NEJMra 1003941

Review article
franklin h. epstein lecture

Franklin H. Epstein, M.D., served the New England Journal of Medicine for more than 20 years.
A keen clinician, accomplished researcher, and outstanding teacher, Dr. Epstein was Chair and Professor of
Medicine at Beth Israel Deaconess Medical Center, Boston, where the Franklin H. Epstein, M.D., Memorial
Lectureship in Mechanisms of Disease has been established in his memory.
Cardiac Development and Implications

for Heart Disease
Jonathan A. Epstein, M.D.
D
From the Department of Cell and Devel- uring the past decade, our understanding of the development
opmental Biology and the Cardiovascular of the embryonic heart has been improved by a number of discoveries. These
Institute, University of Pennsylvania School
of Medicine, Philadelphia. Address reprint new findings will require changes in standard teachings of how the four-
requests to Dr. Epstein at the Department chambered heart forms, and they have implications for the management of con-
of Cell and Developmental Biology, Univer- genital and acquired heart disease. In the coming years, additional advances in our
sity of Pennsylvania School of Medicine,
421 Curie Blvd., 1154 BRB II, Philadelphia, knowledge of cardiac development are likely to further influence the classification
PA 19104, or at epsteinj@mail.med.upenn and treatment of congenital heart disease, inform clinicians on the best uses of re-
.edu. generative treatment (e.g., stem-cell therapy), and revise our understanding of some
N Engl J Med 2010;363:1638-47. cardiovascular disorders in adults. This review gives examples of recent findings in
Copyright © 2010 Massachusetts Medical Society. the field of cardiac development, with an emphasis on those likely to have the
greatest effect on clinical practice.
Ov erv ie w
Classic teaching holds that cardiovascular development proceeds from the early spec-
ification of bilateral clusters of progenitor cells that coalesce to form a cardiac
crescent and a midline linear heart tube. This tube, which consists of an inner cell
layer of endothelium surrounded by myocardial precursor cells,1 undergoes a series
of looping or bending events followed by ballooning or expansion of regions des-
tined to become cardiac chambers. Subsequently, a series of septation events results
in a four-chambered heart with parallel systemic and pulmonary circulations.
Additional cell types that lie outside the heart tube are important in the devel-
opment of the heart and influence its morphogenesis (Fig. 1). For example, neural-
crest cells, which form components of the peripheral nervous system and the cra-
niofacial regions, migrate to the heart, where they are essential for septation of the
cardiac outflow tract.2 The link between neural-crest cells3 and septation helps to
explain the association of craniofacial defects with some forms of congenital heart
disease.
L ine age R e s t r ic t ion
The mature heart consists of many different cell types, including myocardial cells,
endothelial cells, smooth-muscle cells, fibroblasts, and specialized conducting cells.
Until recently, the origins and lineages of these various cell types were unclear.
Recently, however, the technique of gene targeting has allowed rigorous “fate map-
ping” (a method used to determine the cellular derivatives of a cell or population of
cells) and lineage analysis in mammalian embryos and adults.4-7 The results of
these studies, and of clonal analyses of embryonic stem-cell differentiation in vi-
1638 n engl j med 363;17 nejm.org october 21, 2010
The New England Journal of Medicine

Downloaded from www.nejm.org by JUAN SILVA on December 7, 2010. For personal use only. No other uses without permission.
Copyright © 2010 Massachusetts Medical Society. All rights reserved.
Fr anklin H. Epstein Lecture
Figure 1. Overview of Cardiac Development.

