting of an acutely deterio-rating patient, the distinction between viral myocarditisand dilated cardiomyopathy may be difficult.

Familial dilated cardiomyopathyIncreasingly, dilated cardiomyopathy is being recog-nized to be familial because of a history of affectedparents or siblings [2]. From 20% to 65% of dilatedcardiomyopathy cases may be familial [2,11].Mestroni et al. [11] found a number of presentationsamong those patients with familial dilated cardiomy-opathy and distinguished five subtypes. Theseincluded patients with autosomal dominant inheritanceand isolated dilated cardiomyopathy, X-linked inheri-tance with defects of the dystrophin gene, autosomaldominant inheritance with subclinical skeletal muscledisease, dilated cardiomyopathy with conductiondefects, and other rare forms. X-linked dilatedcardiomyopathy, also involving a dystrophin genedefect isolated to myocardium, has been well described[12]. This progressive cardiomyopathy typically occursin adolescent males and follows an X-linked transmis-sion pattern. In the series by Mestrioni et al. [11],autosomal dominant transmission of dilated cardiomy-opathy is the most common pattern, followed by auto-somal recessive and X-linked inheritance. Currently, atleast 10 genes have been mapped to loci in familieswith autosomal dominant dilated cardiomyopathy[2,11], although not all have identified gene prod-ucts (Table 2). In addition to the dystrophinopathies,defects of other cytoskeletal proteins and of contractileproteins have been demonstrated to cause dilatedcardiomyopathy [11,1215].

Several genetic syndromes of importance are seen inchildren and illustrate the genetic complexity ofdilated cardiomyopathy. Barth syndrome, 3-methylglu-catonic aciduria, is characterized by dilated cardiomy-opathy, skeletal myopathy, neutropenia, and mitochon-drial abnormalities and is rapidly progressive. withdeath in infancy and X-linked inheritance[4].Duchenne muscular dystrophy and Becker musculardystrophy, both of which affect children with skeletalmuscle weakness, are associated with cardiomyopathyand defects of the dystrophin gene. Although X-linkedinheritance has been clearly demonstrated, carriers ofDuchenne muscular dystrophy have also been demon-strated to have evidence of cardiomyopathy byechocardiography, and there are reports of carrierspresenting with severe symptoms [1618]. In addition,

Cardiomyopathy and heart transplantation in children Morrow 217

*Mitochondrial encephalopathy, lactic acidosis, and stroke-likeepisodesMyoclonic epilepsy, ragged red fibers

ViralCoxsackievirus A and BEchovirusAdenovirusMumps

MetabolicThyrotoxicosisHypothyroidismCarnitine deficiency syndromeLeigh diseaseBarth syndrome*MELAS syndromeMERRF syndromeKearn-Sayre syndromeSengers syndrome

ToxicAnthracycline toxicityHemachromatosisAlcohol

Neuro/MuscularFriedreich ataxiaDuchenne muscular dystrophyBecker muscular dystrophy

Familial/GeneticX-linkedAutosomal dominantAutosomal recessiveAutosomal dominant dilated cardiomyopathy with conductiondefects

OtherIsolated ventricular noncompactionTachyarrhythmia induced

Table 1. Dilated cardiomyopathy: etiology

other familial dilated cardiomyopathies have beendescribed with defects of the G4.5 gene of chromo-some Xq28, including left ventricular noncompactionand cardiomyopathy [19]. Ichida et al. [20] recentlyreviewed the clinical features of isolated noncom-paction of the ventricular myocardium in the Japanesepopulation. This entity is characterized by ventriculardysfunction, systemic embolization, ventriculararrhythmia, and prominent left ventricular trabecula-tions. Although X-linked transmission has beenproposed, the equal representation of females amongaffected family members in this series suggests otherpotential inheritance patterns.

