H e a r t Fa i l u re i n C o n g e n i t a l

Heart Disease
A Confluence of Acquired and Congenital
Akl C. Fahed, MDa,b, Amy E. Roberts, MDc,
Seema Mital, MDd, Neal K. Lakdawala, MDe,f,*

KEYWORDS
 Heart failure  Congenital heart disease  Genomics  Adult

KEY POINTS
 Heart failure (HF) is a major cause of morbidity and mortality in adults with congenital heart disease
(ACHD) and the current approach for its treatment is rarely evidence based.
 Rare monogenic causes of congenital heart disease (CHD) and HF include Noonan syndrome,
Williams-Beuren syndrome, and 22q11 syndrome.
 Overlapping molecular pathways between CHD and HF exist, and their interrogation will create a
better understanding of the development of HF in CHD.
 HF in ACHD is most commonly a result of a confluence between inherited complex genetic factors
and acquired stressors caused by the defect.
 Current technologies such as next-generation sequencing and iPS will contribute to the under-
standing of this confluence and lead to novel therapeutics.

INTRODUCTION CHD in the United States.2,3 An analysis of

71,686 patients with CHD between 1987 and
Congenital heart disease (CHD) encompasses 2005 revealed that infant CHD mortality has de-
all malformations of the heart that occur in utero creased dramatically, but with a shifting mortality
and exist at birth and is estimated to affect at burden toward adulthood.4 Heart failure (HF)
least 8.1 per 1000 live births.1 The prevalence of is the major problem in ACHD, because nearly
complex and hemodynamically significant lesions, one-quarter of patients develop heart failure at
which result in early deaths if not addressed via 30 years.5 The events inciting HF in patients with
surgical or percutaneous methods, is 2.3 per ACHD are different than in other forms of HF; how-
1000 infants.2 The past 3 decades have witnessed ever, there are limited data available to guide their
marked progress in pediatric cardiology and car- management. Consensus guidelines for diagnosis
diac surgery, allowing patients to survive to adult- and treatment of HF are often used for patients
hood. As a result, the adult population with CHD with ACHD with HF because adequate controlled
(ACHD) outnumbers the pediatric population with data are lacking for this subpopulation.6

The authors have no conflicts of interest to disclose.

a
Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA;
b
Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA;
heartfailure.theclinics.com

c
Division of Genetics, Department of Cardiology, Boston Children’s Hospital, 300 Longwood Avenue, Boston,
MA 02115, USA; d Division of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of
Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada; e Division of Cardiovascular Medicine, Brigham
and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA; f Division of Cardiology, VA Boston Health
Care, Harvard Medical School, 1400 VFW Parkway, Boston, MA, USA
* Corresponding author. Division of Cardiovascular Medicine, Brigham and Women’s Hospital, 75 Francis
Street, Boston, MA 02115.
E-mail address: nlakdawala@partners.org

Heart Failure Clin 10 (2014) 219–227

http://dx.doi.org/10.1016/j.hfc.2013.09.017
1551-7136/14/$ – see front matter Published by Elsevier Inc.
220 Fahed et al

