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Abstract: Heart failure (HF) is a complex clinical syndrome resulting from diverse primary and secondary causes
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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
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
drome that can result from any structural or functional cardiac practice variation across centers significantly confounds this
disorder that impairs the ability of the ventricle to fill or eject problem. Even large multicenter groups, including the Pediatric
Heart Network (PHN), Society of Thoracic Surgeons, Pediatric in the United States, but 2 single-site studies in Europe indicate
Cardiomyopathy Registry, Pediatric Cardiac Genomics that more than half of the pediatric HF cases were in children
Consortium, and National Pediatric Cardiology Quality with CHD.14,15 In these studies, there were differences in the
Improvement Collaborative, use different approaches to iden- rate of HF in their CHD populations, with 1 study identifying
tify HF and classify severity, creating unintended inconsisten- HF in 10.4% of all patients with congenital and acquired heart
cies in the literature, ultimately resulting in studies that are disease and the other identifying HF in 34%, suggesting dif-
difficult to reconcile. For example, the PHN, the field’s premier ferences in study design or HF definitions.14,15 Within the CHD
clinical network, has used different approaches to classifying populations, the rate of HF was 6.2% and 39%, respectively.
cardiac dysfunction or HF in different studies, such as compar-
ing function between groups without distinguishing dysfunc- CHD Is the Most Common Cause of HF in Children
tion,6 using the Ross criteria,7 or focusing on imaging evidence HF has numerous causes that are a consequence of cardiac
of dysfunction without commenting on HF.8 Although there are and noncardiac disorders, either congenital or acquired.1 In
valid reasons for these specific differences in study design, the the pediatric population, rheumatic fever was the most com-
lack of a unified approach to ventricular dysfunction and HF 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-
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Table 2. Causes of Heart Failure in Children mutations in developmental signaling pathways long known
to be associated with CHD such as the Notch pathway and
Congenital heart Left to right shunts (eg, VSD)
disease noncanonical Wnt signaling also cause LVNC in animal mod-
Conotruncal lesions (eg, TOF) els and humans.26–28 Given the developmental importance of
Single ventricle lesions (eg, HLHS) these signaling pathways for cardiogenesis, future research
Valve disease (eg, AS) investigating the shared developmental mechanisms leading
to both CHD and cardiomyopathy from disruption in these
Cardiomyopathy HCM
pathways will likely be informative.
(primary)
DCM In addition to the MYH7 gene, mutations in other sar-
RCM comeric genes can cause both CHD and cardiomyopathy.
Mutations in MHY6, encoding α-myosin heavy chain, cause
ARVC
hypertrophic cardiomyopathy (HCM), dilated cardiomyopa-
LVNC thy (DCM), familial atrial septal defect, and sick sinus syn-
Arrhythmia Tachycardias (eg, supraventricular tachycardia) drome.29 Similarly, mutations in ACTC1, encoding α-cardiac
Bradycardias (eg, complete AV block) actin, a component of the thin filament of the sarcomere, can
cause cardiomyopathy with or without septal defects.30,31
Infection Myocarditis
Mutations in MYBPC3 and TNNI3 have also been described
Acute rheumatic fever with both CHD and cardiomyopathy.32 Surprisingly, sarco-
HIV meric gene mutation analysis has not been applied to the CHD
population in a comprehensive manner to determine whether
Ischemia Coronary anomaly (eg, myocardial bridge)
rare variants or common polymorphisms in these genes might
Kawasaki disease be associated with ventricular function. Whether patients who
Toxin Chemotherapy have CHD with myocardial dysfunction that is out of propor-
Maternal drugs during pregnancy
tion to their heart defect might have a primary heart muscle
disease is unknown. Studies to analyze the natural history of
Other Diabetes mellitus
patients with mutations in sarcomeric genes and CHD are nec-
Essential hypertension essary to assess the penetrance of left ventricular (LV) dys-
ARVC indicates arrhythmogenic right ventricular cardiomyopathy; AS, aortic function or cardiomyopathy in these patients.