Traditional descriptions of cardiac development include progression from the cardiac crescent to the linear heart
tube, which loops and becomes septated as it develops into the mature heart. Multiple cell types extrinsic to the ini-
tial cardiac crescent, including neural-crest cells, cells arising from the second heart field, and epicardial progeni-
tors, contribute to cardiac morphogenesis.
tro,7-10 convincingly document a progressive lin- bryonic stem cells express kinase-domain–related
eage restriction of cells engaged in cardiac devel- (KDR) receptor (a receptor for vascular endothe-
opment (Fig. 2). It is now clear that precursor cells lial growth factor) and NKX2-5 (a transcription
in the embryo have the potential to differentiate factor with a role in cardiac development).8,10
into various types of cardiac cells. As a particular These early cardiac precursor cells have the po-
lineage develops, however, the potential of its tential to become endothelium, smooth muscle, or
member cells to deviate into alternative lineages myocardium. In vivo genetic studies suggest that
becomes progressively restricted. similar precursor cells contribute to multiple lin-
Embryonic stem cells are pluripotent — that is, eages in the developing heart.
they have the ability to become nearly any kind of The phenomenon of progressive lineage re-
cell. Such stem cells can differentiate into sponta- striction during cardiac development has impor-
neously beating myocardial cells when grown in tant implications for the use of stem-cell therapy
tissue culture in the presence of specific growth in cardiac disease. For treatments intended to
factors and under particular conditions.12-14 Car- enhance endogenous myocardial repair or to
diac precursor cells that arise in vitro from em- generate new heart muscle through the delivery
n engl j med 363;17 nejm.org october 21, 2010 1639

The n e w e ng l a n d j o u r na l of m e dic i n e
Figure 2. Progressive Lineage Restriction.

In the hematopoietic system, stem cells become progressively restricted during differentiation. Similarly, cardiac progenitors, which may
share a common precursor with hematopoietic stem cells, become progressively restricted in terms of the types of potential mature de-
rivatives that can ultimately be produced. Adapted from Wu et al.11
of appropriate cardiac progenitor cells, or to grow opathy and other forms of heart failure is un-
bioprostheses of contractile myocardial patches,8 known, and the markers and gene-expression
researchers and practitioners must consider which signatures that characterize various progenitors
cells can best meet these goals.8,15,16 For example, are only now being elucidated.
the regenerated tissue that results from treatment Progressive lineage restriction is also a feature
with a progenitor cell that has the potential to of the differentiation of a multipotent hematopoi-
produce only cardiac myocytes will be unlike nor- etic stem cell into various blood-cell lineages.17
mal cardiac tissue, which has multiple cellular The delineation of each stage of lineage restriction
components. Progenitors with a restricted differ- in blood-cell precursors has allowed for identifi-
entiation capacity may have to be replaced with cation of clinically useful growth factors, such as
multipotent progenitor cells if the goal is to re- granulocyte colony-stimulating factor, granulo-
generate multilineage tissue composed of endo- cyte–macrophage colony-stimulating factor, and
thelium, smooth muscle (regenerating vascula- erythropoietin, each of which affects a different
ture), and contractile myocardium. At this time, progenitor. As is the case with hematopoietic stem
the most appropriate type of progenitor cell to be cells, the identification and characterization of
used in stem-cell therapy for ischemic cardiomy- specific cardiac progenitor cells and cardiac

