Congenital Heart Disease Compendium

Circulation Research Compendium on Congenital Heart Disease

Congenital Heart Disease: The Remarkable Journey From the “Post-Mortem Room” to Adult Clinics
Perspective on Congenital Heart Disease Research
Has the Congenitally Malformed Heart Changed Its Face? Journey From Understanding Morphology to Surgical Cure in
Congenital Heart Disease
Impact of Three-Dimensional Printing on the Study and Treatment of Congenital Heart Disease
Changing Landscape of Congenital Heart Disease
Genetics and Genomics of Congenital Heart Disease
Cardiac Regeneration: Lessons From Development
Neurodevelopmental Abnormalities and Congenital Heart Disease: Insights Into Altered Brain Maturation
Heart Failure in Pediatric Patients With Congenital Heart Disease
Noninvasive Imaging in Adult Congenital Heart Disease
Current Status and Future Potential of Transcatheter Interventions in Congenital Heart Disease
Current Interventional and Surgical Management of Congenital Heart Disease: Specific Focus on Valvular Disease and
Cardiac Arrhythmias
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Ali J. Marian, Editor

Heart Failure in Pediatric Patients With Congenital

Heart Disease
Robert B. Hinton, Stephanie M. Ware

Abstract: Heart failure (HF) is a complex clinical syndrome resulting from diverse primary and secondary causes
and shared pathways of disease progression, correlating with substantial mortality, morbidity, and cost. HF in
children is most commonly attributable to coexistent congenital heart disease, with different risks depending on
the specific type of malformation. Current management and therapy for HF in children are extrapolated from
treatment approaches in adults. This review discusses the causes, epidemiology, and manifestations of HF in
children with congenital heart disease and presents the clinical, genetic, and molecular characteristics that are
similar or distinct from adult HF. The objective of this review is to provide a framework for understanding rapidly
increasing genetic and molecular information in the challenging context of detailed phenotyping. We review clinical
and translational research studies of HF in congenital heart disease including at the genome, transcriptome, and
epigenetic levels. Unresolved issues and directions for future study are presented.  (Circ Res. 2017;120:978-994.
DOI: 10.1161/CIRCRESAHA.116.308996.)
Key Words: cardiovascular malformation ■ genetics ■ mutation ■ single ventricle ■ stem cell ■ ventricular dysfunction

T he International Society for Heart and Lung Transplantation

defines pediatric heart failure (HF) as a clinical and patho-
physiologic syndrome that results from ventricular dysfunc-
tion, volume, or pressure overload, alone or in combination.
In children, it leads to characteristic signs and symptoms, such
as poor growth, feeding difficulties, respiratory distress, exer-
cise intolerance, and fatigue and is associated with circulato-
ry, neurohormonal, and molecular abnormalities.1 Congenital
heart disease (CHD) is frequently associated with ventricular
dysfunction, volume, or pressure overload. HF in pediatric pa-
tients with CHD has various causes, some of which overlap
with the causes of cardiomyopathy, resulting in both distinct
and shared mechanisms leading to ventricular dysfunction and
the clinical manifestation of HF (Figure 1). In this review, we
focus on basic, translational, and clinical research as it applies
to HF in pediatric patients with CHD.

Original received October 17, 2016; revision received December 27, 2016; accepted December 28, 2016.
From the Department of Pediatrics and Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
Correspondence to Stephanie M. Ware, MD, PhD, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, 1044 W
Walnut St, R4-227, Indianapolis, IN 46202. E-mail stware@iu.edu
© 2017 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.116.308996

978
 Hinton and Ware   Heart Failure in Congenital Heart Disease   979
Nonstandard Abbreviations and Acronyms
AVSD atrioventricular septal defect
CHD congenital heart disease
DCM dilated cardiomyopathy
ECM extracellular matrix
HCM hypertrophic cardiomyopathy
HF heart failure
HLHS hypoplastic left heart syndrome
LV left ventricle
LVNC left ventricular noncompaction
lncRNA long noncoding RNA
MFS Marfan syndrome
miRNA microRNA
NSML Noonan syndrome with multiple lentigines
PA/IVS pulmonary atresia with intact ventricular septum
PHN Pediatric Heart Network
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RV right ventricle
SV single ventricle
VSD ventricular septal defect
Diagnosis and Epidemiology
Defining HF in Children With CHD Presents
Significant Challenges
HF is defined by the American Heart Association and
American College of Cardiology as a complex clinical syn-
drome that can result from any structural or functional cardiac
disorder that impairs the ability of the ventricle to fill or eject
blood.2 The criteria for the diagnosis of HF are largely clini-
cal, and several standardized diagnostic classification systems
have been proposed.3 Pediatric HF encompasses a broader
range of associated findings than adult HF in part because of
the variety of ages of presentation. As a clinical entity, HF
is further subdivided based on its onset, acuity, and severity.
The well-known New York Heart Association Heart Failure
Classification does not apply well to children and on a practi-
cal level is thought to lack the sensitivity needed to assess and
capture the progression of HF severity in children. For this
reason, the Ross Heart Failure Classification was developed
for the assessment of infants with HF, and a modified Ross
Classification was developed to apply to additional age ranges
of children.4 The New York University Pediatric Heart Failure
Index provides a weighted score (Table 1).5 In pediatric prac-
tice, these classification systems are not widely used. As dis-
cussed in subsequent sections, this creates specific challenges
for research.
The clinical presentation of CHD is described primarily
in physiological terms, for example, outflow tract obstruction
(pressure overload) or pulmonary over-circulation (volume
overload). The treatment of CHD is typically surgical correc-
tion (anatomic), and because HF lacks specificity in this con-
text, the term ventricular dysfunction is often used. However,
ventricular dysfunction may be associated with poor contractil-
ity (systolic dysfunction) or poor relaxation (diastolic dysfunc-
tion), with or without the clinical presence of HF, thus creating
a semantic challenge that spans clinical and research efforts in
pediatric cardiology and cardiothoracic surgery. Considerable
practice variation across centers significantly confounds this
problem. Even large multicenter groups, including the Pediatric
Figure 1. Model of the relationship of
heart failure (HF) to congenital heart
disease (CHD) and cardiomyopathy.
Three phenotypes are shown: CHD
(yellow), CM (blue), and CHD with CM
(overlap). Cardiomyopathy by definition
results in ventricular dysfunction in 100%
of cases. CHD results in ventricular
dysfunction in ≈20% of cases, whereas
coexisting CHD and CM results in
ventricular dysfunction in 100% of cases.
HF occurs in ≈65%, 6%, and ≈40%,
respectively. Ventricular dysfunction,
either systolic or diastolic, precedes HF
and therefore offers opportunities for
early intervention. Causes of HF may
vary despite common clinical features
(different colored arrows). The clinical
time course (left) and associated causes
and mechanisms (right) suggest that
identifying distinct mechanisms in CM
vs CHD provides opportunities for early
intervention.
 980  Circulation Research  March 17, 2017

Table 1.  Classification Approaches to Heart Failure

NYHA Modified Ross NYU PHFI*
I asymptomatic I asymptomatic 0–7 asymptomatic to minimal signs and
symptoms
II slight or moderate limitation of II mild tachypnea or diaphoresis with feeding in infants; dyspnea on 8–14 moderate signs and symptoms
physical activity exertion in older children
III marked limitation of physical activity III marked tachypnea or diaphoresis with feeding in infants; marked 15–21 advanced signs and symptoms and
dyspnea on exertion; prolonged feeding times with growth failure modest use of medication
IV symptoms at rest IV tachypnea, retractions, grunting, or diaphoresis at rest 22–30 advanced signs and symptoms and
liberal use of medicine
*HF severity is determined from signs and symptoms, medical regimen, and ventricular physiology. A total score can range from zero (no heart failure) to 30 (severe
heart failure) and is derived by adding 1 or 2 points for each of 13 individual criterion.5 NYHA indicates New York Heart Association; and NYU PHFI, New York University
Pediatric Heart Failure Index.