stenosis; AV, atrioventricular; DCM, dilated cardiomyopathy; HIV, human
Genetic syndromes associated With CHD Also
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Table 3. Comparison of Congenital Heart Disease and Cardiomyopathy Genetics in Children
Congenital Heart Disease Cardiomyopathy
Characteristics Syndromic and nonsyndromic (isolated) forms ≈30% and 70%, Syndromic and nonsyndromic forms ≈30% and 70%,
respectively respectively
Inheritance pattern Multifactorial>Mendelian; complex trait most common Mendelian>Multifactorial; autosomal dominant most
common
Decreased penetrance Common Less common
Variable expressivity Common Common
Diagnosis CMA, WES/WGS, NGS panels, single gene testing NGS panels
Diagnostic yield CMA: 3% to 25% in syndromic; 3% to 10% in isolated 20% to 70% depending on type of cardiomyopathy
WES/WGS: ≤10% de novo mutation rate
NGS panels: unknown
Genes Encode transcription factors, developmental signaling pathways, Encode structural proteins of the contractile apparatus, ion
chromatin remodeling, structural proteins of the contractile apparatus channels, signaling pathways, metabolic function
CMA indicates chromosome microarray; NGS, next-generation sequencing; WES, whole exome sequencing; and WGS, whole genome sequencing.
RAS/MAPK pathway.42 These patients may show evidence of I receptor signaling and loss of focal adhesion kinase activ-
HCM, CHD (classically pulmonary valve stenosis), or both.43 ity in the absence of aortic or valvular disease. An additional
There is a lifelong risk for the development of HCM with study identified 2 distinct phenotypes in aged Marfan mice,
Noonan syndrome, necessitating ongoing cardiac surveillance one of which was LV enlargement associated with elevated
even in affected individuals without CHD. Other RASopathies ERK1/2 and p38 MAPK phosphorylation and higher BNP
include Cardiofaciocutaneous syndrome, Costello syndrome, expression.48 The variable phenotypic responses noted in this
and Noonan syndrome with multiple lentigines (NSML; for- study parallel the small subset of MFS patients who develop
merly LEOPARD) syndrome. NSML is usually caused by DCM. Combined approaches using genomics, mouse models,
mutations in PTPN11, a protein tyrosine phosphatase 2 that and patient-oriented research will be required to dissect the
regulates the RAS/MAPK cascade. Mutations in PTPN11 are complex interactions that underlie this phenotypic variability.
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3 to 5 years of life, if at all. Although some of these observa- whereas in other lesions, such as HLHS, the right ventricle
tions simply reflect the underlying anatomy and physiology, (RV) is the systemic ventricle. Differences in left- and right-
it is increasingly recognized that additional factors, including sided ventricles, as well as ventricular–ventricular interactions,
both genes and environment, contribute to the timing of the are critical to understand cardiac function and performance. In
onset of disease. HLHS, the RV is dilated and hypertrophied and managing 3×
Lesion type is another factor useful for risk stratification the normal cardiac output. The morphology of the RV is not
for HF. HF in patients with CHD is typically attributed to con- built for the demands of systemic circulation. The size of the
comitant pressure or volume overload. Therefore, infants with RV is known to be important in PA/IVS, and the shape has been
specific types of CHD will universally experience HF with- shown to result in different outcomes in HLHS.8,52 It is possible
out surgical correction, for example, critical aortic stenosis that each lesion may be further distinguished by the pattern of
(pressure overload) or Ebstein anomaly with severe tricuspid specific findings, for example, whether the aortic valve is atretic
regurgitation (volume overload). However, genetic factors, or stenotic in HLHS. Careful phenotyping is important to deter-
as well as various environmental triggers, are implicated in mine whether specific subphenotypes have unique genetic and
the complex process leading to HF. Accordingly, identifying molecular causes and characteristics.
new-onset ventricular dysfunction is important for emerging Although functional SV defects have high rates of ventricu-
early intervention strategies. In general, children beyond the lar dysfunction or HF, many lesions are more difficult to gauge.
first year of life have better overall health and greater cardiac For example, predicting the need for and timing of surgery for
reserve than adults and can remain in a compensated state for valve diseases (stenosis and regurgitation) can be challenging.
longer periods, but tend to transition rapidly to acute HF. The Aortic stenosis may be an emergency in the newborn period but
proportion of cases of specific types of CHD that have ven- typically is asymptomatic in childhood until progression results
tricular dysfunction or HF at the time of diagnosis varies. For in HF. HF is also common, but not universal, in the context of
example, pulmonary insufficiency in a patient with repaired chronic severe pulmonary insufficiency after repair later in life.