Other causes of dilated cardiomyopathyCardiomyopathy may also be caused by toxic exposureand may be preceded by viral infection. The mostcommon toxic cardiomyopathy commonly encounteredin children is the cardiomyopathy caused by anthracy-cline toxicity following treatment for childhood cancer.Viral etiologies have been established as the majorsource of the cardiomopathy in patients with HIV infec-tion [21]. Cardiomyopathy may be associated with neuro-muscular disease and metabolic disease [4,22]. Patientswith neuromuscular disease or metabolic disease usuallyhave some form of recognizable encephalopathy ormuscle weakness at presentation. These entities havebeen thoroughly reviewed, and an in depth discussion ofthese is beyond the scope of this report [4,22]. It isparticularly important to identify metabolic disease thatmay be treatable, such as some forms of carnitine defi-ciency and 3-hydroxyacyl coenzyme A dehydrogenasedeficiency, or diseases that may recur in patients whoundergo cardiac transplantation (storage disease).

Diagnostic evaluationInfants and children with cardiomyopathy present withsymptoms and signs of congestive heart failure or witharrhythmia, syncope, or sudden death. Myocarditis maybe present in 2 to 15% of children who present withcongestive failure but may be more common in infants[1]. The diagnosis of myocarditis may be establishedwith endomyocardial biopsy by standard histologic crite-ria or by demonstration of viral genome in cardiac tissue[2,9,10,11,23]. In fact, many patients with familialdilated cardiomyopathy may have associated cellularinfiltrate [11]. A careful history often reveals symp-toms of chronicity, which favor a diagnosis of cardiomy-opathy over myocarditis (poor feeding, exertionalfatigue). Often a diagnosis of cardiomyopathy is madeby exclusion of myocarditis on biopsy and lack ofimprovement of cardiac function over months followinga presentation with acute failure.

Schwartz et al. [4] reviewed the diagnostic evaluation ofcardiomyopathy in infants and children. History andphysical examination will direct the nature of the evalu-ation to be undertaken. Clearly, family history and eval-uation of first-degree relatives for cardiomyopathy isimportant in patients with isolated cardiomyopathy.First-degree relatives should undergo electrocardio-graphic and echocardiographic studies, since manyaffected individuals are asymptomatic. In all patients,routine electrolytes, creatinine, blood urea nitrogen,magnesium, calcium, and glucose measurements shouldbe obtained. An electrocardiogram may give specificindications of hypertrophic cardiomyopathy, storagedisease, and certain familial forms of cardiomyopathy,and may exclude an anomalous left coronary artery.When the clinical presentation with dilated cardiomy-opathy in an infant in the first 3 months of life iscompatible with anomalous left coronary artery, echocar-diography and angiography should be performed tomake or exclude the diagnosis. When metabolic acidosisis present or the patient is hypoglycemic or hyperam-monemic, a more thorough metabolic evaluation is indi-cated [4]. This is also true in patients with encephalopa-thy. Urine for amino acids and organic acids, serumlactate and pyruvate, quantitative ketones, blood foracyl carnitine, T4 and thyroid-stimulating hormone, andcreatine kinase should be obtained. For patients withdysmorphic features, developmental delay, or failure tothrive, a karyotype is also indicated. Endomyocardialbiopsy, although not without risk, has been shown to besafe and efficacious in infants and children [24] andshould be performed if other diagnostic studies fail toreveal a definitive diagnosis. As noted earlier, biopsymay be useful in excluding acute myocarditis, but cellu-lar infiltrates may be seen in patients with cardiomyopa-thy. Although routine histology usually demonstratesmyocyte hypertrophy and variable degrees of fibrosis,

218 Pediatrics

DCM, dilated cardiomyopathy; MD, muscular dystrophy.

