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Heart Failure in Children: Etiology and Treatment

Joseph W. Rossano, MD, and Robert E. Shaddy, MD

A
lthough much of the care of pediatric patients with failure, and sepsis.4,7,8 Many of these morbidities are associ-
heart disease has focused on the treatment and pallia- ated with a striking increase in the risk of death (Figure 1).
tion of various forms of congenital heart disease, there It is unknown how many children have heart failure
is increasing recognition of the importance of heart failure in outside of the hospital. The annual incidence of cardiomyop-
child health.1 Many children with heart disease are at risk for athies has been reported as 1.1-1.2 per 100 000 children, with
developing heart failure, and heart failure can occur in the the peak incidence occurring in infancy (7.8-8.3 per 100 000
context of other diseases such as sepsis, cancer, and inflamma- per year).9,10 Although these patients are at risk for heart fail-
tory diseases. The diagnosis and treatment of heart failure in ure, not all will develop heart failure. Andrews et al11 reported
children has emerged during the past decade as a subspecialty that new-onset heart failure due to heart muscle disease
field within cardiology, with heart failure specialists being occurred at a rate of 0.87 per 100 000 children aged <16 years
trained at many centers throughout the world. As the field per year. Only 66% were free from death or transplantation 1
has expanded rapidly over time, this review will focus on the year later.11 This high risk of death or transplant has been
epidemiology of pediatric heart failure, the diagnosis and confirmed in multiple single-center and multicenter reports,
risk-stratification of patients with heart failure, advanced ther- with the 5-year transplant-free survival ranging from 50% to
apies for heart failure, and new paradigms for management. 65%.12-14 However, not all patients deteriorate, and a signif-
icant minority of patients will have meaningful recovery of
Epidemiology ventricular function.12,15

Heart failure is defined as a clinical and pathophysiologic Diagnosis and Risk Stratification
syndrome that results from any structural or functional
impairment of ventricular filling or ejection of blood.2 There The diagnosis of heart failure is made through a series of in-
is no single diagnostic test that establishes the diagnosis of vestigations that include history, physical examination, and
heart failure; rather, it remains a clinical diagnosis with char- diagnostic studies. It is generally possible to not only confirm
acteristic signs and symptoms resulting from a combination or refute the presence of heart failure in the pediatric patient
of circulatory, neurohormonal, and molecular abnormal- but also diagnose the structural abnormality that has caused
ities.1 Even though it is estimated that there are >5 million the heart failure. There is a long list of possible etiologies for
adults with heart failure, the prevalence of heart failure in pediatric heart failure, but this review will focus on the etiol-
children is not known.3 This is in part due to the diverse dis- ogies that relate to abnormalities of systemic ventricular sys-
eases that lead to heart failure including simple and complex tolic function. Other causes that will not be discussed are
forms of congenital heart diseases, cardiomyopathies, those that are related to left-to-right intracardiac shunts
rhythm abnormalities, and acquired conditions such as that result in pulmonary overcirculation and those related
myocarditis and Kawasaki disease.4-6 to the unique abnormalities after the Fontan operation.
In the US, there are currently >14 000 pediatric heart fail- Most causes of systemic ventricular systolic dysfunction in
urerelated hospitalizations annually, which corresponds to children that can lead to heart failure can be categorized as
14-18 hospitalizations per 100 000 children.4 The majority a form of dilated cardiomyopathy. The list of potential causes
of these children have some form of congenital heart disease, of this in children is very long, but most causes can be divided
although a significant number have a form of cardiomyopa- into several large categories: intrinsic myopathies, congenital
thy or myocarditis. This is a disease state associated with sig- heart disease, acquired conditions, arrhythmias, or ischemic
nificant morbidity and mortality.7 The overall hospital (Table).16 A thorough history (including family and social
mortality is 7%, and because the hospital mortality for chil- history) will reveal possible risk factors that could account
dren is very low, children whose hospitalization is compli- for or contribute to heart failure. This includes
cated by heart failure have a >20-fold increase in the risk of developmental and growth history, respiratory and/or
death.4 Patients hospitalized with heart failure are at risk exercise symptoms, infectious or toxic exposures, and
for multiple morbidities including respiratory failure, renal previous surgeries or interventions. Abnormal development