tetralogy of Fallot may or may not lead to ventricular dysfunc- The manifestation of ventricular dysfunction or HF by lesion
tion and HF, and the ability to predict these events is limited. is also variable. Left to right shunts include complete AVSDs,
The higher the rate of HF at diagnosis, the higher the risk for which uniformly develop refractory HF within months of birth
HF later in life.16 Coordinated lesion-specific approaches to without surgical correction. In contrast, conotruncal lesions,
HF may provide enhanced surveillance algorithms. such as tetralogy of Fallot, may have HF at the time of diagnosis
Standardized and Detailed Phenotyping Is Critical if there is little to no RV outflow tract obstruction, but typically
cyanosis dictates the clinical course of these children before re-
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genomic findings.57 The field of phenomics results from the this mechanism.66–68 Interestingly, mutations in histone-mod-
need to obtain structured, comprehensive phenotype data, ifying proteins were commonly observed to occur as de novo
termed deep phenotyping, as well as computational phenomic mutations, suggesting that abnormal heart patterning resulting
analysis.58–60 These big data analysis methods provide major op- from epigenetic alterations may be relatively common.
portunities for progress. As whole exome and whole genome The distinction between monogenic and complex traits
sequencing become more common both in research and clini- can be overly simplistic, as is drawing a distinct boundary be-
cal care, a wealth of data is accumulating that can be iteratively tween syndromic and nonsyndromic causes given that variants
interrogated. However, to exploit this resource to begin to un- in genes known to cause syndromic forms of CHD are now
derstand complex clinical phenotypes such as HF in the CHD identified in nonsyndromic cases. In addition, traits that seem
population, it needs to be properly combined with accurate, stan- to be monogenic can be influenced by variation in multiple
dardized phenotyping and longitudinal patient follow-up.55,56,60,61 modifier genes, as the above example of cardiac dysfunction
in MFS illustrates. The reverse is also true: complex traits can
Distinct Mechanisms be strongly influenced by variation in a single gene. These
findings may explain the decreased penetrance and variable
Genome and Transcriptome in CHD and HF
expressivity that are so common in CHD.
Because the transcription factors, signaling pathways, and
In an effort to better understand genetic causes of CHD,
structural proteins that are important for cardiogenesis are
systems biology approaches have been used to assess func-
delineated, an overlapping network with genes required for
tional convergence of causative CHD genes, effectively
both cardiac structure and cardiac function is emerging. As
combining knowledge from genetics and developmental
discussed above, there are now clear examples of CHD result-
biology.69,70 Developmental pathways acting independently
ing from mutations in genes that cause cardiomyopathy and
or coordinately contribute to heart development.71,72 These
HF, providing evidence that abnormal expression of a gene re-
pathways often exhibit extensive cross-talk, suggesting a
sponsible for cardiac contractile function can also cause struc-
highly complex milieu in which individual or multiple ge-
tural heart defects. Likewise, there are examples of genetic
netic variants could potentially act to disrupt normal heart
defects causing CHD that can also lead to cardiomyopathy or
morphogenesis. The integration of genetic analysis with
HF in some proportion of patients. These examples imply that
developmental biology knowledge provides an ability to
the redundant gene networks responsible for cardiac structure
begin to unravel the additive effects of multiple susceptibil-
and function can lead to divergent phenotypes when abnor-
ity alleles in combination. Interestingly, these approaches
mal. As reviewed in Fahed et al,62 there is increasing evidence
have suggested that different CHD risk factors are more
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Figure 2. Genes causing congenital heart disease (CHD) and cardiomyopathy form a complex network. The network diagrams were
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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 lncRNAs are >200 base pair RNAs that function in the
consist of 18 to 22 nucleotides. They have been identified regulation of transcriptional and post-transcriptional events.
as important regulators of gene expression at the post-tran- Although less well studied in HF than miRNAs, lncRNAs
scriptional level and act as important modulators of cardiac are emerging as important in this disease process. For exam-
hypertrophy, HF, and fibrosis.74 miRNAs show promise as ple, the mitochondrial lncRNA LIPCAR identified patients
circulating biomarkers and their relative stability in the undergoing cardiac remodeling who were independently at
blood when compared with mRNA enhances their suitability risk for future cardiovascular deaths.78 CHAST is another
for translation to clinical care. Study of miRNAs in mouse lncRNA that has recently been shown to be deregulated in
models has shown that overexpression can result in cardiac pressure overload–induced cardiac hypertrophy in mouse
hypertrophy and HF and that deletion can be protective. and significantly upregulated in hypertrophic heart tissue
Profibrotic miRNAs can be blocked by antagomirs result- from aortic stenosis patients.79 It will be important to de-
ing in decreased interstitial fibrosis and improved cardiac termine the degree to which pediatric miRNA and lncRNA
function in a mouse model of hypertrophy caused by pres- profiles change in a developmental stage–specific manner.