Syndrome

X-linked DCMDuchene MDBecker MDBarth syndromeIsolated ventricular

noncompactionCardiomyopathy with MDFamilial DCM

(autosomal dominant)

Familial DCM withconduction defects

Systemic carnitinedeficiency

Loci

Xp21Xp21Xp21Xq28Xq28

17q12-2115q41q211q322q312q352q14-223p25-229q13-2210q21-231p1-q1

22q

Gene/Product

DystrophinDystrophinDystrophinTafazzin (G4.5)G4.5

Alpha sarcoglycanCardiac actinMetavinculinLamin A/Cdesmin

Carnitine palmityltransferase

Table 2. Dilated cardiomyopathy: genetics

myocardial biopsy is necessary for the diagnosis ofcardiac phosphorylase kinase deficiency. Skeletalmuscle biopsy, nerve conduction velocity studies, andelectromyography are useful in patients with suspectedneuromuscular disease.

Treatment of myocardial diseaseStabilizationInfants and children with dilated cardiomyopathy oftenpresent with congestive heart failure and are frequentlyprofoundly ill, requiring aggressive medical manage-ment to achieve stabilization. In addition to supplemen-tal oxygen and diuretic therapy, these children requireinotropic support with dobutamine and dopamine, andmany require mechanical ventilation. The addition ofmyocardial phosphodiesterase inhibitors, such as milri-none, may be very useful in providing additionalinotropic support and afterload reduction. Correction ofacidosis with sodium bicarbonate is important, providedthe patient has adequate ventilation. Arrhythmiamanagement is key and may require the use of intra-venous therapy for those with intractable ventriculararrhythmia.

Recent studies have demonstrated the usefulness ofexamining tissue for viral genome and may establish theetiology of myocarditis [9,10,11]. However, poly-merase chain reaction studies are seldom useful in themanagement of acutely ill children. Frequently, patientswho present with a clinical presentation compatible withmyocarditis are often treated empirically with either -globulin or corticosteroids. Some evidence existssuggesting that -globulin may be useful in reducingmorbidity and mortality of myocarditis in children [25].More aggressive treatment of myocarditis with otherimmunosuppressants and cytolytics has also beenproposed [26]. Patients with cardiac failure who fail torespond to therapy and continue to deteriorate, whetherdue to myocarditis or cardiomyopathy, should be consid-ered for mechanical support and are potential candidatesfor cardiac transplantation.

Mechanical support in childrenA number of investigators have demonstrated the effi-cacy of providing mechanical support of the circulation,principally by extracorporeal membrane oxygenation(ECMO) in children with refractory heart failure[2732]. Patients with myocarditis or cardiomyopathywho progress to cardiogenic shock despite maximalinotropic support should be placed on mechanicalsupport, provided contraindications do not exist. In chil-dren, the primary modality for mechanical supportcontinues to be ECMO. Left ventricular assist devicesare applicable only in some adolescent patients,although devices for smaller children are currently beingevaluated [3032]. When patients with left ventricular

failure are placed on ECMO, left ventricular ejectionmay cease, leading to left atrial hypertension andpulmonary venous congestion. Adequate decompressionof the left atrium is essential in reducing left ventricularwall stress and preventing pulmonary complications ofpulmonary venous congestion. Seib et al. [33] hasdescribed the technique for blade and balloon atrialseptostomy in patients requiring ECMO and demon-strated the superiority of this technique to surgicaldecompression. Patients with myocarditis may improveand be weaned from support. It is clear that a majority ofpatients with acute cardiac failure can either be weanedfrom support or are successfully transplanted, althoughthe rate of mortality while waiting is certainly significant[27,28]. It is most important to progress to mechanicalsupport prior to cardiac arrest or onset of generalizedorgan failure. The prognosis for full recovery with orwithout transplant is much poorer if cardiac arrest hasoccurred prior to instituting mechanical support.