From the The Cardiac Center, The Childrens Hospital of Philadelphia, and the
ACE Angiotensin-converting enzyme Department of Pediatrics, Perelman School of Medicine at the University of
Pennsylvania, Philadelphia, PA
BNP B-type natriuretic peptide
The authors declare no conflicts of interest.
ECMO Extracorporeal membrane oxygenation
VAD Ventricular assist device 0022-3476/$ - see front matter. Copyright 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jpeds.2014.04.055

228
Vol. 165, No. 2  August 2014

Figure 1. Hospital mortality of children with heart failure related hospitalizations. CVD, cerebrovascular disease; HTN, hyper-
tension. *Indicates a significantly increased hospital mortality (P < .05). Reproduced with permission from Rossano et al.4

can suggest a possible genetic abnormality that can include Toxic exposures are generally easy to diagnose (eg,
cardiac abnormalities. Abnormal growth could suggest the anthracyclines). In those patients with no previous medical
same but could also point toward a more longstanding history and with evidence of systemic ventricular
cardiac problem. The duration and severity of respiratory dysfunction, a thorough family history can help determine
and/or exercise abnormalities can also provide clues as to possible genetic causes. In those with a history of
the timing of cardiac compromise. Infectious illnesses can congenital heart disease, a complete review of all medical
either be an etiologic factor in heart failure or possibly records and imaging studies is necessary.
contribute to an increase in metabolic demands in a child A complete physical examination is also necessary to deter-
and therefore unmask an underlying cardiac problem. mine the presence of heart failure and to determine its
severity. Vital signs (including 4 extremity blood pressures)
can provide important information about hemodynamic sta-
Table. Etiologies of dilated cardiomyopathy tus. Four-extremity blood pressures, pulses, and perfusion
I. Intrinsic myopathies provide information about cardiac output and any aortic
a. Metabolic arch obstruction. A thorough respiratory examination can
b. Mitochondrial
c. Neuromuscular
assess for left-sided congestion, whereas hepatomegaly,
d. Familial peripheral edema, or jugular venous distention occurs with
e. Idiopathic right-sided congestion. Precordial examination may reveal
II. Congenital heart lesions (a few examples below)
a. Aortic valve stenosis
a prominent right-sided impulse in patients with elevated
b. Coarctation of the aorta right ventricular pressure (eg, pulmonary hypertension),
c. Volume overload lesions (eg, mitral valve regurgitation) whereas a prominent and displaced left-sided ventricular
III. Acquired conditions
a. Myocarditis
impulse suggests left ventricular hypertrophy, dilatation,
b. Drug- or toxin-related (eg, oncologic therapy, iron overload) and/or dysfunction. Heart tones can be soft in the presence
c. Anemia of very poor ventricular function or pericardial effusion.
d. Thyrotoxicosis
IV. Arrhythmias
An accentuated second heart sound can indicate elevated
a. Tachyarrhythmias (eg, longstanding supraventricular tachycardia) pulmonary artery pressures, which can reflect elevation in
b. Bradyarrhythmias (eg, congenital heart block) pulmonary venous pressure secondary to systemic ventricu-
V. Ischemic
a. Early coronary artery disease
lar dysfunction. A gallop rhythm is common in heart failure
b. Coronary anomaly due to ventricular dysfunction. A murmur may or may
c. Postoperative not contribute to the diagnosis of heart failure in a child.
Data from Gleason MM, Rychik J, Shaddy RE, eds. Pediatric practice: cardiology. New York: However, it is very common to have heart failure in the
McGraw-Hill; 2012. absence of a murmur, so the absence of a murmur should
229
THE JOURNAL OF PEDIATRICS  www.jpeds.com Vol. 165, No. 2