sure overload. Upregulation of specific miRNAs can also be In summary, it seems likely that genetic and epigenetic
seen in patients with HF.75 The development of antagomirs factors may combinatorially affect the susceptibility to both
for therapeutic use in HF is reportedly in preclinical devel- CHD and HF, and some variants will increase or decrease risk
opment.76 Interestingly, pediatric HF patients seem to have for either CHD or HF or both. Identifying these molecular pat-
unique miRNA profiles,77 suggesting that further investiga- terns requires systems biology approaches, bioinformatics ex-
tion that is specific to the pediatric population is required pertise, and statistical genetic methods. In addition, improved
for the application of antagomir-based therapy. Long non- attention to and methodology for accurate phenotyping is es-
coding RNAs (lncRNAs) are another group of RNA mol- sential. The integration of genetic and epigenetic findings with
ecules that play important roles in development and disease. 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
in part by an increased mismatch of the supply:demand ratio.83 mitochondrial biogenesis in the myocardium during the peri-
Because metabolic remodeling progresses from adaptation to 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 it is logical to infer that additional differences and ongoing
in upregulation of glycolytic genes and rapidly fatal neona- changes impact HF in older children.
tal HF.89,90 Interestingly, there is now evidence that the transi-
tion from a low oxygen to a high oxygen environment after New Findings in Regulation of the Adrenergic
birth leads to mitochondrial damage which results in a block
Signaling Cascade in Infants and Children
There is a vast literature describing adrenergic signaling dur-
of cell cycle progression and withdrawal from the cell cycle.
ing HF, the deleterious effects of chronic stimulation and in-
In contrast, hypoxic cardiomyocytes retain a fetal or neonatal
creased sympathetic drive, the distinct functions of α1, α2, and
phenotype characterized by smaller size, fewer mitochondria,
β receptors, and the importance of the adrenergic system as a
and less evidence of oxidative damage, mononucleation, and,
therapeutic target.80,105 In pediatric patients with HF, therapy is
importantly, increased proliferative capacity.91,92 These studies
directed at mitigating this increased sympathetic drive, analo-
have implications for approaches to cardiac regeneration and
gous to treatment in the adult population. However, clinical
management of energetic demands during HF.
and translational research studies are beginning to identify im-
Sarcomeric Architecture Can Revert to Fetal State portant differences in the pediatric HF patient. Animal models
Through Molecular Switching have previously shown that β-adrenergic receptor-adenylyl
Sarcomere isoform switching and reinduction of the fetal gene cyclase cAMP pathway–mediated contractility responsive-
program occurs in HF.93–97 More recent evidence indicates that ness is less robust in the fetal/newborn heart versus the adult
these switches apply to miRNAs as well.74,98 The contractile heart. Furthermore, phosphodiesterase inhibition has less ef-
apparatus is responsive to ions, particularly calcium, and the fect on contractility alone, but enhanced contractility when
autonomic nervous system. The excitation–contraction cou- combined with isoproterenol.101 Several recent studies investi-
pling that occurs as a result of calcium influx to the myocyte gate the molecular findings in explanted hearts from children
and subsequent calcium release from the sarcoplasmic re- with HF and demonstrate age-related differences similar to
ticulum is fundamentally abnormal in HF, typically resulting those seen in mouse. Pediatric patients with DCM showed a
in decreased contractile force and delayed or incomplete re- differential adaptation of the β-adrenergic signaling pathway
laxation. Although pediatric HF recapitulates many of these when compared with adults with DCM or nonfailing con-
changes, the sarcomere of a fetus and neonate is not identical trols.106 Specifically, downregulation of β1- and β2-adrenergic
to that of an adult.99 The sarcomeric proteins, myosin, actin, receptors is identified in children, whereas β2-AR expression
troponin, tropomyosin, and titin, show isoform switching is maintained in adults. Differences in the phosphorylation
during development as a result of distinct gene expression or status of phospholamban are also noted in children versus
adults.106 Investigation of phosphodiesterase isoform expres-
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the Pediatric Cardiac Genomics Consortium has not reported high risk or low risk of myocardial dysfunction could lead to
the presence of ventricular dysfunction or HF as a distinct or more tailored approaches and protocols to monitor patients
modifying phenotype, and the National Pediatric Cardiology and medically intervene.