growth factors may lead to useful treatments for tal abnormality, or similar developmental abnor-
myocardial infarction or heart failure. malities, can underlie anatomically distinct con-
genital heart disorders. An example is the group
The Sec ond He a r t Fiel d of clinically dissimilar congenital heart defects
(e.g., a double-outlet right ventricle and right ven-
Not all precursors of cardiac muscle reside in the tricular hypoplasia) that are related through their
cardiac crescent and the early linear heart tube. association with abnormalities of second-heart–
Many right ventricular myocytes and, to a variable field progenitor cells.25 Aberrations of these pre-
degree, myocytes in the atria, left ventricle, and cursor cells may also cause anatomical abnor-
cardiac inflow and outflow tracts enter the devel- malities of the left or right side of the heart (e.g.,
oping heart after its initial looping stages are com- defects of atrial septation, ventricular septation,
plete.18-20 These additional cells arise from a sec- conus positioning, and great-vessel alignment)
ond heart field that is medial and ventral to the because the cells contribute to both the inflow
primary cardiac crescent. (In the embryo, a field and the outflow tracts of the heart.26 Moreover,
consists of a group of related cells within a de- recent studies of what have come to be known as
fined boundary.) Cells in the second heart field second-heart–field cardiac defects suggest that in-
migrate first to the pharyngeal regions, where flow and outflow abnormalities frequently coex-
they can be identified in mouse embryos in early ist.26 Anatomical classification is undoubtedly
gestation or midgestation according to the prod- clinically useful, but it is likely that classification
ucts of specific marker genes, including the tran- systems based on developmental relationships and
scription factor islet 1.20 These second-heart–field genetic causes will provide additional diagnostic
cardiac precursors in the pharyngeal regions invade and prognostic information. Consensus opinions
the developing heart and migrate along its inflow that explicitly define developmentally based clas-
and outflow tracts. Second-heart–field progeni- sifications of congenital heart disorders will also
tors that express islet 1 are multipotent cells that promote enhanced communication among basic
can give rise to smooth-muscle cells at the base researchers and their clinical colleagues.
of the aorta and pulmonary arteries, to endothe-
lial cells, or to myocardium.7 The Epic a r dium in C a r di ac
The existence of a second heart field has im- De v el opmen t a nd R epa ir
portant implications for understanding congeni-
tal heart diseases. For example, abnormalities in The epicardium, a layer of connective tissue lo-
the distinct genetic pathways that mediate for- cated between the myocardium and the pericar-
mation of myocytes in either the right or the left dium,27 arises from a transient embryonic struc-
ventricle could explain congenital defects whose ture called the proepicardial organ (Fig. 3). Cells
predominant effect is on the right or left ventri- in this organ derive from the septum transver-
cle. The results of induced genetic perturbations in sum, which separates the embryo’s thorax from
only second-heart–field cells of embryonic mice its abdomen, and to the diaphragm and liver. Some
suggest that abnormalities in this population can proepicardial cells migrate to the developing heart
cause double-outlet right ventricle, right ventricu- and contribute to the formation of the epicardial
lar hypoplasia, pulmonic stenosis, and tetralogy of layer. Descendants of proepicardial cells invade
Fallot.21,22 Moreover, genetic studies in humans the myocardium, where they develop into fibro-
have shown that haplotypes within the ISL1 lo- blasts in the heart and smooth-muscle cells of
cus are strongly associated with these forms of the coronary arteries.29-32 Signals from the epi-
congenital heart disease.23 Perhaps other right- cardium are required for proper maturation of the
sided disorders, such as hypoplastic right ventri- myocardium and normal development of the cor-
cle, Ebstein’s anomaly, and some forms of arrhyth- onary arteries.33-35
mogenic right ventricular dysplasia,24 are also the Recent studies suggest that epicardial pro-
result of abnormalities in second-heart–field cells. genitor cells are multipotent, with the ability to
The usual classification of congenital heart differentiate into smooth muscle, fibroblasts, and
diseases depends on the anatomical characteris- perhaps also cardiac muscle and endothelium36,37
tics of the abnormality. These traditional classi- (although the idea that these cells form coronary
fication systems may have to be changed in light endothelium has been challenged38). These stud-
of emerging evidence that the same developmen- ies used genetic markers expressed by the proepi-

Figure 3. Development and Derivatives of the Epicardium.