Heart Network (PHN), Society of Thoracic Surgeons, Pediatric
Cardiomyopathy Registry, Pediatric Cardiac Genomics
Consortium, and National Pediatric Cardiology Quality
Improvement Collaborative, use different approaches to iden-
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in the United States, but 2 single-site studies in Europe indicate
that more than half of the pediatric HF cases were in children
with CHD.14,15 In these studies, there were differences in the
rate of HF in their CHD populations, with 1 study identifying

tify HF and classify severity, creating unintended inconsisten-
cies in the literature, ultimately resulting in studies that are
difficult to reconcile. For example, the PHN, the field’s premier
clinical network, has used different approaches to classifying
cardiac dysfunction or HF in different studies, such as compar-
ing function between groups without distinguishing dysfunc-
tion,6 using the Ross criteria,7 or focusing on imaging evidence
of dysfunction without commenting on HF.8 Although there are
valid reasons for these specific differences in study design, the
lack of a unified approach to ventricular dysfunction and HF
confounds integrated analyses of the collective literature. The
small population sizes available for each specific type of CHD
further hamper the ability to make generalizable observations.
Together, these observations illustrate that primary challenges
in the field are overcoming practice variation and standardizing
phenotyping. Nevertheless, it is important to recognize that it is
feasible to work toward a solution using the multiple existing
networks and consortia to optimize the use of data already col-
lected in these large cohorts.
Epidemiology of Pediatric HF Is Poorly Understood
Factors that have contributed to difficulties in compiling accu-
rate incidence and prevalence estimates for pediatric HF include
the lack of standardized phenotyping for both CHD and HF and
the diversity of causes of HF in children with CHD. HF has
been a major public health problem for decades. In the United
States, >550 000 new cases are diagnosed each year, and the
overall prevalence is >6 million individuals.2 Pediatric HF con-
tributes substantially to the economic impact of this disease as a
result of the frequent need for procedure-based intervention and
the significant morbidity and mortality.9 Children whose hospi-
talizations are complicated by HF have over a 20-fold increased
risk of death.10 It is estimated that 11 000 to 14 000 children will
be hospitalized with HF annually in the United States.10,11 These
numbers include children with cardiomyopathy, with an annual
incidence estimated at 1.13 cases per 100 000 children,12 and
children with CHD, with a traditionally cited incidence of 8 per
1000 live births and a need for cardiac intervention in 3 of ev-
ery 1000 newborns.13 There have been no comprehensive epi-
demiological studies addressing HF in the pediatric population
HF in 10.4% of all patients with congenital and acquired heart
disease and the other identifying HF in 34%, suggesting dif-
ferences in study design or HF definitions.14,15 Within the CHD
populations, the rate of HF was 6.2% and 39%, respectively.
CHD Is the Most Common Cause of HF in Children
HF has numerous causes that are a consequence of cardiac
and noncardiac disorders, either congenital or acquired.1 In
the pediatric population, rheumatic fever was the most com-
mon cause of HF in children in the United States in the 1950s
and continues to be a common cause of pediatric HF in devel-
oping countries (Table 2). Traditionally, HF has been synony-
mous with cardiomyopathy in the literature of pediatric heart
disease, but over time, it became clear that cardiomyopathy
is but one cause of HF. Although the proportion of CHD pa-
tients with HF is lower than the proportion with rhythm dis-
turbances or cardiomyopathy, CHD is a much more common
disease and therefore contributes a greater number of cases
to the overall HF count. Nearly 60% of HF cases in pediatric
patients occurred within the first year of life, but in these stud-
ies, the overall mortality was lower in the CHD population
than in patients with HF from other causes.14,15 The fact that
the risk of HF varied depending on the underlying cause raises
the fundamental question of whether HF is the same disease
process across the spectrum of age ranges and precipitating
causes. In addition, it suggests that there may be the potential
for risk stratification and customization of therapy.
HF is a common morbidity identified in the adult CHD
population, an age range complicated by additional factors
and not covered in many pediatric studies. HF is known to
occur in ≈25% of adult CHD patients by the age of 30, and the
incidence increases with age.16 Tracking the natural history of
specific CHD types or specific genetic causes, and comparing
the similarities and differences of HF in children and adults,
promises to provide insight into the risk of HF at the time
of diagnosis in childhood. Taken together, these data indicate
that HF is an important cause of morbidity and mortality in
pediatric and adult CHD, and HF in this population is hetero-
geneous with regard to underlying cause and outcome. The
issues emerging in the management of the growing adult CHD
 Hinton and Ware   Heart Failure in Congenital Heart Disease   981
Table 2.  Causes of Heart Failure in Children
Congenital heart Left to right shunts (eg, VSD)
disease
Conotruncal lesions (eg, TOF)
Single ventricle lesions (eg, HLHS)
Valve disease (eg, AS)
Cardiomyopathy HCM
(primary)
DCM
RCM
ARVC
LVNC
Arrhythmia Tachycardias (eg, supraventricular tachycardia)
Bradycardias (eg, complete AV block)
Infection Myocarditis
Acute rheumatic fever
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HIV
Ischemia Coronary anomaly (eg, myocardial bridge)
Kawasaki disease
Toxin Chemotherapy
Maternal drugs during pregnancy
Other Diabetes mellitus
Essential hypertension
ARVC indicates arrhythmogenic right ventricular cardiomyopathy; AS, aortic
stenosis; AV, atrioventricular; DCM, dilated cardiomyopathy; HIV, human
immunodeficiency virus; HCM, hypertrophic cardiomyopathy; HLHS, hypoplastic
left heart syndrome; LVNC, left ventricular noncompaction; RCM, restrictive
cardiomyopathy; TOF, tetralogy of Fallot; and VSD, ventricular septal defect.
population have been reviewed recently.17–20 Herein, we focus
specifically on children with CHD and HF.
Overlapping Causes
Mutations That Cause Cardiomyopathy Can Also
Cause CHD
Recent data indicate that mutations in sarcomeric genes
are associated with CHD in addition to cardiomyopathy.21
Mutations in specific protein domains of the MYH7 gene cause
Ebstein anomaly in addition to causing cardiomyopathy.22
Interestingly, in the original description, 6% of a cohort of
patients with Ebstein anomaly, a defect of tricuspid valve for-
mation and position, had MYH7 mutations, of whom 75% had
left ventricular noncompaction cardiomyopathy (LVNC). In
their families, the familial MYH7 mutation was also identified
in individuals with other types of CHD and in individuals with
isolated LVNC but was not found in unaffected family mem-
bers. These cases illustrate that CHD and cardiomyopathy
phenotypes occur with variable expressivity in family mem-
bers carrying the same disease causing mutation, suggesting
that other factors, including genetic modifiers, can influence
phenotypic expression. LVNC is known to be associated with
specific types of CHD in a subset of cases.23–25 LVNC is char-
acterized by abnormal and excessive ventricular trabeculation
and a thin-walled myocardium. Whereas mutations in sarco-
meric genes have been associated with the LVNC phenotype,
mutations in developmental signaling pathways long known
to be associated with CHD such as the Notch pathway and
noncanonical Wnt signaling also cause LVNC in animal mod-
els and humans.26–28 Given the developmental importance of
these signaling pathways for cardiogenesis, future research
investigating the shared developmental mechanisms leading
to both CHD and cardiomyopathy from disruption in these
pathways will likely be informative.
In addition to the MYH7 gene, mutations in other sar-
comeric genes can cause both CHD and cardiomyopathy.
Mutations in MHY6, encoding α-myosin heavy chain, cause
hypertrophic cardiomyopathy (HCM), dilated cardiomyopa-
thy (DCM), familial atrial septal defect, and sick sinus syn-
drome.29 Similarly, mutations in ACTC1, encoding α-cardiac
actin, a component of the thin filament of the sarcomere, can
cause cardiomyopathy with or without septal defects.30,31
Mutations in MYBPC3 and TNNI3 have also been described
with both CHD and cardiomyopathy.32 Surprisingly, sarco-
meric gene mutation analysis has not been applied to the CHD
population in a comprehensive manner to determine whether
rare variants or common polymorphisms in these genes might
be associated with ventricular function. Whether patients who
have CHD with myocardial dysfunction that is out of propor-
tion to their heart defect might have a primary heart muscle
disease is unknown. Studies to analyze the natural history of
patients with mutations in sarcomeric genes and CHD are nec-
essary to assess the penetrance of left ventricular (LV) dys-
function or cardiomyopathy in these patients.
Genetic syndromes associated With CHD Also
Cause Cardiomyopathy
The development of the heart is under genetic control, and
CHD is primarily a genetic disease, although teratogens may
independently cause malformation, and maternal factors may
contribute to disease manifestation.33,34 The genetic causes of
CHD include chromosome abnormalities, genomic disorders,
single gene causes, and multifactorial causes.34–36 Overall,
the likelihood of identifying the genetic cause of CHD is less
than for cardiomyopathy (Table 3). In part, this stems from
the fact that cardiomyopathy most often illustrates Mendelian
inheritance in an autosomal dominant pattern. CHD, in con-
trast, is most often multifactorial with a complex interplay of
multiple genes and environment contributing a susceptibility
to the development of a structural defect.34,35 An exception to
this is syndromic CHD, in which the diagnostic rate is higher.
Genetic syndromes are often associated with specific classes
of cardiovascular malformations, but phenotypic heteroge-
neity is common. In addition to this variability, these cases
illustrate occasional nonpenetrance of cardiac defects that is
not well understood. Overall, genetic syndromes have been
tremendously informative for identifying genes that cause