Advances in cardiac genetics have paralleled mechanical, with no genetic element, and includes
improvements in the treatment of CHD. Over the incomplete or palliative correction of a lesion lead-
past 2 decades, 50% to 70% of the genetic ing to a chronic state of hemodynamic stress and
causes of inherited cardiomyopathies were estab- subsequent heart failure.6 The probability of heart
lished through increasingly powerful methods of failure in CHD lesions such as tetralogy of Fallot
DNA analysis. Discovery of the genetics of (TOF), and transposition of the great arteries
nonsyndromic CHD lags behind the inherited car- (TGA) can be as high as 80% at 50 years of age,
diomyopathies. Sequencing initially identified mu- whereas it is around 20% to 30% for isolated
tations in transcription factor genes involved in valvular disease or defects that result in left-to-
heart development in familial cases, and most right shunt.6 Additional myocardial insults can
sporadic CHD has remained unexplained. This is complicate surgery, including injury to the myocar-
likely because of the complexity of the underlying dium, coronary arteries, and conduction system.6
genetic causes; multiple mutations may increase Postsurgical conduction disease may require per-
the risk of CHD, in an additive fashion, or manifest manent ventricular pacing, which can lead to pro-
in the presence of environmental factors and result gressive contractile dysfunction.6 Because these
in cardiac malformation. Current research empha- insults often occur in the first years of life, the ef-
sizes the important role of gene-environment inter- fects of altered hemodynamics or tissue injury
actions and epigenetics in CHD. accumulate over the years, resulting in early devel-
As the molecular signatures of CHD and HF are opment of HF.
characterized with the use of available technology, Although the increased prevalence of HF in
it is increasingly appreciated that at least some ACHD is primarily a result of a volume or pressure
disease pathways are shared. Determining the overload, whereby the starting point is an abnormal
molecular basis of HF in ACHD will play a crucial heart, an independent genetic component is also
role in developing treatment strategies for this present. This second route (depicted in Fig. 1) de-
growing population. This article summarizes the lineates a purely genetic component that causes
limited current knowledge of the genetics of HF both cardiac malformation and a cardiomyopathy
in ACHD, and discusses how innovative therapies that result in HF, unrelated to hemodynamic stress.
may be discovered for this population. Many of the pathways involved in cardiac develop-
ment in utero are also involved in myocardial struc-
ROUTES TO HF IN PATIENTS WITH CHD ture and stability. Therefore, certain molecular
perturbations can cause both a cardiac defect at
The progression to HF in patients with CHD birth and a cardiomyopathy that can present later
involves proven and hypothesized mechanisms, in life, often in childhood. As described in greater
which we classify into 3 routes (Figs. 1 and 2). detail later, Noonan syndrome (NS) is the second
The first route is purely acquired and most frequent syndromic form of CHD and can

Fig. 1. The hypothesized mechanisms linking CHD with HF. We propose 3 putative routes that lead to HF in ACHD:
rare monogenic entities that cause both CHD and HF (middle arrow); severe CHD lesions in which acquired he-
modynamic effects of CHD or surgery result in HF (top arrow); and, most commonly, a combined effect of complex
genetics in overlapping pathways and acquired stressors caused by the lesion (bottom arrow).
 Heart Failure in Congenital Heart Disease 221

Fig. 2. Current genomic technologies and proposed mechanisms of contribution to the understanding of HF
in ACHD. iPS, induced pluripotent stem cells. ACHD, adults with congenital heart disease; CNV, copy number
variation; SNV, single nucleotide variants.