Figure 2. Multidisciplinary model for the care of pediatric heart failure patients. MD, medical doctor; NP, nurse practitioner; RN,
registered nurse.

not dissuade a clinician from considering a diagnosis of heart ill due to advanced heart failure. Echocardiographically,
failure. risk factors for worse outcomes include the degree of sys-
Although not an exact science, risk stratification of chil- temic ventricular dilation, the degree of depression in sys-
dren with heart failure is possible and is based on a large temic ventricular ejection fraction, and the degree of
number of findings. From the history, patients with long- systemic atrioventricular valve regurgitation.17-19 One retro-
standing feeding difficulties, respiratory symptoms, and/or spective analysis from the Pediatric Cardiomyopathy Regis-
failure to thrive secondary to systemic ventricular dysfunc- try determined 3 risk factors for sudden cardiac death in
tion generally have advanced heart failure. On physical exam- children with dilated cardiomyopathy: age <14 years at
ination, patients with respiratory distress and/or time of diagnosis, left ventricular end-diastolic dimension
hepatomegaly, with poor pulses, and with poor perfusion z-score >4, and a ratio of the left ventricular end-diastolic
due to systemic ventricular dysfunction are generally quite diameter to left ventricular posterior wall thickness of

Figure 3. Outline of diagnostic and therapeutic strategies in pediatric heart failure. ARB, angiotensin receptor blockers; ECG,
electrocardiogram; MRI, magnetic resonance imaging. Reproduced with permission from OConnor et al.47