Chronic heart failure managementStudies in adults with heart failure have shown substan-tial benefit for aggressive treatment of heart failure. Inaddition to the beneficial effects of digoxin and diuret-ics, therapy directed at the pathophysiology of the acti-vation of the sympathetic axis have proven benefit.Children with heart failure should receive digoxin,diuretics including spironolactone, and angiotensin-converting enzyme inhibitors. Studies of heart failuretreatment directed at reducing the effects of adrenergicactivation have been limited in children. The benefit ofmetoprolol in the treatment of heart failure [34] andinitial studies with carvedilol have shown encouragingresults [35]. However, owing to the small number ofpediatric patients with heart failure at any individualcenter, these studies have had low statistical power.Also, the pathophysiology of heart failure in childrenmay be different. Children characteristically presentwith fewer symptoms for any given degree of leftventricular dysfunction and have worse ventricular func-tion at presentation. Therefore, the end points forimprovement in children may in fact be different fromthose in studies in adults. Prospective multicenter trialsare currently underway to evaluate the effect of beta-blockade in pediatric cardiomyopathy patients. The useof beta-blockade should be undertaken cautiously untilfurther evidence of efficacy is forthcoming.

Patients with severe systolic dysfunction and severe leftventricular dilatation should be treated with anticoagu-lants, preferably coumadin, to prevent the developmentof intracardiac thrombus and systemic embolization.Arrhythmia should be treated aggressively, as suddendeath is a common cause of death for patients withdilated cardiomyopathy. Predictors of sudden death indilated cardiomyopathy are few. Clearly preexisting

Cardiomyopathy and heart transplantation in children Morrow 219

arrhythmia is a risk factor for sudden death in children[36]. QT dispersion may be associated with greaterarrhythmia and therefore be a risk factor for suddendeath [37]. Patients with more severe cardiomyopathy,such as greater degrees of ventricular dilatation andworse systolic dysfunction, as well as patients withpulmonary hypertension, may be more likely to diesuddenly. Since many anti-arrhythmic agents have nega-tive inotropic effects, treatment may lead to a deteriora-tion in cardiac function. Amiodarone may be the bestagent for treating arrhythmia, particularly in patientslisted for cardiac transplantation. Although experience islimited, the use of implantable defibrillators has beeneffective in pediatric patients large enough for thesedevices [38]. Patients who continue to deteriorateshould be considered for mechanical support [2732].

Cardiac transplantationIndications for listingThe registry of the International Society for Heart andLung Transplantation (ISHLT) records 4178 cardiactransplant procedures in children, ranging from 147 in1987 to 324 in 1998 [3], although the frequency of trans-plantation has declined slightly since a peak of 395 in1993. The indications for cardiac transplantation in chil-dren were recently reviewed by Fricker et al. [39].Patients with refractory symptomatic heart failure arecandidates for listing for transplantation providedcontraindications do not exist. Serious central nervoussystem, renal, hepatic, and pulmonary dysfunction arecontraindications in children as in adults. Patients withBecker muscular dystrophy may be successfully trans-planted depending on the severity of their skeletalmyopathy.

Pulmonary hypertension may be a contraindication totransplant in some patients with dilated cardiomyopa-thy. The upper limit of pulmonary resistance associatedwith successful cardiac transplantation has not beenestablished [39,40,41,42,43]. Transplantation inpatients with pulmonary arteriolar hypertension inexcess of 5 Wood units or a transpulmonary gradientgreater than 15 mm Hg is potentially contraindicated.However, if pulmonary resistance is reactive anddecreases with the administration of oxygen, nitricoxide, or prostaglandin, transplantation is not necessarilycontraindicated. All patients with elevated pulmonaryresistance must undergo hemodynamic testing to estab-lish both resting and best pulmonary arteriolar resistanceand transpulmonary gradient prior to transplantation orexclusion from listing. Best values should always includeresponse to oxygen and nitric oxide, but the latter maybe omitted if resistance falls into an acceptable rangewith other interventions (inotropic agents, intravenousafterload reduction, prostaglandin)[43]. When theresponse is marginal, repeat values after a 1- to 2-week

course of intravenous inotropic support, afterload reduc-tion, and pulmonary vasodilatation may demonstrateimprovement. Patients known to have marginal valuesshould be tested at least every 6 months while waitingfor transplantation, since reactive pulmonary hyperten-sion may worsen and become fixed. Patients with fixedelevation of pulmonary resistance on the basis of cardiacfailure may be candidates for heart-lung transplantation.Fricker et al. [39] discuss other potential contraindica-tions to transplantation.