cause both CHD and cardiomyopathy. Another DNA, RNA, protein, and metabolic analysis, this
example of congenital cardiomyopathy is left ven- hypothesis can be studied using a systems biology
tricular noncompaction (LVNC), a heterogeneous approach to investigate the development of HF in
disorder that often results in HF. LVNC has been patients with CHD, particularly those with mild
associated with CHD including atrial and ventricular phenotypes whose progression to HF might not
septal defects, Ebstein anomaly, and outflow tract be justified by the degree of volume or pressure
lesions, and is caused by genes such as MYH7 overload caused by the lesion.
and the transcription factor NKX2-5, among
others.7–10 MONOGENIC CAUSES OF HF IN
In a Dutch registry of 10,808 patients with CARDIOMYOPATHY AND CHD
CHD followed for 21 years (median), the incidence
of HF admissions was 1.2 per 1000 patient The genetic basis of hypertrophic cardiomyopathy
years and median age at first HF admission was (HCM) was first described in 1990.12,13 Following
46.7 years. This incidence of HF admissions in pa- this discovery, the principal genetic causes of
tients with ACHD is more than 10 times what is hypertrophic, dilated, and arrhythmogenic cardio-
reported in an age-matched cohort without CHD myopathies have been identified. Depending on
(0.1 per 1000 person years).11 The true prevalence phenotype, a disease-causing mutation can be
of HF is thought to be higher because not all HF found in 30% to 70% of patients. Culprit genes
events in patients with CHD resulted in hospital encode structural proteins such as those that
admission. Low-prevalence CHD lesions such as form the sarcomere, cellular cytoskeleton, or ion
TGA and TOF that result in HF via markedly channels (Table 1).14 Genetic testing for inherited
abnormal hemodynamics do not solely account cardiomyopathies is clinically available and im-
for the epidemic of HF in CHD. Moreover, gene proves the efficiency of family screening, enabling
mutations that cause both cardiomyopathy and early diagnosis and timely clinical management in
CHD are rare. Therefore, it is unlikely that these at-risk individuals.15
two routes alone explain the high incidence of As an alternative, the clinical application of CHD
HF in CHD, which suggests additional mecha- genetics remains limited. Monogenic causes of
nisms through which patients with CHD can CHD are estimated to account for only 5% to
develop HF. This mechanism is the third route 10% of disease, usually related to loss-of-function
shown in Fig. 1, which is a combination of congen- mutations in transcription factor genes and other
ital genetic risk and acquired hemodynamic signaling molecules that disturb molecular path-
stressors. There is significant overlap in the molec- ways during cardiac development (see Table 1).16
ular pathways that result in CHD during develop- Monogenic causes have predominantly been iden-
ment and those that are responsible for the tified in syndromic cases in which CHD occurs with
integrity of the postnatal myocardium. This overlap noncardiac congenital malformations.16 In only a
suggests that molecular perturbations that result minority of presentations is genetic testing avail-
in abnormal cardiac development can increase able and useful. Genetic testing is available for
the risk for HF in adulthood, especially in the pres- most syndromic cases. To name few examples,
ence of chronically perturbed hemodynamics. HF Holt-Oram syndrome, which causes CHD and up-
also involves the reactivation of many fetal genes. per limb malformations, is caused by mutations in
The reactivation of a mutated pathway is expected TBX5 and SALL4 genes.16 Alagille syndrome,
to exacerbate the progression to HF in the setting causing CHD along with liver disease, is caused
of CHD. With the current era of high-throughput by mutations in the JAG1 or NOTCH2 genes.16
222 Fahed et al

Table 1
Comparison of differences and similarities between CHD and cardiomyopathy

CHD Cardiomyopathy
Differences
Phenotype Wide spectrum of cardiac Dilation or hypertrophy of the
malformations including the myocardium  disease of the
valves, septa, and great vessels conduction system; results in HF
or SCD
Expression Present at birth (by definition) Typical disease onset is in
adolescence or adulthood, but
can express at any age
Genetics LOF mutations in transcription Mutations in structural genes
factor genes and other signaling involving proteins of the
molecules that disturb molecular sarcomere, cellular cytoskeleton,
pathways during cardiac or ion channels
development
Population attributable 5–10 50–70
risk of genetic causes (%)
Clinical genetic testing Not recommended except in rare Recommended in most familial
syndromic cases cases
Similarities
Phenotype Several syndromes with CHD and congenital CMP; co-occurrence of LVNC
with CHD
Expression Congenital cardiomyopathies occurring in the setting of CHD
Genetics Multiple shared pathways between heart development and myocardial
disease; few genes that cause both CHD and congenital CMP; multiple
genes that cause CHD have altered expression in the setting of HF

Abbreviations: CMP, cardiomyopathy; LOF, loss of function; SCD, sudden cardiac death.