The epicardium derives from the proepicardial organ (Panel A), a multipotent cluster of cells that arises dorsal to
the looped heart. Epicardial progenitors migrate to and encompass the developing heart and form the mature epi-
cardium (Panel B). Some epicardial progenitors undergo an epithelial-to-mesenchymal transition, invade the myo-
cardium, and differentiate into various mature cardiac cell types, which may include vascular smooth-muscle cells,
fibroblasts, endothelial cells, and cardiac myocytes. Adapted from Schlueter.28
cardial organ — the Wilms’ tumor 1 gene (Wt1)37 components of scars, it is possible that the abil-
and the T-box 18 gene (Tbx18)36 — to map the ity of mammals to grow new heart muscle was
fate of epicardial precursor cells throughout the lost during evolution in a trade-off for the abil-
course of their differentiation. The results sug- ity to rapidly form a scar after injury.
gest that some epicardial precursors contribute Epicardium-derived progenitor cells (EPDCs)
to myocardium, an indication of an additional have been isolated from human, rat, and mouse
developmental avenue for the generation of car- hearts and have been grown in tissue culture.42
diac muscle. In adult zebrafish, which can re- In rodents (as in zebrafish), these cells reactivate
generate myocardium after injury,39 the epicar- fetal genes after myocardial infarction and pro-
dium becomes activated by surgical resection of liferate.43,44 Ex vivo, EPDCs can differentiate into
heart muscle40; the activated epicardium express- multiple cell types and express contractile proteins
es fetal genes, including wt1 and tbx18. It remains of myocytes. Various growth factors, including
unclear whether these activated epicardial cells thymosin β4, have been found to promote the pro-
contribute directly to the regeneration of myocar- liferation of EPDCs and to improve recovery and
dium or produce signals that cause cardiac myo- myocardial function after injury in animals45-47;
cytes to enter the cell cycle.41 Since epicardium it remains unclear whether these changes are due
normally gives rise to cardiac fibroblasts, the main to myocardial regeneration or to factors secreted

by EPDCs that have paracrine effects influencing abnormalities induced in these cells increase the
myocyte survival or function. These studies sug- susceptibility to atrial arrhythmia.
gest that interventions involving the manipulation The region of slow-conducting myocardium
of epicardial activation and EPDCs after injury — that separates atria from ventricles in the embryo
whether through the use of systemic therapy, treat- and provides atrioventricular delay initially oc-
ments administered within the pericardial space, cupies the entire atrioventricular ring.48,49,55 As
or the application of a drug-eluting patch to the cardiac development proceeds, fibroblasts derived
epicardial surface of the damaged heart — may from the epicardium invade the atrioventricular
be worthwhile avenues for further investigation. sulcus and form the annulus fibrosis,56,57 which
isolates the atria from the ventricles electrically.
The C a r di ac C onduc t ion S ys tem The atrioventricular canal myocardium regresses,
and the property of slow conduction becomes
The specialized cells of the cardiac conduction sys- restricted to the specialized cells of the atrioven-
tem arise from myocardial precursor cells. The tricular node. In animal models, deficient devel-
mature cells have relatively poor contractility and opment of the annulus fibrosis causes abnormal
express specialized ion channels and gap-junction electrical connectivity between the atria and ven-