Outcome of listing for transplantationVery few studies have addressed pretransplant mortalityin infants and children after listing for cardiac transplan-tation. However, death after listing is not the onlypotential outcome of listing for transplantation. Any offour potential outcomes may occur after listing, includ-ing death while waiting, transplantation, removal fromthe list, or continuing on the list waiting for transplanta-tion. Competing outcome analysis has been used todescribe outcome after listing for transplant in pediatricpatients in the Pediatric Heart Transplant Study(PHTS)[57,8]. McGiffin et al. [5] reported outcome oflisting in 264 pediatric patients listed for transplantationover a 1-year period. Patients ranged in age from 3 daysto 17.9 years, with a mean age of 4.7 years. In this initialreport from the PHTS, 60% of patients underwenttransplantation by 6 months after listing, 23% died whilewaiting, 14% remained on the list awaiting transplanta-tion, and 4% improved and were removed from the list.In a separate analysis of infants (less than 6 months ofage) who were listed for transplantation [6], nearly onethird of infants died awaiting transplantation, although60% did undergo transplantation by 6 months. Only 6%remained on the list awaiting transplantation. The useof blood type O donors (universal donor) in non-bloodtype O recipients resulted in more deaths while waitingamong blood type O patients. In older children, deathwas more likely to occur in Status 1 patients andpatients requiring mechanical ventilation [7]. UNOSpolicy now prioritizes allocation of type O donor heartsto type O recipients. In addition, under new urgencystatus categories (Status 1a, Status 1b, and Status 2)prostaglandin-dependent infants with greater than 50%systemic pulmonary artery pressure (prostaglandin-dependent, single-ventricle physiology) are prioritizedto Status 1a, the most urgent status. Whether thesechanges ultimately lead to more equitable organ distrib-ution remains to be determined.

Survival after transplantationA number of institutions have reported excellent earlyand intermediate survival in both infants and children[4454] following cardiac transplantation. When all agegroups and diagnoses are analyzed together, an actuarialsurvival of at least 75 to 85% at 1 year and 65 to 75% at 5

220 Pediatrics

years is seen. Survival data reported by the Registry ofthe ISHLT are more or less in keeping with othermulticenter studies and single-institution experiences[3]. Shaddy et al. [55] and Canter et al. [56] havereported survival in infants and older children in thePHTS experience. Survival in the recent PHTS experi-ence indicates some improvements over time [8]. One-year survival among infants less than 1 year of age attransplant 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 thePHTS study was also virtually identical to survivalamong adults and was approximately 70% (Fig. 1).There was no difference in survival between patientswith congenital heart disease and those with cardiomy-opathy. A number of individual programs have recentlyreported survival in excess of 90% (Morrow WR, FrazierEA, unpublished data, 1999) [57,58]. Four-year survivalhas improved at Arkansas Childrens Hospital from thefirst to the second half of our transplant experience(Morrow WR, Frazier EA, unpublished data, 1999). Aninitial survival of 61% at 4 years is now 94% in thecurrent era. The most current analysis of data from theISHLT registry also demonstrates a generally improvingsurvival rate over the period of data collection. Factorsaccounting for this apparently improving survival ratehave not yet been determined.

Late survivalAttention has recently turned to late survival in childrenafter cardiac transplantation. In particular, there isconcern about increasing attrition with age because oflate complications such as late rejection due to noncom-pliance and occurrence of graft atherosclerosis. Few data