Among the nonsyndromic genes, GATA4 and less common malformations include ventricular
Nkx2-5 are two well-established genes in familial septal defect, atrioventricular canal, aortic ste-
CHD,16 and are also available for clinical genetic nosis, and coarctation.19 Common extracardiac
testing. The genetic cause of nonsyndromic CHD manifestations of NS include short stature
is less well understood, and clinical genetic testing and facial dysmorphism.20 Adults with NS have
is not routinely advised for such patients.17,18 How- cardiac complications of the syndrome that
ever, there are several genetically characterized frequently result in HF, whether caused by the car-
syndromes in which CHD and HF are common mor- diomyopathy, the associated valvular disease, or
bidities, including NS, Williams-Beuren syndrome both.21 The limited natural history data in NS sug-
(WBS), and 22.q11.2 deletion syndrome. gest that cardiovascular complications are a major
NS, in which HCM is the second most common cause of mortality.22 NS with multiple lentigenes
cardiac manifestation, is a representative example. (formerly known as LEOPARD [lentigines, electro-
NS results from abnormal RAS-MAPK signaling, cardiogram abnormalities, ocular hypertelorism,
which normally regulates cellular proliferation, dif- pulmonic stenosis, abnormalities of genitalia,
ferentiation, and survival.19 Mutations in different retardation of growth, and deafness] syndrome) is
components of the RAS-MAPK pathway have similar to NS, is caused by loss of function muta-
been described, including PTPN11, KRAS, SOS1, tions in the PTPN11 gene, and has a high frequency
NRAS, RAF1, SHOC2, and CBL19,20; which typi- (>70%) of associated HCM.23 Additional manifes-
cally result in constitutive activation.19 The 20% tations of this rare syndrome include multiple lenti-
of patients with NS who develop HCM present gines and sensorineural deafness.24
with a wide phenotypic spectrum, with approxi- WBS is caused by a microdeletion on chromo-
mately 25% dying of HF in the first year of life.19 some 7q11.23, a region that includes 26 to 28
The CHD manifestations of NS are pulmonary genes.25 The syndrome is characterized in most
stenosis, present in more than 50% of cases, and cases by supravalvular aortic stenosis (SVAS),
secundum atrial septal defect in 6% to 10%. Other mental retardation, and distinctive facial features.25
 Heart Failure in Congenital Heart Disease 223

Loss of 1 allele of the ELN gene, which encodes highlighting a unique role for epigenetic mecha-
elastin and resides on the 7q11.23 locus, causes nisms involved in the molecular pathophysiology
familial SVAS without the other manifestations of of CHD.18 Identification of CHD as part of a genetic
WBS.25 Severe SVAS in children leads to cardiac syndrome would allow prediction of not only car-
hypertrophy and HF unless corrected surgically. diac but also extracardiac outcomes as well as in-
Adults with SVAS have high risk of cardiovascular terventions to modify them (eg, aggressive
complications; of 113 patients with median 6-year monitoring and treatment of hypertension and of
follow-up, 7.3% developed new-onset HF.26 coronary artery lesions in WBS that may contribute
The 22q11.2 microdeletion syndrome (also to cardiac hypertrophy and dysfunction). This
known as DiGeorge or velocardiofacial syndrome) development may help personalize the care of
has a diverse phenotypic spectrum. Common the adult patient with CHD at risk for HF.
manifestations include ventricular outflow tract de-
fects, facial dysmorphism, hypocalcemia, and im- OVERLAPPING PATHWAYS IN CHD AND HF