Quality Improvement Collaborative has analyzed only cases The anatomic and morphological features of the ventricle
that are at least moderately abnormal.68,110 A clear overarch- are also important determinants of outcome. The RV does not
ing need is to leverage existing cohorts by combining them to adapt well to the demands of the systemic ventricle. Previous
facilitate trials where both primary and secondary questions work has shown that at least 50% of patients with CHDs where
can be answered. Adopting a learning health system, such the RV is the systemic ventricle, such as l-TGA (congenitally
as the National Pediatric Cardiology Quality Improvement corrected transposition of great arteries) and HLHS, develop
Collaborative, may improve the results of trials performed us- RV dysfunction. In addition, there is a 15% incidence of death
ing existing cohorts because this approach has shown signifi- or heart transplantation in early adulthood caused by myocar-
cant increases in patient participation, a common limitation in dial dysfunction.125,126 Transcriptional profiling has shown that
pediatric heart disease trials.111,112 Clinical trials using learn- the inability of the RV to respond to chronic pressure over-
ing health systems may improve outcomes through quality load is correlated with its inability to assume a LV expression
improvement efforts and accelerate findings and subsequent pattern of genes such as angiotensin, adrenergic receptors,
dissemination. Partnerships with nonprofit organizations fa- G-proteins, cytoskeletal, and contractile components.127–129
cilitate this type of research in part by assuming some of the Just as variation in sarcomeric genes might explain a propor-
cost, but more importantly by mobilizing patients and orga- tion of HF, or predisposition to HF in CHD cases, it is possible
nizing patients’ collective experience to identify and advance that genetic variation in these pathways predisposes some in-
clinically relevant patient-oriented research questions.113 dividuals to myocardial dysfunction when superimposed on
In patients with CHD, complex defects have a higher rate the background of CHD (Figure 1). Thus, variation that might
of associated HF. Functional SV heart defects account for be silent in the normal population may strongly predispose to
a disproportionate share of the morbidity and mortality in (or protect from) poor outcome in the CHD population. This
CHD, and mortality in the first year of life ranges from 10% level of genetic variation has not yet been explored. Although
to 35%.114,115 In addition, management of these patients is as- expression analyses have not been performed in SV patients,
sociated with a significant economic burden and high levels it is tempting to speculate that the maladaptive responses that
of resource requirements. Clinical research, including stud- the RV exhibits under pressure overload would be similar
ies performed by the PHN, has reported detailed clinical out- under chronic volume overload. Thus, patients with LV SVs
comes in this population of patients. traditionally have had better survival than those with RV SVs.
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The clinical predictors of poor outcome in functional Better understanding the developmental and genetic basis of
SV defects are based on the type of CHD and complications these differences and the progression to HF should not only
developed during staged palliative repairs. Although the sur- provide insight into the relative contribution of pressure and
gical approach is similar among SV lesions, the underlying volume overload but also provide new important data for nov-
genetic causes are different, and well-characterized genetic el therapeutics.
syndromic conditions predict worse outcome. The PHN SV Clinical trials are ongoing to evaluate stem cell therapy as
Reconstruction Trial has provided information on outcomes a treatment for SV defects such as HLHS. In 2015, intracoro-
nary injection of umbilical cord blood-derived mononuclear
in this patient population.6,116–123 In the initial comparison of
cells or intracoronary administration of autologous cardio-
Blalock–Taussig versus RV–pulmonary artery shunt types for
sphere-derived cells was successfully used in HLHS patients.