proteins, including connexins, that mediate elec- tricles, pre-excitation, and characteristics of the
trical coupling with neighboring cells.48,49 Early Wolff–Parkinson–White syndrome.56,58 Ectopic
in development, at the time of chamber specifi- myocardium that bridges the atrioventricular re-
cation, the myocardium between the developing gion is, however, more common than breakdown
atria and ventricles has slow conduction charac- of the annulus fibrosis in humans with this syn-
teristics and other properties reminiscent of the drome. Consequently, some forms of the syn-
atrioventricular node. Similarly, the myocardium drome may result when the normal regression of
of the inflow tract acquires autonomous activity the atrioventricular canal myocardium fails to oc-
and develops pacemaker function. The sinus node cur during development.
develops from this tissue. The cells that give rise Proper formation of the atrioventricular node
to the sinus node express the fetal TBX18 gene, depends on transcription factors that play reiter-
whereas the cells that give rise to the atrioven- ated roles during cardiac development. These fac-
tricular node and the Purkinje system express the tors include NKX2-5, TBX5, and GATA4.48 In mice,
NKX2-5 transcription factor.48 The possibility that Tbx5 and Gata4 regulate the expression of con-
precursors of pacemaker cells of the sinus node nexin 30.2, which is required for slow conduction
are related to the myocardium surrounding the in the atrioventricular node.59 Haploinsufficiency
pulmonary veins could be important (and is cur- of Gata4 in mice causes a short PR interval.59 Mu-
rently under investigation) because atrial fibrilla- tation of NKX2-5, TBX5, or GATA4 has been associ-
tion commonly arises from an arrhythmia within ated with an atrial septal defect in humans as well
the pulmonary veins. The myocardium of the pos- as in animal models.60-63 Hence, structural inter-
terior wall of the left atrium extends to and en- ference of conducting fibers by the septal defect
sheathes the proximal pulmonary vein, thereby may not entirely explain the association between
providing electrical continuity, and atrial fibrilla- atrial septal defects and conduction abnormalities.
tion can be successfully treated through electrical Rather, a single underlying genetic defect may
isolation of the pulmonary veins.50 The develop- affect septal closure and specialized conduction
ment of pulmonary-vein myocardium requires cells independently.64 Indeed, patients with
the PITX2 transcription factor,51 and recent ge- NKX2-5 mutations can have isolated conduction
nomewide association studies have identified defects. These factors, and the cellular processes
haplotypes at 4q25, near PITX2, that are associated that these factors regulate, may continue to play
with atrial fibrillation.52,53 Thus, the response of important roles in conduction tissues through-
pulmonary-vein myocardial cells to altered PITX2 out adult life. For example, progressive degenera-
function may underlie the susceptibility to atrial tion of the atrioventricular node and heart block
fibrillation. It is also possible that melanocyte- develop when the Nkx2-5 gene has been inacti-
like cells in the heart,54 which are present in the vated in adult mice.65 It seems likely that an as-
atrioventricular ring, the atria, and the pulmo- sociation between certain risk alleles of this gene
nary veins in the developing embryo, play a role or related genes will be found in — and may
in atrial fibrillation. In animal models, genetic predict — heart block in elderly patients.