are available regarding long-term survival in pediatricheart transplant recipients. Late survival at Stanford wasdisappointingly low, with a reported 10-year survivalrate of 60% [8]. Importantly, many patients underwenttransplantation prior to the cyclosporin era. The ISHLTregistry report gives an 8-year actuarial survival rate ofapproximately 55% for all ages [3]. Long-term survivalamong patients transplanted early in the pediatric hearttransplant experience of some institutions appears to beless favorable than current survival [59]. Ultimately,improvements in early survival will translate into betterlate survival. Since most late deaths occur due to rejec-tion or rejection-related complications such as graftvasculopathy [60,61], the development of new immuno-suppressive agents promises to lead to improving long-term survival as well. Death from myocardial infarctionremains decidedly uncommon within 5 years of trans-plantation in children, although a disturbing increase insudden deaths has been observed [61]. Data from therecent Loma Linda experience indicate that latesurvival in neonates may in fact be superior to that inolder infants [62]. With improved rejection surveillanceand treatment in these high-risk patients and with new,more effective immunosuppressive regimens on thehorizon, mortality from rejection can potentially bereduced. Likewise, since graft atherosclerosis is at leastin part a rejection phenomenon, improved treatment ofrejection could lead to a reduced incidence and severityof graft coronary disease.

ConclusionsIn the past, the diagnosis of dilated cardiomyopathy inchildren was associated with a generally poor prognosis.However, with improved diagnosis, hopefully before

Cardiomyopathy and heart transplantation in children Morrow 221

Actuarial survival in pediatric patients 0 to 18 years of agewho underwent primary cardiac transplantation betweenJanuary 1, 1993 and December 31, 1998 in centers of thePediatric Heart Transplant Study. Mortality after transplan-tation is characterized by an early phase of risk followed bya constant phase of lower risk of death.

0

Surv

ival

, %

Years after transplant

0

20

10

30

50

40

60

70

80

90

100

653 41 2

PHTS: Jan 1993Dec 1998All institutions

Event: death after transplantation

Primary transplants: (n = 847)Years1/121/212345

Survival, %92868481787573

Figure 1. Actuarial survival percentages

222 Pediatrics

symptoms become severe, and with improved medicaltherapy, it is likely that many children will survive withouttransplantation. The promise of specific therapy for mostpatients with dilated cardiomyopathy is as yet unrealized.However, when medical therapy fails, heart transplanta-tion is effective and can provide good intermediate-termsurvival. Lack of availability of donors results in significantmortality while waiting among pediatric patients awaitingheart transplantation, although most eventually undergosuccessful transplantation. In fact, this mortality rate isvirtually equal to the 5-year mortality rate after transplant.Survival after transplantation in infants and children isequal to if not better than survival in adults. Despite latesurvival estimates of 50% at 10 years, early and intermedi-ate survival rate may be improving, based on recentstudies at individual institutions (Morrow WR, Frazier EA,unpublished data, 1999) [57,58] and multicenter studies[3,8]. The recent development of new immunosuppres-sive agents may also significantly affect long-term survivalby reducing the incidence and severity of acute andchronic rejection. However, increased organ donation orstrategies to increase the size of the organ donor pool, suchas xenotransplantation [63], are needed to significantlyreduce overall mortality.

AcknowledgmentThe author is indebted to the members of the Pediatric Heart Transplant StudyGroup for their dedication and support.

References and recommended readingPapers of particular interest, published within the annual period of review,have been highlighted as: Of special interest Of outstanding interest

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

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 comprehe-sive fashion. The author is expert in both the genetics of cardiomyopathy andtreatment by cardiac transplantation.

3 Boucek MM, Faro A, Novick RJ, et al.: The Registry of the International

Society of Heart and Lung Transplantation: Third Official Pediatric Report1999. J Heart Lung Transplant 1999, 18(12):11511172.

The annual report of the ISHLT Registry provides an excellent overview ofsurvival of transplantation in children. In addition to cardiac transplantation, theRegistry 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 ina comprehensive way. The authors also give useful insight into associateddisease states and the management of pediatric patients presenting withcardiomyopathy.

5 McGiffin DC, Naftel DC, Kirklin JK, et al., and the Pediatric Heart

Transplant Study Group: Predicting outcome after listing for heart trans-plantation in childen: comparison of Kaplan-Meier and parametric compet-ing risk analysis. J Heart Lung Transplant 1997, 16:713722.