CHD.37–41 The paradigm that understanding the genetic basis
of syndromic CHD can identify important genes that cause or
modify isolated CHD is conceptually important.
Several genetic conditions with highly penetrant CHD are
also associated with HF and cardiomyopathy. For example,
Noonan syndrome, an autosomal dominant genetic condi-
tion characterized by short stature, cardiac defects, and dys-
morphic features, is caused by mutations in genes within the
 982  Circulation Research  March 17, 2017
Table 3.  Comparison of Congenital Heart Disease and Cardiomyopathy Genetics in Children
Congenital Heart Disease
Characteristics Syndromic and nonsyndromic (isolated) forms ≈30% and 70%,
respectively
Inheritance pattern Multifactorial>Mendelian; complex trait most common
Decreased penetrance Common
Variable expressivity Common
Diagnosis CMA, WES/WGS, NGS panels, single gene testing
Diagnostic yield CMA: 3% to 25% in syndromic; 3% to 10% in isolated
WES/WGS: ≤10% de novo mutation rate
NGS panels: unknown
Genes Encode transcription factors, developmental signaling pathways,
chromatin remodeling, structural proteins of the contractile apparatus
CMA indicates chromosome microarray; NGS, next-generation sequencing; WES, whole exome sequencing; and WGS, whole genome sequencing.
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RAS/MAPK pathway.42 These patients may show evidence of
HCM, CHD (classically pulmonary valve stenosis), or both.43
There is a lifelong risk for the development of HCM with
Noonan syndrome, necessitating ongoing cardiac surveillance
even in affected individuals without CHD. Other RASopathies
include Cardiofaciocutaneous syndrome, Costello syndrome,
and Noonan syndrome with multiple lentigines (NSML; for-
merly LEOPARD) syndrome. NSML is usually caused by
mutations in PTPN11, a protein tyrosine phosphatase 2 that
regulates the RAS/MAPK cascade. Mutations in PTPN11 are
also the most common cause of Noonan syndrome, where
they result in constitutive activation of the protein. In con-
trast, in NSML, mutations in PTPN11 render the protein cata-
lytically impaired. Greater than 80% of patients with NSML
have HCM that is caused by the hyperactivation of the AKT/
mTOR pathway. Using a mouse model of NSML, the ability
to prevent HCM was investigated by early treatment with the
mTOR inhibitor rapamycin. Mice treated early did not devel-
op HCM, and those treated at later stages demonstrated rever-
sal of disease.44 Recently, the first trial of an mTOR inhibitor
was reported in an infant with NSML and rapidly progressive
HCM with a goal of halting progression of hypertrophy and
outflow tract obstruction until the time of transplant.45 An un-
derstanding of the genetic basis of HF in this case led to trial
of a pathway-specific inhibitor for treatment.
Marfan syndrome (MFS), a connective tissue disorder
caused by mutations in an extracellular matrix (ECM) protein
encoded by FBN1,46 is another syndrome for which new data
implicate a propensity to HF in a subset of affected individu-
als. Mutations in fibrillin-1 lead to an upregulation of trans-
forming growth factor-β signaling in individuals with MFS.
The structural network of the microfibril controls the release
of signaling molecules important for morphogenesis and tis-
sue homeostasis. Case reports documenting the development
of LV dysfunction or DCM in patients with MFS suggest a
potential overlap in molecular networks controlling cardiac
function. Using a mouse model of MFS, it was determined
that DCM in fibrillin-1–deficient mice results from abnor-
mal mechanosignaling by cardiomyocytes.47 Specifically, the
mice spontaneously developed increased angiotensin II type
Cardiomyopathy
Syndromic and nonsyndromic forms ≈30% and 70%,
respectively
Mendelian>Multifactorial; autosomal dominant most
common
Less common
Common
NGS panels
20% to 70% depending on type of cardiomyopathy
Encode structural proteins of the contractile apparatus, ion
channels, signaling pathways, metabolic function
I receptor signaling and loss of focal adhesion kinase activ-
ity in the absence of aortic or valvular disease. An additional
study identified 2 distinct phenotypes in aged Marfan mice,
one of which was LV enlargement associated with elevated
ERK1/2 and p38 MAPK phosphorylation and higher BNP
expression.48 The variable phenotypic responses noted in this
study parallel the small subset of MFS patients who develop
DCM. Combined approaches using genomics, mouse models,
and patient-oriented research will be required to dissect the
complex interactions that underlie this phenotypic variability.
Surveillance
The Development of HF in CHD Is Dependent on
Age and Lesion Type
Although genetic causes of CHD or cardiomyopathy can
identify children at high risk of developing HF, this occurs
in a minority of cases. Clinical factors related to phenotype
and presentation remain the most common means for evaluat-
ing risk and instituting surveillance for HF. Age is an impor-
tant factor in assessing clinical features of HF. In the fetus,
HF is characterized by decreased fetal movement, pericar-
dial effusion, and ascites.49 In the preterm low birth weight
newborn, HF is characterized by acidemia, anemia, and hy-
poxemia. In the term newborn, tachypnea, fatigue with feed-
ings, and decreased urine output are common symptoms of
HF. Decompensation at this age is often rapid, with the in-
fant moving from asymptomatic to cardiac shock quickly in
part because of the decreased cardiac reserve at this age.50,51
Accordingly, more classic signs of HF, such as edema and
pathological pulses, are less common and often not present.
The timing of HF is a clue to the underlying malformation.
For example, HF in hypoplastic left heart syndrome (HLHS)
develops on days 3 to 7 of life, whereas HF in severe coarcta-
tion of the aorta tends to develop on days 7 to 10. Some CHD
types do not manifest HF until after the pulmonary vascular
resistance decreases, for example, a large ventricular septal
defect (VSD) or an atrioventricular septal defect (AVSD), in
which case HF develops in 1 to 3 months. But other lesions,
such as an atrial septal defect, do not lead to symptoms until
 Hinton and Ware   Heart Failure in Congenital Heart Disease   983
3 to 5 years of life, if at all. Although some of these observa-
tions simply reflect the underlying anatomy and physiology,
it is increasingly recognized that additional factors, including
both genes and environment, contribute to the timing of the
onset of disease.
Lesion type is another factor useful for risk stratification
for HF. HF in patients with CHD is typically attributed to con-
comitant pressure or volume overload. Therefore, infants with
specific types of CHD will universally experience HF with-
out surgical correction, for example, critical aortic stenosis
(pressure overload) or Ebstein anomaly with severe tricuspid
regurgitation (volume overload). However, genetic factors,
as well as various environmental triggers, are implicated in
the complex process leading to HF. Accordingly, identifying
new-onset ventricular dysfunction is important for emerging
early intervention strategies. In general, children beyond the
first year of life have better overall health and greater cardiac
reserve than adults and can remain in a compensated state for
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longer periods, but tend to transition rapidly to acute HF. The
proportion of cases of specific types of CHD that have ven-
tricular dysfunction or HF at the time of diagnosis varies. For
example, pulmonary insufficiency in a patient with repaired
tetralogy of Fallot may or may not lead to ventricular dysfunc-
tion and HF, and the ability to predict these events is limited.
The higher the rate of HF at diagnosis, the higher the risk for
HF later in life.16 Coordinated lesion-specific approaches to
HF may provide enhanced surveillance algorithms.
Standardized and Detailed Phenotyping Is Critical
Specific types of CHD universally result in HF that can be
addressed by surgical repair. Functional single ventricle (SV)
lesions (a variety of malformations grouped for their com-
mon physiology, whereby 1 ventricle is under-developed,
and the other ventricle supports both pulmonary and sys-
temic circulations) have the highest incidence of ventricular
dysfunction and HF at the time of diagnosis, followed by
conotruncal lesions (eg, tetralogy of Fallot and transposition
of the great arteries), left to right shunts (eg, VSD and AVSD),
and valve disease (eg, aortic stenosis and pulmonary insuf-
ficiency). In some cases, decisions about the timing of sur-
gery are based on balancing the need for the infant to age and
grow and the morbidities associated with HF, including poor
growth. Postsurgically, identifying patients at risk for persis-
tent ventricular dysfunction or HF is confounded by many
factors, including the heterogeneity within groups of lesions,
surgery-specific factors, and differences in medical manage-
ment. Approaches to improve our ability to identify patients
at risk for HF pre- and postsurgically are needed. Analyzing
outcomes within subgroups of large multicenter cohorts will
elucidate the common clinical characteristics and molecular
features of patients whose ventricular dysfunction does not
resolve and progresses to HF.
Functional SV defects are complex malformations that con-
tribute disproportionately to the prevalence of HF in part be-
cause they may have both pressure and volume overload issues
affecting both systemic and pulmonary circulations, and in part
because cyanotic lesions are also at risk for subendocardial isch-
emia. In some SV lesions, such as pulmonary atresia with intact
ventricular septum (PA/IVS), the LV is the systemic ventricle,
whereas in other lesions, such as HLHS, the right ventricle
(RV) is the systemic ventricle. Differences in left- and right-
sided ventricles, as well as ventricular–ventricular interactions,
are critical to understand cardiac function and performance. In
HLHS, the RV is dilated and hypertrophied and managing 3×
the normal cardiac output. The morphology of the RV is not
built for the demands of systemic circulation. The size of the
RV is known to be important in PA/IVS, and the shape has been
shown to result in different outcomes in HLHS.8,52 It is possible
that each lesion may be further distinguished by the pattern of
specific findings, for example, whether the aortic valve is atretic
or stenotic in HLHS. Careful phenotyping is important to deter-