SV, transplant-free survival at 12 months was 74% and 64%,
In the case of cardiosphere-derived cells infusion, RV ejec-
respectively, with no significant differences seen at 3 years.6,119
tion fraction remained persistently improved during 36-month
Mortality with stage I palliation (Norwood) ranges from 7%
follow-up.130,131 Additional clinical trials are in progress using
to 19% and between stage I and stage II palliation, 4% to
sources of progenitor cell types that have had reliable and safe
15%. Interestingly, genetic abnormalities were identified as
results in earlier studies, including allogenic mesenchymal
independent risk factors, suggesting that some degree of the
stem cells, bone marrow–derived cells, c-kit+ cells, or um-
variation observed in HF occurrence in severity is attributable
bilical cord cells.132 Although there is optimism that stem cell
to genetic factors.122 SV patients with Fontan circulation, in
therapy represents a novel direction that could provide signifi-
which the venous return bypasses the SV and is directed to the
cant gains to management in the pediatric population, there is
pulmonary artery, face many medical issues, including growth
much still to be learned about the cell-type–specific require-
problems, hemodynamic compromise, including cyanosis,
ments, the timing of administration, the long-term impact on
pathway obstructions and valve dysfunction, arrhythmias, or
cardiac status, and the mechanisms of action.132–135 Induced
pleural effusions, and ascites.124 Fontan circulation results in
pluripotent stem cells are another mechanism for studying and
progressive multiorgan system dysfunction, and Fontan fail-
modeling patient-specific disease processes.
ure requires cardiac transplantation. Studies to determine sur-
vival of different types of SV malformations, such as HLHS Medical Therapy and Pharmacogenomics
versus tricuspid atresia, are ongoing. In this complex context, Medical therapy for HF in patients with CHD is typically ex-
it is difficult to isolate the cause and impact of ventricular dys- trapolated from adults with ischemic HF. There are limited
function and HF, but the potential use of this knowledge is data to support use in children. For example, a recent trial of
substantial. For example, the ability to stratify patients into 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- The results demonstrated an association with renin–angioten-
mary end point of RV ejection fraction.136 Similarly, a ran- sin–aldosterone genotype and failure of reverse remodeling
domized trial of enalapril in infants with SV did not alter HF after surgery. The limitations of this important study were that
severity or improve growth or ventricular function.117 Taken it consisted of a relatively small population and was biased
together, these observations suggest that pediatric HF may toward patients surviving past stage I palliation. In 2014, the
have different causes and additional contributing factors and same renin–angiotensin–aldosterone single-nucleotide poly-
therefore will require new and different therapies. morphism was shown to be independently associated with
Pharmacogenomics is defined as the association between increased tachyarrhythmia after CHD surgery (odds ratio, 1.6;
genetic factors and drug response. Interindividual variation in 95% confidence interval, 1.1–2.3; P=0.02).138 Thus, there is
drug response can lead to therapeutic failure (eg, ultrarapid preliminary evidence for the potential use of pharmacogenet-
metabolizers) and adverse drug responses (poor metaboliz- ics in the CHD population, but larger studies with increased
ers). Whereas numerous pharmacogenomic clinical trials have numbers are required. Ultimately, individual risk stratification
occurred in the adult HF population, very few studies have and personalized care are dependent on our ability to (1) de-
been performed in the CHD population.137 Specific challenges fine primary causes of CHD, (2) identify secondary genetic
to the study of pharmacogenomics in the CHD population factors that lead to susceptibility to or protection from myo-
include variability in underlying cause (genetic variabil- cardial dysfunction in the context of CHD and environmen-
ity), heterogeneity in the types of CHDs and their treatment tal/mechanical stressors, and (3) select appropriate medical
(phenotypic variability), small sample sizes, frequent dosing therapy based on predicted pharmacogenomic response. It is
changes with age and changes in drug responsiveness with the combinatorial interaction of these primary, secondary, and
age. Furthermore, there is significant variability in the treat- tertiary genetic influences which ultimately determines the
ment and management of these patients at different centers, clinical phenotype and outcome in a multifactorial fashion.
leading to challenges for multisite studies.
To date, the only study to address HF or ventricular remod- Summary
eling in CHD was performed by Mital et al,7 with a combina- Pediatric HF is a clinical entity that results from an inabil-
torial approach to investigate the impact of 5 single-nucleotide ity of the heart to meet working demands. Although shar-
polymorphisms in genes within the renin–angiotensin–aldo- ing many metabolic and molecular features with adults with
sterone pathways as part of the PHN SV Reconstruction Trial. HF, as shown in Figure 3, children have underlying causes,
Table 4. Research Approaches to Investigate Congenital Heart Disease and Heart Failure
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