This report from the Pediatric Heart Transplant Study is the first to emphasizethe need for competing outcomes analysis to correctly analyze outcome afterlisting for transplantation. It sets the standard for statistical analysis in the settingof multiple, potentially mutually exclusive, outcomes.

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

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

7 Addonizio L, Naftel D, Fricker J, et al., and the Pediatric Heart TransplantStudy Group: Risk factors for pretransplant outcome in children listed forcardiac transplantation: a multi-institutional study (abstract). J Heart LungTransplant 1995, 14:S48.

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

9 Griffin LD, Kearney D, Ni J, et al.: Analysis of formalin-fixed and frozenmyocardial autopsy samples for viral genome in childhood myocarditis anddilated cardiomyopathy with endocardial fibroelastosis using polymerasechain reaction (PCR). Cardiovasc Pathol 1995, 4:311.

10 Bowles NE, Richardson PJ, Olsen EGJ, et al.: Detection of coxsackie-B-virus specific RNA sequences in myocardial biopsy samples from patientswith 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 Cardiol1999, 34:181190.

In this article, data are presented from an impressive series of patients withdilated cardiomyopathy. The authors define subtypes of familial cardiomyopathyand in doing so propose a useful framework for classification. The paperincludes 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 adystrophin-associated glycoprotein (adhalin) in a patient with musculardystrophy and cardiomyopathy. N Engl J Med 1996, 334:362366.

14 Maeda M, Holder E, Lowes B, Bies RD: Dilated cardiomyopathy associatedwith deficiency of the cytoskeletal protein metavinculin. Circulation 1997,95:1720.

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

16 Politano L, Nigro V, Nigro G, et al.: Development of cardiomyopathy infemale carriers of Duchenne and Becker muscular dystrophies. JAMA1996, 275(17):13351338.

17 Hoogerwaard EM, Bakker E, Ippel PF, et al.: Signs and symptoms ofDuchenne muscular dystrophy and Becker muscular dystrophy amongcarr iers in The Netherlands: a cohort study. Lancet 1999,353(9170):21162119.

18 Melacini P, Fanin M, Angelini A, et al.: Cardiac transplantation in aDuchenne muscular dystrophy carrier. Neuromuscular Disorders 1998,8:585590.

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

20 Ichida F, Hamamichi Y, Miyawaki T, et al.: Clinical features of isolatednoncompaction of the ventricular myocardium. J Am Coll Cardiol 1999,34:233240.

21 Bowles NE, Kearney DL, et al.: The detection of viral genomes by poly-merase chain reaction in the myocardium of pediatric patients withadvanced 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 inend-stage dilated cardiomyopathy in children and adolescents. J Med Virol1998, 56(4):364371.

24 Shaddy RE, Bullock EA: Efficacy of 100 consecutive right ventricularendomyocardial biopsies in pediatric patients using the right internaljugular venous approach. Pediatr Cardiol 1993, 14:58.

25 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 encouragingdata in pediatric patients with myocarditis.

26 Ahdoot J, Galindo A, Alejos JC, et al.: Use of OKT3 for acute myocarditis ininfants 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 lifesupport for bridging to transplant: technical and mechanical considera-tions. Perfusion 1997, 12:9398.

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

29 Galantowicz ME, Stolar CJ: Extracorporeal membrane oxygenation for peri-operative support in pediatric heart transplantation. J Thorac CardiovascSurg 1991, 102:148152.

30 Weyend M, Kececioglu D, Kehl HG, et al.: Neonatal mechanical bridging tototal orthotopic heart transplantat ion. Ann Thorac Surg 1998,66:519522.

31 Hetzer R, Loebe M, Potapov EV, et al.: Circulatory support with pneumaticparacorporeal ventricular assist device in infants and children. Ann ThoracSurg 1998, 66:14981506.

32 Sidiropoulos A, Hotz H, Konertz W: Pediatric circulatory support. J HeartLung Transplant 1998, 17:11721176.

33 Seib PM, Faulkner SC, Erickson CC, et al.: Blade and balloon atrialseptostomy for left heart decompression in patients with severe ventriculardysfunction on extracorporeal membrane oxygenation. Cathet CardiovascIntervent 1999, 46(2):179186.