mine whether specific subphenotypes have unique genetic and
molecular causes and characteristics.
Although functional SV defects have high rates of ventricu-
lar dysfunction or HF, many lesions are more difficult to gauge.
For example, predicting the need for and timing of surgery for
valve diseases (stenosis and regurgitation) can be challenging.
Aortic stenosis may be an emergency in the newborn period but
typically is asymptomatic in childhood until progression results
in HF. HF is also common, but not universal, in the context of
chronic severe pulmonary insufficiency after repair later in life.
The manifestation of ventricular dysfunction or HF by lesion
is also variable. Left to right shunts include complete AVSDs,
which uniformly develop refractory HF within months of birth
without surgical correction. In contrast, conotruncal lesions,
such as tetralogy of Fallot, may have HF at the time of diagnosis
if there is little to no RV outflow tract obstruction, but typically
cyanosis dictates the clinical course of these children before re-
pair. Postsurgical scarring or rhythm abnormalities can lead to
HF over time. However, in the absence of these injuries, the
varying susceptibility of patients to HF, either in the immediate
postsurgical period or as long-term sequelae, suggests that ad-
ditional factors such as genetics may impact the relative risk for
HF and ultimately the long-term outcome. The ability to predict
ventricular dysfunction and HF using genetic and molecular in-
formation such as predictive biomarkers may inform care and
improve outcomes in the future.
Numerous classification schemes for CHD have been de-
veloped, the first being Maude Abbott’s atlas.53 Fyler et al54
subsequently developed a refined system emphasizing anato-
my and physiology, and this classification system remains in
wide use given its practical application to surgical intervention.
More recently, the National Birth Defects Prevention Network
has developed a new scheme that incorporates developmental
and etiologic considerations into a system that organizes de-
tailed lesions in groups.55 This type of organization will be nec-
essary to incorporate genetic and molecular information into
the phenotype. In addition, the Society of Thoracic Surgeons
has developed a classification system used by their Registry in
North America, and the International Nomenclature Committee
has recently produced the International Pediatric Cardiac Code
for cross-mapping.56 However, none of these systems identify
ventricular dysfunction or HF as an independent phenotype,
but emerging evidence showing the genetic basis of these traits
suggests it may be prudent to reconsider.
In many ways, our ability to standardize detailed and accu-
rate phenotype data has lagged behind our ability to database
 984  Circulation Research  March 17, 2017
genomic findings.57 The field of phenomics results from the
need to obtain structured, comprehensive phenotype data,
termed deep phenotyping, as well as computational phenomic
analysis.58–60 These big data analysis methods provide major op-
portunities for progress. As whole exome and whole genome
sequencing become more common both in research and clini-
cal care, a wealth of data is accumulating that can be iteratively
interrogated. However, to exploit this resource to begin to un-
derstand complex clinical phenotypes such as HF in the CHD
population, it needs to be properly combined with accurate, stan-
dardized phenotyping and longitudinal patient follow-up.55,56,60,61
Distinct Mechanisms
Genome and Transcriptome in CHD and HF
Because the transcription factors, signaling pathways, and
structural proteins that are important for cardiogenesis are
delineated, an overlapping network with genes required for
both cardiac structure and cardiac function is emerging. As
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discussed above, there are now clear examples of CHD result-
ing from mutations in genes that cause cardiomyopathy and
HF, providing evidence that abnormal expression of a gene re-
sponsible for cardiac contractile function can also cause struc-
tural heart defects. Likewise, there are examples of genetic
defects causing CHD that can also lead to cardiomyopathy or
HF in some proportion of patients. These examples imply that
the redundant gene networks responsible for cardiac structure
and function can lead to divergent phenotypes when abnor-
mal. As reviewed in Fahed et al,62 there is increasing evidence
that at least some cases of LV dysfunction in CHD result from
a genetic predisposition and that combinatorial interactions
of genes and environment (eg, hemodynamic stressors) result
in HF in this patient population. Studying the genetic back-
ground in specific CHD types may further develop this idea
and help identify at risk individuals.
Overlapping HF Molecular Pathways in CHD and
Cardiomyopathy
There are shared genetic causes between CHD and cardio-
myopathy that increase the likelihood of HF in the context
of CHD. However, given the frequency with which ventric-
ular dysfunction and HF occurs in individuals with CHD, a
shared single genetic cause is unlikely to explain most cases.
The development of HF in subsets of patients with specific
genetic syndromes hints at overlapping gene networks. What
about the more common nonsyndromic CHD? Here, the ge-
netic architecture suggests that a majority of cases result from
multifactorial causes and behave as a complex trait, although
Mendelian inheritance does occur, albeit less frequently.
Recent studies in multiplex families with isolated CHD
have identified mutations in TBX5, GATA4, TFAP2B, ELN,
MYH6, and NOTCH1.63–65 Of note, 2 of these genes, MYH6
and NOTCH1, are known to overlap with cardiomyopathy.
Second, TBX5 and TFAP2B cause Holt–Oram syndrome and
Char syndrome, respectively, 2 genetic syndromic conditions
that can have very subtle extracardiac findings, highlighting
the importance of careful phenotyping. De novo mutations are
another important cause of isolated CHD. Recent studies in-
dicate that ≤10% of nonsyndromic CHD may be explained by
this mechanism.66–68 Interestingly, mutations in histone-mod-
ifying proteins were commonly observed to occur as de novo
mutations, suggesting that abnormal heart patterning resulting
from epigenetic alterations may be relatively common.
The distinction between monogenic and complex traits
can be overly simplistic, as is drawing a distinct boundary be-
tween syndromic and nonsyndromic causes given that variants
in genes known to cause syndromic forms of CHD are now
identified in nonsyndromic cases. In addition, traits that seem
to be monogenic can be influenced by variation in multiple
modifier genes, as the above example of cardiac dysfunction
in MFS illustrates. The reverse is also true: complex traits can
be strongly influenced by variation in a single gene. These
findings may explain the decreased penetrance and variable
expressivity that are so common in CHD.
In an effort to better understand genetic causes of CHD,
systems biology approaches have been used to assess func-
tional convergence of causative CHD genes, effectively
combining knowledge from genetics and developmental
biology.69,70 Developmental pathways acting independently
or coordinately contribute to heart development.71,72 These
pathways often exhibit extensive cross-talk, suggesting a
highly complex milieu in which individual or multiple ge-
netic variants could potentially act to disrupt normal heart
morphogenesis. The integration of genetic analysis with
developmental biology knowledge provides an ability to
begin to unravel the additive effects of multiple susceptibil-
ity alleles in combination. Interestingly, these approaches
have suggested that different CHD risk factors are more
likely to act on distinct components of a common func-
tional network than to directly converge on a single genetic
or molecular target.69,70
HF is a phenotypic result of multiple heterogeneous
causes, both environmentally acquired and genetic. Like
CHD, systems biology approaches have been applied to HF
in an effort to integrate complex interactions.73 However,
patients with CHD and HF represent a combination that
most studies have not considered. The molecular adaptive
responses to the mismatch of energetic demands on the heart
involve the reinduction of the fetal gene program and mul-
tiple transcriptional and signaling pathways. Preexisting
genetic abnormalities in these pathways could potentially
compromise the adaptive response, thereby leading to HF
(Figure 1). To illustrate how pathogenic mutations leading
to either cardiomyopathy or CHD might intersect, we per-
formed a basic network analysis using genes available on
current clinical genetic testing panels (Figure 2). Although
there are some categories associated with only CHD or car-
diomyopathy, Figure 2A illustrates that a variety of catego-
ries are associated with both cardiomyopathy and CHD. For
example, the cardiac chamber morphogenesis feature maps
to both, whereas striated muscle contraction maps only to
cardiomyopathy. The line darkness denotes the strength of
association, such that arrhythmia is more strongly associated
with cardiomyopathy than CHD. Figure 2B shows similar
findings at the gene level.
In addition to genetic factors contributing to HF, there
is substantial interest in the role of epigenetics in CHD
 Hinton and Ware   Heart Failure in Congenital Heart Disease   985
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Figure 2. Genes causing congenital heart disease (CHD) and cardiomyopathy form a complex network. The network diagrams were
generated using ToppCluster (www.toppcluster.cchmc.org) software. Gene lists were derived from clinically available next-generation
sequencing panels for cardiomyopathy genes (n=50) and CHD genes (n=44). A, Abstracted cluster network showing a selected subset
of features from the following categories: Gene ontology (GO): molecular function; GO: biological processes; GO: cellular component;
human phenotype; mouse phenotype; pathway; disease (cardiomyopathy and CHD). The features are color coded by category and
connected to cardiomyopathy (white circle) and CHD gene nodes. B, Gene level network with nodes (blue) selected from features in GO:
biological processes category. The network illustrates that regulation of cellular component of movement, actin filament-based processes,
and cardiac chamber morphogenesis are shared in common between cardiomyopathy and CHD genes, whereas regulation of force of
heart contraction and tube development are unshared.