munodeficiency.21 The syndrome is caused by a GENETICS
1.5-Mb to 3-Mb hemizygous deletion on chromo-
some 22q11.2 and most clinical manifestations, Although the genetics of CHD and HF in humans
especially the cardiac malformations, are ex- has been studied separately, with the few directly
plained by the loss of 1 allele of the TBX1 gene.21 shared disease genes described to date, there is
The most common outflow tract defects seen in significant evidence from model organisms and
the syndrome are TOF, type B interrupted aortic in vitro studies that similar molecular pathways
arch (IAA), and truncus arteriosus (TA). Microdele- are involved (Table 2). Several genes involved in
tion in the same region may cause isolated CHD embryonic cardiac development continue to be
without obvious extracardiac syndromic manifes- expressed in the adult heart, in which they play a
tations.21 Complications of these malformations role in maintaining cardiomyocyte survival and
in adulthood are common and include recoarcta- integrity. GATA4 and GATA6 are transcription fac-
tion of an IAA that was previously surgically recon- tor genes that are mutated in familial cases of
structed, residual or acquired obstruction of the CHD.16 In addition to their role in cardiac develop-
left ventricular outflow tract, or arrhythmias that ment, they are potent activators of cardiac pro-
arise after repair of TOF.21 Genetic testing for moters such as atrial natriuretic factor and
22q11.2 deletion is readily available and recom- B-type natriuretic peptide in the adult heart.30
mended for CHD lesions typical of the 22q11.2 They also regulate the transcription of cardiac
syndrome, including aortic arch abnormalities.27 sarcomere genes, namely alpha-myosin and
Genetic diagnosis may have clinical implications, beta-myosin heavy chain.30 Moreover, GATA4 is
because in patients with isolated TOF and
22q11.2 deletion there is evidence for an increased Table 2
prevalence of aortic root dilatation.28 Canonical pathways from IPA analysis of CHD
Several other genes have been associated with candidate genes that have major roles in HF
familial forms of nonsyndromic CHD. Evidence is
most robust for loss of function (LOF) mutations Pathway Candidate Genes in CHD
in GATA4, TBX5, and NKX2-5, which are transcrip- Wnt/b-catenin SOX2, GJA1, CREBBP
tion factors expressed in the developing heart,16 signaling
although other transcription factors and signaling HIF1a signaling CREBBP, HRAS, NAA10
molecules have been implicated. The transcripts Cardiac hypertrophy NKX2-5, ADCY2, SOS1,
of these three genes form a complex that regulates signaling CREBBP, HRAS, GATA4
downstream targets involved in the regulation of Noonan pathway SOS1, PTPN11
cardiac development. LOF mutations in these
BMP signaling NKX2-5, SOS1, CREBBP,
genes can be a result of nonsense or frameshift pathway HRAS, PITX2
mutations that cause a truncated protein or can
TGF-b signaling NKX2-5, SOS1, CREBBP,
be caused by copy number variation (CNV), which HRAS, PITX2
result in loss or gain of a copy of a gene. For
JAK/Stat signaling PTPN11, SOS1, HRAS
example, at least 10% of TOF are caused by de
novo CNVs.29 In addition to identifying the role of RAR activation NSD1, ADCY2, CREBBP,
PML, CITED2
CNVs in CHD, the advent of exome sequencing
is starting to yield a better understanding of novel PPARa/RXRa ADCY2, SOS1, CREBBP,
molecular causes of CHD. A recent study showed activation HRAS, MED12
that de novo LOF mutations in histone-modifying Abbreviations: BMP, bone morphogenetic protein; TGF,
genes contribute to 10% of severe CHD, transforming growth factor.
224 Fahed et al