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

35 Brune L, Kichuk MR, Lamour JM, et al.: Carvedilol as therapy in pediatricheart failure: an initial multi-center experience. Circulation 1999, 100(18):I-530.

36 Wiles HB, McArthur PD, Taylor AB, et al.: Prognostic features of childrenwith idiopathic di lated cardiomyopathy. Am J Cardiol 1991,68:13721376.

37 Dubin AM, Rosenthal DN, Chin C, et al.: QT dispersion predicts ventriculararrhythmia in pediatric cardiomyopathy patients referred for heart transplan-tation. J Heart Lung Transplant 1999, 18(8):781785.

38 Silka MJ: Implantable cardioverter-defibrillators in children: a perspectiveon current and future uses. J Electrocardiol 1996, 29(Suppl):223225.

39 Fricker FJ, Addonizio L, Bernstein D, et al.: Heart transplantation in chil-

dren: indications. Report of the Ad Hoc Subcommittee of the PediatricCommittee of the American Society of Transplantation (AST). PediatricTransplantation 1999, 3(4):333342.

This is an important review of the current indications for cardiac transplantationin children authored by leaders in the field. The group also considers a numberof controversial issues with regard to transplantation and provides insight onmanaging patients with potential contraindications.

40 Gajarski RJ, Towbin JA, Bricker JT, et al.: Intermediate follow-up of pediatricheart transplant recipients with elevated vascular resistance index. J AmColl 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 pretransplantpulmonary vascular resistance predicts outcome after pediatric heart trans-plantation. J Heart Lung Transplant 1993, 12:965973.

43 Kieler-Jensen N, Ricksten S, Stenqvist O, et al.: Inhaled nitric oxide in theevaluation of heart transplant candidates with elevated pulmonary vascularresistance. J Heart Lung Transplant 1994, 13(3):366375.

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

45 Canter CE, Moorhead S, Huddleston CB, Spray TL: Restrictive atrialcommunication as a determinant of outcome of cardiac transplantation forhypoplastic left heart syndrome. Circulation 1993, 88:II-456II-460.

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

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

48 Bailey LL, Wood M, Razzouk A, et al.: Heart Transplantation during the first12 years of life. Arch Surg 1989, 124:12211226.

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

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

51 Baum D, Bernstein D, Starnes VA, et al.: Pediatric heart transplantation atStanford: results of a 15-year experience. Pediatrics 1991, 88:203214.

52 Starnes VA, Bernstein D, Oyer PE, et al.: Heart transplantation in children. JHeart Lung Transplant 1989, 8:2026.

53 Slaughter MS, Braunlin E, Bolman RM, et al.: Pediatric heart transplanta-tion: 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 ininfants and children. Ann Thorac Surg 1994, 57:546554.

55 Shaddy RE, Naftel DC, Kirklin JK, et al., for the Pediatric Heart TransplantStudy: Outcome of cardiac transplantation in children: Survival in acontemporary multi-institutional experience. Circulation 1996, 94(supplII):II-69II-73.

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

57 Fullerton DA, Campbell DN, Jones SD, et al.: Heart transplantation in chil-dren and young adults: early and intermediate-term results. Ann ThoracSurg 1995, 59:804812.

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

59 Webber SA: 15 years of pediatric heart transplantation at the University ofPittsburgh: lessons learned and future prospects. Pediatric Transplantation1997, 1:821.

60 Pahl E:. Transplant coronary artery disease in children. Progr PediatrCardiol 2000, 11:137143.

61 Frazier EA, Naftel DC, Canter CE, et al., and the Pediatric Heart TransplantStudy Group: Death after cardiac transplantation in children: who dies,when, and why [abstract]. J Heart Lung Transplant 1999, 18:6970.

62 Chinnock RE: Clinical outcome 10 years after infant heart transplantation.Progr Pediatr Cardiol, in press 2000, 11:165169.

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.