and HF. MicroRNAs (miRNAs) are noncoding RNAs that
consist of 18 to 22 nucleotides. They have been identified
as important regulators of gene expression at the post-tran-
scriptional level and act as important modulators of cardiac
hypertrophy, HF, and fibrosis.74 miRNAs show promise as
circulating biomarkers and their relative stability in the
blood when compared with mRNA enhances their suitability
for translation to clinical care. Study of miRNAs in mouse
models has shown that overexpression can result in cardiac
hypertrophy and HF and that deletion can be protective.
Profibrotic miRNAs can be blocked by antagomirs result-
ing in decreased interstitial fibrosis and improved cardiac
function in a mouse model of hypertrophy caused by pres-
sure overload. Upregulation of specific miRNAs can also be
seen in patients with HF.75 The development of antagomirs
for therapeutic use in HF is reportedly in preclinical devel-
opment.76 Interestingly, pediatric HF patients seem to have
unique miRNA profiles,77 suggesting that further investiga-
tion that is specific to the pediatric population is required
for the application of antagomir-based therapy. Long non-
coding RNAs (lncRNAs) are another group of RNA mol-
ecules that play important roles in development and disease.
lncRNAs are >200 base pair RNAs that function in the
regulation of transcriptional and post-transcriptional events.
Although less well studied in HF than miRNAs, lncRNAs
are emerging as important in this disease process. For exam-
ple, the mitochondrial lncRNA LIPCAR identified patients
undergoing cardiac remodeling who were independently at
risk for future cardiovascular deaths.78 CHAST is another
lncRNA that has recently been shown to be deregulated in
pressure overload–induced cardiac hypertrophy in mouse
and significantly upregulated in hypertrophic heart tissue
from aortic stenosis patients.79 It will be important to de-
termine the degree to which pediatric miRNA and lncRNA
profiles change in a developmental stage–specific manner.
In summary, it seems likely that genetic and epigenetic
factors may combinatorially affect the susceptibility to both
CHD and HF, and some variants will increase or decrease risk
for either CHD or HF or both. Identifying these molecular pat-
terns requires systems biology approaches, bioinformatics ex-
pertise, and statistical genetic methods. In addition, improved
attention to and methodology for accurate phenotyping is es-
sential. The integration of genetic and epigenetic findings with
deep phenotyping will improve our understanding of disease
 986  Circulation Research  March 17, 2017