a survival factor for adult cardiomyocytes because patients with CHD. Addressing this hypothesis is
it also regulates the antiapoptotic gene BCL-X.31 a methodological challenge that has only recently
Myocyte apoptosis is a major element in the path- become possible with the advent of technologies
ophysiology of HF, and genetic or pharmacologic such as next-generation sequencing. Although
enhancement of GATA4 can prevent cardiomyo- this article does not explore all potential overlap-
cyte toxicity and drug-induced cardiotoxicity, ping molecular pathways in HF and CHD, the ex-
such as with doxorubicin treatment, in which amples of epigenetics, transcription factors, and
GATA4 depletion is an early event.31 These data calcium-dependent signaling that are discussed
suggest that GATA4 is a potential target in HF serve as putative examples. Using IPA (Ingenuity
treatment, and that patients with CHD with LOF Systems, www.ingenuity.com), a software toolkit
mutations in their GATA4 or GATA6 genes might to model and analyze complex biologic systems,
have increased apoptosis of their cardiomyocytes we performed a rapid analysis of canonical path-
predisposing them to HF in the setting of other ways on a set of 146 literature-curated genes
insults such as volume overload caused by CHD. known to be involved in CHD in humans or in
GATA4 also plays a role in calcium-calcineurin animal models. This analysis yielded multiple path-
signaling responsible for cardiac hypertrophy and ways that are known to be involved in HF (see
HF.32 Calcineurin dephosphorylates nuclear fac- Table 2). Genes involved in hypoxia-inducible
tor of activated T cells (NFATC), which results in factor (HIF) 1-alpha signaling are activated in
its translocation to the nucleus, where it binds cardiac hypertrophy,41 whereas their downregula-
GATA4 and activates transcription of a hypertro- tion is associated with the development of TGA
phic gene program.32 NFATC transcription factor in mice.42 Other signaling pathways such as Wnt/
is essential for valve formation in mice,33 and mu- b-catenin, transforming growth factor-b, and
tations in NFATC1 have been associated with CHD JAK/Stat are similarly involved in HF and, at the
in humans.34,35 Recent murine data also suggest same time, harbor CHD candidate genes. In un-
an important role for NFATC transcription factors derstanding the genomics of HF there have been
in the cardiomyocyte response to stress.36 Calci- many milestones, but most of the work has been
neurin also activates calmodulin-dependent pro- focused on identifying the molecular signature of
tein kinase and results in phosphorylation of ischemic and nonischemic cardiomyopathies and
histone deacetylase (HDAC), a nuclear protein trying to target the ensuing HF.43,44 Patients with
causing its dissociation from the transcription fac- CHD with HF constitute a smaller niche that has
tor myocyte enhancer factor 2 (MEF2) and its not been interrogated. Studies of gene expression
externalization from the nucleus.32 MEF2 tran- profiles through RNA sequencing of human hearts
scription factors are the second effectors of with CHD and HF and corresponding controls will
calcineurin signaling, and also play critical roles be valuable to the understanding of the unique
in both cardiac development and normal postnatal molecular causes of HF in patients with CHD.
myocardial survival.37 This calcium-dependent
signaling pathway constitutes an excellent poten- THE FUTURE OF PERSONALIZED TREATMENT
tial target in HF and/or cardiac hypertrophy.32 OF HF IN ACHD
Epigenetics, particularly the role of molecules
such as HDAC that are responsible for DNA Current treatment of HF in ACHD involves therapies
methylation and histone modifications, represents that limit neurohumoral activation and are based
another shared pathway in CHD and HF. The on extrapolation from adults with HF unrelated to
importance of increased DNA methylation of CHD. Although using beta-adrenergic blockers,
genes in cardiomyopathy hearts compared with aldosterone antagonism, and angiotensin inhibition
controls has been described,38,39 and a large has intuitive appeal, there are limited data to sup-
exome sequencing project recently identified that port the use of these drugs in the ACHD population
de novo truncating mutations in similar histone- with HF. Emerging data challenge the notion that
modifying genes is seen in w10% of sporadic conventional HF therapies can be extrapolated to
CHD.18 HF progression involves a pattern of patients with ACHD with HF. For example, a recent
gene expression including reexpression of fetal trial of valsartan in patients with a systemic right
genes involved in cardiac development, increased ventricle failed to show any beneficial effect on
expression of genes encoding extracellular matrix the primary end point of right ventricular ejection
proteins, altered calcium signaling, and histone fraction, and most secondary end points.45 This
modification.40 These processes involve genes trial suggests that the ACHD population might
that can be mutated in the setting of CHD. There- have unique genetic and acquired factors that
fore, preexisting defects in these pathways can make medications used in common causes of
potentially worsen the progression to HF in HF ineffective. Pharmacogenomic studies have
 Heart Failure in Congenital Heart Disease 225

established that single-nucleotide polymorphisms of CHD and HF include NS, WBS, and 22q11 syn-
(SNPs) in adrenergic receptors could modify the drome. Overlapping molecular pathways between
response to b-blockers.46 In patients with CHD, CHD and HF exist, and their interrogation will lead
SNPs in HF pathways targeted by pharmaco- to a better understanding of the development of
therapy can potentially result in resistance to drug HF in CHD. HF in ACHD is most commonly a result
therapy. Such studies are needed for patients of a confluence between inherited complex ge-
with CHD to have better tailored therapies. In one netic factors and acquired stressors caused by
successful example, polymorphisms in the renin- the defect. Current technologies such as next-
angiotensisn-aldosterone system genes were generation sequencing and iPS will contribute to
used to identify a subgroup of high-risk patients the understanding of this confluence and lead to
with single ventricles that did not show reverse re- novel therapeutics.
modeling after staged surgery.47 This high-risk sub-
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