230 Rossano and Shaddy


August 2014 MEDICAL PROGRESS

<0.14.17 Biomarkers have emerged as another metric for both there is compelling evidence in adults that ACE inhibitors
diagnosing and stratifying risk for heart failure in children. and b-blockers are efficacious in delaying the onset of symp-
The most extensively studied and widely used biomarkers toms. Stage C heart failure is the stage where patients develop
are B-type natriuretic peptide (BNP) and N-terminal pro- symptoms from a structural abnormality such as reduced ejec-
BNP.20-23 In a patient with evidence of fluid retention and/ tion fraction. In this stage, there is also a strong evidence base
or respiratory symptoms where there is concern for the pos- in adults that ACE inhibitors,30,31 b-blockers,32-35 and aldoste-
sibility of heart failure, BNP can help confirm or exclude a rone antagonists36,37 improve symptoms, ventricular function,
cardiac cause of these symptoms. In patients with known sys- and survival in patients with heart failure with reduced ejec-
temic ventricular dysfunction, the level of elevation of BNP tion fraction. Other medications used for the management
has been shown to be a discriminator for predicting future of chronic heart failure with reduced ejection fraction include
cardiac events or hospitalization.22,24 If the treatment of heart angiotensin receptor blockers in those patients intolerant to
failure is effective, one should see a decrease in BNP over ACE inhibitors. In children, there are no good data to conclu-
time.25 Although troponin leak reflects myocyte damage sively support or refute the use of these medications in stage B
and/or necrosis, one may see an elevated serum troponin or stage C heart failure.38 Although a randomized controlled
level in settings such as myocarditis, acute anthracycline trial of carvedilol did not show an improvement in outcomes
toxicity, or ischemic heart disease. Many new biomarkers vs control patients, these medications are commonly used and
are being studied in heart failure, primarily in adults.26 included in pediatric heart failure guidelines.39,40 There are
some data showing that certain etiologies, such as dystrophi-
New Paradigms in Pediatric Heart Failure nopathies, respond well to these medications.29,41,42 However,
it is much less clear whether these medications are of benefit in
The concept of pediatric heart failure as a subspecialty of pedi- pediatric patients with heart failure due to systemic ventricular
atric cardiology is relatively new. Pediatric heart failure as a systolic dysfunction whose systemic ventricle is a single or
discipline emerged from the development of pediatric heart right ventricle.39,43 Stage D heart failure is heart failure that re-
transplant programs in the 1980s and 1990s. As pediatric car- quires special interventions such as inotropes or mechanical
diologists started forming pediatric heart transplant programs, circulatory support. Even though inotropes are necessary to
it became apparent that the providers in these programs would improve perfusion in patients with low cardiac output, they
need to develop focus and expertise in the management of pe- are likely detrimental to long-term myocardial function.
diatric heart failure. There were 2 main reasons for this: (1) to Several studies in adult patients with heart failure have found
keep children with heart failure stable while awaiting heart increased mortality and side effects with the use of inotropic
transplantation; and (2) to optimize the treatment of heart medications.7,8,44-46 Limited data from pediatric heart failure
failure in children to avoid the need for heart transplantation patients also support this notion.7,8 Figure 3 provides a
whenever possible. Many of these pediatric heart transplant schematic for diagnosis and treatment of pediatric heart
centers soon realized that the best model for these programs failure from no symptoms through severe symptoms.47
was a multidisciplinary pediatric heart failure program that
included physicians, nurses, nurse practitioners, dieticians, so- Mechanical Circulatory Support and Heart
cial workers, and others. These programs have now become Transplantation
linked to other disciplines where children either are at risk
for heart failure or have developed heart failure. These other Heart failure is a progressive disease, and many children with
disciplines include neuromuscular disorders, oncology, ge- heart failure will progress to end-stage disease even with
netics, and others (Figure 2). This model is now widespread advanced medical therapy. Heart transplantation offers pro-
in the larger pediatric cardiology centers and provides a longed survival for patients with end-stage disease; however,
comprehensive, multidisciplinary, integrated approach to the the supply of available organs remains small relative to the
management of these complex children. number of patients that could potentially benefit from
With the onset of pediatric heart failure as a discipline, pe- them. There are <400 pediatric heart transplants performed
diatric cardiologists initially turned to their adult heart failure annually in the US, and the mortality while waiting for a heart
colleagues to extrapolate medical therapies that had been transplant remains high, especially for certain high-risk pop-
proved effective in the adult. Heart failure and its treatments ulations including infants, patients with congenital heart dis-
can be divided into 4 stages.27 Stage A is the stage where pa- ease, and those supported with extracorporeal membrane
tients are at risk for heart failure (eg, hypertension, diabetes, oxygenation (ECMO).48,49
anthracycline exposure, genetic predisposition). In this stage, Until relatively recently ECMO, which provides total car-
most therapies are directed toward periodic observation for diopulmonary support, was the only modality available to
the development of abnormalities and/or the use of medica- support small children with end-stage heart failure. With
tions to prevent or delay onset of abnormalities (eg, the use of the Berlin Excor ventricular assist device (VAD),
angiotensin-converting enzyme (ACE) inhibitors in infants as small as 3 kg could be supported successfully to
Duchenne muscular dystrophy).28,29 Stage B is the stage where heart transplant. The Berlin Heart is a paracorporeal pulsatile
there is asymptomatic structural abnormality (eg, asymptom- VAD that can be used for left, right, or biventricular support.
atic systemic ventricular systolic dysfunction). In this stage, The landmark prospective Berlin Heart Trial, which
Heart Failure in Children: Etiology and Treatment 231
THE JOURNAL OF PEDIATRICS  www.jpeds.com Vol. 165, No. 2

compared patients supported on the Berlin Heart VAD with Reprint requests: Joseph W. Rossano, MD, Division of Cardiology, The
Childrens Hospital of Philadelphia, 34th Street and Civic Center Boulevard,
a historic matched cohort of patients supported on ECMO, Room 6NE 40, Philadelphia, PA 19104. E-mail: jrossano@me.com
led to US Food and Drug Administration approval of the de-
vice in 2011. The limitation of ECMO for long-term circula-
tory support is evident in this study as there were no patients References
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Submitted for publication Feb 3, 2014; last revision received Mar 18, 2014; risk of death or cardiac transplantation in children with idiopathic
accepted Apr 30, 2014. dilated cardiomyopathy. Pediatr Cardiol 2014;35:232-8.

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