cause, in part by elaborating distinct and shared genetic fac- maladaptation, the failing heart loses the ability to function
tors and ultimately advance medical care. efficiently.84

Shared Mechanisms Regulation of Cardiac Metabolism Impacts the

HF Is Modified by Metabolic, Molecular, and
Neurohormonal Factors
Most of what we know about HF results from studies in adults.
These metabolic, molecular, and neurohormonal abnormali-
ties that occur in HF have been the subject of recent reviews,
including a previous Compendium issue on HF, and the reader
is referred there for in-depth information on these complex
topics.80 These findings have been applied to the pediatric
population. At the molecular level, HF is characterized by
transcriptional, translational, and epigenetic alterations that
are a consequence of the adaptive and compensatory mecha-
nisms used by the heart in an attempt to respond to its func-
tional demands (Figure 3). In both adult and pediatric HF, the
progressive deterioration of myocardial function leads to an
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Course of HF
At the metabolic level, HF represents a state of inefficient
energy expenditure. The heart uses fatty acids and glucose
as energy sources with the former as the preferred substrate.
Mitochondrial dysfunction is a key characteristic of HF and
is both a cause and a consequence of abnormal energetics.85
A few of the consequences of mitochondrial dysfunction in-
clude impaired fatty acid oxidation, increased DNA damage
and apoptosis, and alterations in mitochondrial calcium lev-
els. Prenatally, the heart uses glucose as its primary energy
substrate. Postnatally, there is a transition from a low oxygen
intrauterine environment to a high oxygen environment that is
accompanied by a switch from anaerobic glycolysis to fatty
acid oxidation and oxidative phosphorylation as a means of
ATP production, a metabolically more efficient method of en-

inability of the heart to meet body requirements and is, essen-
tially, a mismatch of supply and demand. Energy starvation is
proposed as a unifying mechanism underlying cardiac con-
tractile failure.81,82 This is frequently the result of a downward
spiral of events in which decreases in oxygen and substrate
availability trigger adaptive mechanisms, including neuro-
endocrine overdrive, activation of signaling pathways, ECM
remodeling, and alterations in mechanical load, among oth-
ers. Although these adaptive mechanisms stabilize contractile
function in the short term, over the long term they may result in
further compromise because of a vicious cycle characterized
in part by an increased mismatch of the supply:demand ratio.83
Because metabolic remodeling progresses from adaptation to
ergy generation.86,87 This transition in substrate utilization is
accompanied by mitochondrial proliferation and is a critical
transition window. For example, infants with rare inborn er-
rors of metabolism such as fatty acid oxidation disorders or
mitochondrial disorders often experience cardiac decompen-
sation during this transition. There are important differences
in the expression of nuclear-encoded mitochondrial genes
during development, suggesting that stage-specific control
of mitochondrial biogenesis exists.88 The temporal span over
which this occurs in humans has not been well defined. Mouse
models have demonstrated that there is a strong activation of
mitochondrial biogenesis in the myocardium during the peri-
natal period. Ablation of transcription factors critical for this

Figure 3. Schematic of the interactions between causal, predisposing, and contributing factors that result in congenital heart
disease (CHD) and heart failure (HF). The figure depicts that CHD has a genetic cause and additional genetic components that
predispose the heart to maladaptive responses to environmental factors and may, individually or synergistically, lead to a mismatch
between cardiac output and demand with subsequent decompensation and ventricular dysfunction (yellow arrow). This in turn triggers
epigenetic modifications and many metabolic, molecular, and neurohormonal compensatory responses, which are also under primary
genetic regulation and therefore may predispose to disease. The effectiveness of these responses is a critical determinant of the
progression to HF. The signs and symptoms of HF are also subject to individual genetic variation; individual genetic and epigenetic
variation can provide protective or deleterious effects that influence severity. HF leads to the institution of medical therapies and surgical
interventions, including transplantation, which provide an additional layer of individual variation because of differential pharmacogenomics
and molecular responses to the stresses of surgery. ECM indicates extracellular matrix; lncRNA, long noncoding RNA; miRNA, microRNA;
and RAAS, renin–angiotensin–aldosterone system.
 Hinton and Ware   Heart Failure in Congenital Heart Disease   987
metabolic switch, such as TFAM or PGC-1 isoforms, results
in upregulation of glycolytic genes and rapidly fatal neona-
tal HF.89,90 Interestingly, there is now evidence that the transi-
tion from a low oxygen to a high oxygen environment after
birth leads to mitochondrial damage which results in a block
of cell cycle progression and withdrawal from the cell cycle.
In contrast, hypoxic cardiomyocytes retain a fetal or neonatal
phenotype characterized by smaller size, fewer mitochondria,
and less evidence of oxidative damage, mononucleation, and,
importantly, increased proliferative capacity.91,92 These studies
have implications for approaches to cardiac regeneration and
management of energetic demands during HF.
Sarcomeric Architecture Can Revert to Fetal State
Through Molecular Switching
Sarcomere isoform switching and reinduction of the fetal gene
program occurs in HF.93–97 More recent evidence indicates that
these switches apply to miRNAs as well.74,98 The contractile
apparatus is responsive to ions, particularly calcium, and the
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autonomic nervous system. The excitation–contraction cou-
pling that occurs as a result of calcium influx to the myocyte
and subsequent calcium release from the sarcoplasmic re-
ticulum is fundamentally abnormal in HF, typically resulting
in decreased contractile force and delayed or incomplete re-
laxation. Although pediatric HF recapitulates many of these
changes, the sarcomere of a fetus and neonate is not identical
to that of an adult.99 The sarcomeric proteins, myosin, actin,
troponin, tropomyosin, and titin, show isoform switching
during development as a result of distinct gene expression or
alternative splicing.100 During HF, isoform transitions occur,
often with reinduction of the fetal gene program. In addition,
calcium transients are different in neonates, with increased
utilization of trans-sarcolemmal calcium flux. Taken together
with the differences in contractility because of sarcomere iso-
form differences, the neonatal heart is stiffer, with less con-
tractile reserve than the adult heart.101
The Matrix Has a Structural and Functional Impact
In addition to the components of the sarcomere, the ECM
plays an important structural and signaling role during HF pro-
gression. Increasing ECM deposition results in interstitial and
perivascular fibrosis. Elevated levels of serum markers of col-
lagen turnover may be useful for risk stratification of those at
high risk of death and HF hospitalization in adults.102 In addi-
tion, studies on ECM deposition and difference in microfibril
content of neonatal cardiomyocytes suggest that the likeli-
hood of fibrosis differs depending on the age of the cardio-
myocyte. The ultrastructure of fetal cardiomyocytes is distinct
from adult cardiomyocytes, containing fewer microfibrils and
mitochondria. Furthermore, the numbers of cardiomyocytes
differ by age, with cardiomyocyte numbers increasing imme-
diately after birth but subsequently permanently withdrawing
from the cell cycle leaving the heart with limited regenerative
capacity.103,104 Clearly, an understanding of the developmen-
tal differences in cardiomyocyte response to injury has im-
portant therapeutic implications, but these studies also show
that treatment of infants with HF may require substantially
different approaches than adult HF patients. Because the hu-
man heart continues to grow in size in a developing organism,
it is logical to infer that additional differences and ongoing
changes impact HF in older children.
New Findings in Regulation of the Adrenergic
Signaling Cascade in Infants and Children
There is a vast literature describing adrenergic signaling dur-
ing HF, the deleterious effects of chronic stimulation and in-
creased sympathetic drive, the distinct functions of α1, α2, and
β receptors, and the importance of the adrenergic system as a
therapeutic target.80,105 In pediatric patients with HF, therapy is
directed at mitigating this increased sympathetic drive, analo-
gous to treatment in the adult population. However, clinical
and translational research studies are beginning to identify im-
portant differences in the pediatric HF patient. Animal models
have previously shown that β-adrenergic receptor-adenylyl
cyclase cAMP pathway–mediated contractility responsive-
ness is less robust in the fetal/newborn heart versus the adult
heart. Furthermore, phosphodiesterase inhibition has less ef-
fect on contractility alone, but enhanced contractility when
combined with isoproterenol.101 Several recent studies investi-
gate the molecular findings in explanted hearts from children
with HF and demonstrate age-related differences similar to
those seen in mouse. Pediatric patients with DCM showed a
differential adaptation of the β-adrenergic signaling pathway
when compared with adults with DCM or nonfailing con-
trols.106 Specifically, downregulation of β1- and β2-adrenergic
receptors is identified in children, whereas β2-AR expression
is maintained in adults. Differences in the phosphorylation
status of phospholamban are also noted in children versus
adults.106 Investigation of phosphodiesterase isoform expres-
sion and responsiveness to phosphodiesterase inhibition also
differed in pediatric versus adult samples.107,108 Although the
approach to medical therapy is similar, there is a lack of data
on the adaptive responses triggered in patients with structur-
ally abnormal hearts when compared with those with primary
heart muscle disease. In the investigation of phosphodiesterase
expression, intriguing differences were noted in samples from
DCM explants when compared with single RV CHD hearts
in the myocardial response to milrinone.108,109 Additional stud-
ies are required to understand the characteristic adaptive pro-
grams invoked by ventricular dysfunction of different causes.
These findings suggest a differential responsiveness to HF
medical therapy depending on age, a conclusion that requires
more investigation.
Clinical Research for Pediatric Ventricular
Dysfunction and HF Is Limited
HF has been extensively studied in adults but has only re-
cently begun to be evaluated in the pediatric population. To
assess the current clinical research in this area, we queried
the clinical trials website (www.clinicaltrials.gov) and deter-
mined that 1.3% of HF studies currently open for enrollment
include children with CHD (n=29). Fundamental questions
about whether HF represents the same disease in children re-
main to be answered, but small numbers and heterogeneity are
problematic. Below, we give examples of clinical trials within
the SV population, which has been studied rigorously in re-
cent years. One limitation to current studies is the difficulty
with comparing results between different trials. For example,
 988  Circulation Research  March 17, 2017
the Pediatric Cardiac Genomics Consortium has not reported
the presence of ventricular dysfunction or HF as a distinct or
modifying phenotype, and the National Pediatric Cardiology
Quality Improvement Collaborative has analyzed only cases
that are at least moderately abnormal.68,110 A clear overarch-
ing need is to leverage existing cohorts by combining them to
facilitate trials where both primary and secondary questions
can be answered. Adopting a learning health system, such
as the National Pediatric Cardiology Quality Improvement
Collaborative, may improve the results of trials performed us-
ing existing cohorts because this approach has shown signifi-
cant increases in patient participation, a common limitation in
pediatric heart disease trials.111,112 Clinical trials using learn-
ing health systems may improve outcomes through quality
improvement efforts and accelerate findings and subsequent
dissemination. Partnerships with nonprofit organizations fa-
cilitate this type of research in part by assuming some of the
cost, but more importantly by mobilizing patients and orga-
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nizing patients’ collective experience to identify and advance
clinically relevant patient-oriented research questions.113
In patients with CHD, complex defects have a higher rate
of associated HF. Functional SV heart defects account for
a disproportionate share of the morbidity and mortality in
CHD, and mortality in the first year of life ranges from 10%
to 35%.114,115 In addition, management of these patients is as-
sociated with a significant economic burden and high levels
of resource requirements. Clinical research, including stud-
ies performed by the PHN, has reported detailed clinical out-
comes in this population of patients.
The clinical predictors of poor outcome in functional
SV defects are based on the type of CHD and complications
developed during staged palliative repairs. Although the sur-
gical approach is similar among SV lesions, the underlying
genetic causes are different, and well-characterized genetic
syndromic conditions predict worse outcome. The PHN SV
Reconstruction Trial has provided information on outcomes
in this patient population.6,116–123 In the initial comparison of
Blalock–Taussig versus RV–pulmonary artery shunt types for
SV, transplant-free survival at 12 months was 74% and 64%,
respectively, with no significant differences seen at 3 years.6,119
Mortality with stage I palliation (Norwood) ranges from 7%
to 19% and between stage I and stage II palliation, 4% to
15%. Interestingly, genetic abnormalities were identified as
independent risk factors, suggesting that some degree of the
variation observed in HF occurrence in severity is attributable
to genetic factors.122 SV patients with Fontan circulation, in
which the venous return bypasses the SV and is directed to the
pulmonary artery, face many medical issues, including growth
problems, hemodynamic compromise, including cyanosis,
pathway obstructions and valve dysfunction, arrhythmias, or
pleural effusions, and ascites.124 Fontan circulation results in
progressive multiorgan system dysfunction, and Fontan fail-
ure requires cardiac transplantation. Studies to determine sur-
vival of different types of SV malformations, such as HLHS
versus tricuspid atresia, are ongoing. In this complex context,
it is difficult to isolate the cause and impact of ventricular dys-
function and HF, but the potential use of this knowledge is
substantial. For example, the ability to stratify patients into
high risk or low risk of myocardial dysfunction could lead to
more tailored approaches and protocols to monitor patients
and medically intervene.
The anatomic and morphological features of the ventricle
are also important determinants of outcome. The RV does not
adapt well to the demands of the systemic ventricle. Previous
work has shown that at least 50% of patients with CHDs where
the RV is the systemic ventricle, such as l-TGA (congenitally
corrected transposition of great arteries) and HLHS, develop
RV dysfunction. In addition, there is a 15% incidence of death
or heart transplantation in early adulthood caused by myocar-
dial dysfunction.125,126 Transcriptional profiling has shown that
the inability of the RV to respond to chronic pressure over-
load is correlated with its inability to assume a LV expression
pattern of genes such as angiotensin, adrenergic receptors,
G-proteins, cytoskeletal, and contractile components.127–129
Just as variation in sarcomeric genes might explain a propor-
tion of HF, or predisposition to HF in CHD cases, it is possible
that genetic variation in these pathways predisposes some in-
dividuals to myocardial dysfunction when superimposed on
the background of CHD (Figure 1). Thus, variation that might
be silent in the normal population may strongly predispose to
(or protect from) poor outcome in the CHD population. This
level of genetic variation has not yet been explored. Although
expression analyses have not been performed in SV patients,
it is tempting to speculate that the maladaptive responses that
the RV exhibits under pressure overload would be similar
under chronic volume overload. Thus, patients with LV SVs
traditionally have had better survival than those with RV SVs.
Better understanding the developmental and genetic basis of
these differences and the progression to HF should not only
provide insight into the relative contribution of pressure and
volume overload but also provide new important data for nov-
el therapeutics.
Clinical trials are ongoing to evaluate stem cell therapy as
a treatment for SV defects such as HLHS. In 2015, intracoro-
nary injection of umbilical cord blood-derived mononuclear
cells or intracoronary administration of autologous cardio-
sphere-derived cells was successfully used in HLHS patients.
In the case of cardiosphere-derived cells infusion, RV ejec-
tion fraction remained persistently improved during 36-month
follow-up.130,131 Additional clinical trials are in progress using
sources of progenitor cell types that have had reliable and safe
results in earlier studies, including allogenic mesenchymal
stem cells, bone marrow–derived cells, c-kit+ cells, or um-
bilical cord cells.132 Although there is optimism that stem cell
therapy represents a novel direction that could provide signifi-
cant gains to management in the pediatric population, there is
much still to be learned about the cell-type–specific require-
ments, the timing of administration, the long-term impact on
cardiac status, and the mechanisms of action.132–135 Induced
pluripotent stem cells are another mechanism for studying and
modeling patient-specific disease processes.
Medical Therapy and Pharmacogenomics
Medical therapy for HF in patients with CHD is typically ex-
trapolated from adults with ischemic HF. There are limited
data to support use in children. For example, a recent trial of
valsartan, an angiotensin II receptor blocker, in patients with
 Hinton and Ware   Heart Failure in Congenital Heart Disease   989
a systemic RV failed to show any beneficial effect on the pri-
mary end point of RV ejection fraction.136 Similarly, a ran-
domized trial of enalapril in infants with SV did not alter HF
severity or improve growth or ventricular function.117 Taken
together, these observations suggest that pediatric HF may
have different causes and additional contributing factors and
therefore will require new and different therapies.
Pharmacogenomics is defined as the association between
genetic factors and drug response. Interindividual variation in
drug response can lead to therapeutic failure (eg, ultrarapid
metabolizers) and adverse drug responses (poor metaboliz-
ers). Whereas numerous pharmacogenomic clinical trials have
occurred in the adult HF population, very few studies have
been performed in the CHD population.137 Specific challenges
to the study of pharmacogenomics in the CHD population
include variability in underlying cause (genetic variabil-
ity), heterogeneity in the types of CHDs and their treatment
(phenotypic variability), small sample sizes, frequent dosing
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changes with age and changes in drug responsiveness with
age. Furthermore, there is significant variability in the treat-
ment and management of these patients at different centers,
leading to challenges for multisite studies.
To date, the only study to address HF or ventricular remod-
eling in CHD was performed by Mital et al,7 with a combina-
torial approach to investigate the impact of 5 single-nucleotide
polymorphisms in genes within the renin–angiotensin–aldo-
sterone pathways as part of the PHN SV Reconstruction Trial.
Table 4.  Research Approaches to Investigate Congenital Heart Disease and Heart Failure
Approach Benefits/Questions Answered
Basic In vivo Modeling anatomy and physiology;
functional testing; genetic manipulation
(some model organisms)
In vitro Faster and less expensive functional
testing than in vivo
Translational Genetic/ Disease causation; individual variation
genomic
Epigenetic Gene regulation; disease-specific
alterations
Omics Large data sets; comprehensive;
hypothesis generating
Companion Personalized medicine; risk stratification
diagnostics
Stem cell Personalized/patient specific
Systems Unbiased comprehensive analyses
biology
Clinical Epidemiology/ Disease incidence and determinants;
population evidence-based practice and analysis
health
Clinical trial Direct comparisons in patients
3D indicates 3-dimensional; ChIPseq, chromatin immunoprecipitation sequencing; CMA, chromosome microarray analysis; GWAS, genome-wide association study;
iPS, cell-induced pluripotent stem cell; lncRNA, long noncoding RNA; miRNA, microRNA; piRNA, Piwi-interacting RNA, RNASeq RNA sequencing; siRNA, small interfering
RNA; WES, whole exome sequencing; and WGS, whole genome sequencing.
The results demonstrated an association with renin–angioten-
sin–aldosterone genotype and failure of reverse remodeling
after surgery. The limitations of this important study were that
it consisted of a relatively small population and was biased
toward patients surviving past stage I palliation. In 2014, the
same renin–angiotensin–aldosterone single-nucleotide poly-
morphism was shown to be independently associated with
increased tachyarrhythmia after CHD surgery (odds ratio, 1.6;
95% confidence interval, 1.1–2.3; P=0.02).138 Thus, there is
preliminary evidence for the potential use of pharmacogenet-
ics in the CHD population, but larger studies with increased
numbers are required. Ultimately, individual risk stratification
and personalized care are dependent on our ability to (1) de-
fine primary causes of CHD, (2) identify secondary genetic
factors that lead to susceptibility to or protection from myo-
cardial dysfunction in the context of CHD and environmen-
tal/mechanical stressors, and (3) select appropriate medical
therapy based on predicted pharmacogenomic response. It is
the combinatorial interaction of these primary, secondary, and
tertiary genetic influences which ultimately determines the
clinical phenotype and outcome in a multifactorial fashion.
Summary
Pediatric HF is a clinical entity that results from an inabil-
ity of the heart to meet working demands. Although shar-
ing many metabolic and molecular features with adults with
HF, as shown in Figure 3, children have underlying causes,
Limitations Example
Cost and time; may not predict Large animal—surgical models and
human biology bioprosthetics139
Small animal—mouse models of disease44
Nonphysiological; no 3D heart Cell signaling,47 expression studies, siRNA,
structure tissue engineering
Costly; sample size requirements GWAS, CMA, WES,66 WGS,
Pharmacogenomics
Heterogeneous cell types; miRNA,140,141 lncRNA,79 piRNA, chromatin
throughput and efficiency remodeling
Large data sets; descriptive Transcriptome (microarray, RNAseq),
regulome (ChIPseq), microbiome/
metabolome, proteome72,142
Association and validation difficult WES/Biomarker pairs143
Labor intensive; reprogramming iPS cell, cardiac progenitor cell134,144
artifacts mesenchymal derived
Dependent on accurate annotation Bioinformatics70
and curation in databases
Not mechanistic; may not Registry61,145
determine causality
Costly; multiple regulatory layers; Drug trial,117,136,146 surgical outcome122
study size requirements difficult in
pediatrics
 990  Circulation Research  March 17, 2017
presentations, and disease courses that may differ from adults.
Thus, a fundamental question is whether HF in the pediat-
ric population is the same disease process as it is in adults.
What is the evidence for standard HF therapy in pediatric
CHD patients? Do standard HF prognostic tools work in these
patients? How do differences in the myocardium in infancy
and early childhood affect management and therapeutics?
Additional research is needed to organize existing data and
leverage established cohorts to answer these questions. For
example, analyzing outcomes within subgroups of large co-
horts with CHD is necessary to understand the common clini-
cal characteristics and molecular features of patients whose
ventricular dysfunction does not resolve or progresses to HF.
There is preliminary evidence that the myocardium has dis-
tinct molecular properties based on age and location (RV ver-
sus LV). Furthermore, responsiveness of the myocardium to
medication varies based on age. Additional investigation of
these differences is necessary to risk stratify and customize
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therapy. Stem cell therapy holds great promise as a novel ap-
proach to HF in CHD, but basic, translational, and clinical
research is necessary to understand how to apply it. Future
research investigating the shared developmental mechanisms
leading to both CHD and cardiomyopathy will likely be infor-
mative for understanding genetic and epigenetic pathways that
increase susceptibility to HF.
Numerous research approaches have been used to in-
vestigate HF (Table 4), and the research community is well
positioned to leverage these resources. Basic research in HF
is substantial, and although not a focus of this review, there
is a clear need for additional animal models of HF in CHD.
Genetic and genomic approaches are progressing rapidly, but
we need standardized biorepositories that combine harmo-
nized data collection to realize improved treatment strategies.
Secondary studies from large multicenter trials are needed to
further characterize disease in those cohorts. Increasing the
emphasis on integration of the different components of HF
may accelerate the identification of new therapeutic windows
(Figure 3). Ultimately, multifaceted and combined research
approaches will advance medical care by allowing risk strati-
fication by age, lesion, and underlying cause and will lead to
improved protocols for medical intervention and therapy.
Sources of Funding
This work is supported in part by the National Institutes of Health,
an American Heart Association Established Investigator Award,
the March of Dimes, and the Indiana University Health—Indiana
University School of Medicine Strategic Research Initiative and
Physician Scientist Initiative (S.M. Ware).
Disclosures
None.
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 Heart Failure in Pediatric Patients With Congenital Heart Disease
Robert B. Hinton and Stephanie M. Ware
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Circ Res. 2017;120:978-994

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