C a r diova scul a r M at ur at ion transcribed loci); it also represses gene transcrip-

tion by enzymatically deacetylating histones and
At the time of birth, the cardiovascular system un- condensing chromatin. Epigenetic control of chro-
dergoes a series of abrupt and critical changes. matin structure, a mechanism that mediates glob-
Blood must be diverted to the lungs for oxygen- al changes in gene-expression programs, is critical
ation, and the portal circulation must perfuse the to cellular reprogramming (the directed altera-
liver when enteric feeding begins. Increased oxy- tion in which one cell type is changed to another
gen tension associated with a baby’s first breaths, — e.g., a fibroblast becomes a pluripotent stem
coupled with withdrawal from exposure to mater- cell) and to the determination of cell fate.
nal prostaglandins, stimulates closure of the duc- There are indications that the activities of spe-
tus arteriosus, sending blood from the right ven- cific histone deacetylase enzymes are necessary
tricle to the lungs and establishing the parallel for regulation of the expression of the fetal gene
pulmonary and systemic circulations. The foramen program in the heart during development and
ovale of the atrial septum closes. The ductus veno- that these enzymes are involved in heart failure
sus constricts, sending portal blood to the liver. in adults. Genetic inactivation of histone deacety
Less obvious but equally important changes lase 2 in mice, for example, decreases the expres-
occur in myocardial cells during the neonatal pe- sion of fetal cardiac genes and inhibits reactiva-
riod. There is a shift in gene-expression profiles tion of the fetal gene program in situations
within the heart; many fetal isoforms of genes involving cardiac stress in adults.69 Chemical in-
become down-regulated or replaced by their adult hibitors of this enzyme, now being studied in
counterparts. Examples include genes encoding phase 3 clinical trials for the treatment of cer-
contractile components of the sarcomere, calcium- tain cancers, can prevent reactivation of the fetal
handling machinery, energy-utilization enzymes, gene program, cardiac hypertrophy, and heart
and natriuretic factors.66-68 Re-expression of fe- failure in animal models (e.g., ClinicalTrials.gov
tal genes occurs in nearly every form of heart numbers NCT00773747 and NCT01023308).70-75
failure in adults, and this phenomenon is thought These results suggest that epigenetic mechanisms
to contribute to the progression of heart failure. regulate the transition of fetal cardiac gene pro-
Elucidation of the mechanisms that regulate the grams to adult programs and that these mecha-
re-expression of fetal genes during disease states nisms could be targets for new treatments of
may reveal new targets for the treatment of heart heart failure.
failure. In addition, an improved understanding MicroRNA (miRNA) molecules are short, single
of the genetic programs governing myocyte mat- strands of RNA that modulate gene expression
uration should inform the development of regen- by binding to complementary regions in mRNA
erative treatments; the use of such treatments transcripts. The miRNA genes in chromosomal
for cardiac disease has been hampered by a lim- DNA can be expressed as independent genes un-
ited ability to engineer fully mature adult cardiac der the control of their own promoters or can be
myocytes from progenitor cells. coexpressed with other genes in which they are
Our knowledge of the mechanisms that regu- embedded. In mice, the fetal heart expresses beta-
late gene expression has increased considerably myosin heavy chain (β-MHC), whereas the adult
in recent years. Gene expression requires spe- heart expresses alpha-myosin heavy chain (α-MHC).
cific transcription factors — proteins that acti- In adult mice, cardiac stressors such as pressure
vate or inhibit transcription from genomic DNA overload or chronic adrenergic stimulation in-
to messenger RNA (mRNA) by binding to produce re-expression of β-MHC and suppression of
moter or enhancer regions of genes. Changes in α-MHC.66 The basis of this reciprocal regulation
DNA packaging that are effected by chromatin is the embedding of a regulatory miRNA gene in
and the enzymatic modification of histones, the the intron of the genes for each of the two MHC
principal protein component of chromatin, also isoforms.76 The expression of α-MHC results in
influence gene expression through a mechanism coexpression of miR-208 (a cardiac-specific miRNA
termed epigenetic modification. This mechanism gene), which, in the presence of stress-induced
regulates gene expression by affecting the enzy- signals, indirectly activates transcription of β-MHC
matic acetylation of histones (and causing other (Fig. 4). In the absence of miR-208, stress signals
chemical modifications) and triggering the un- fail to activate β-MHC and other fetal genes, and
winding of chromatin (which exposes actively both the hypertrophic response and associated

Figure 4. MicroRNA-Mediated Regulation of Myosin Heavy-Chain Gene Isoform Expression.

MicroRNA-208 (miRNA-208), which is embedded within an intron of the gene encoding alpha-myosin heavy chain
(α-MHC), indirectly regulates the expression of beta-myosin heavy chain (β-MHC) in response to stress-induced
signals. AAA represents the polyadenylated tail of messenger RNA; LA denotes left atrium, LV left ventricle, RA right
atrium, and RV right ventricle. Adapted from a drawing provided courtesy of Dr. E. Olson.
fibrosis are blunted. The possibility of targeting only partially known, and specific stages of the
miRNA genes with therapeutic agents is an progressive lineage restriction of these cardiac
emerging area of investigation.77-79 progenitors require further characterization. The
ability to expand cardiac progenitor populations,
Sum m a r y either in situ or ex vivo, and to direct cell fate
will have important implications for regenera-
Recent studies have revealed a surprising num- tive cardiovascular therapies. The cell biology of
ber of previously unappreciated aspects of car- myocyte maturation and the effects of the tran-
diac morphogenesis that are relevant to both sition from the fetal heart to the adult heart re-
congenital and adult cardiovascular disease. It main areas of investigation that are likely to
is now clear that cell populations extrinsic to inform our understanding of heart failure. Stud-
the primary heart field and the linear heart tube ies of the regulation of gene-expression programs
of the embryo contribute to the development of in the heart are likely to suggest new therapeu-
the mature heart and modulate cardiac mor- tic targets for cardiovascular disease.
phogenesis. These cell populations include neu- Supported by a grant from the National Institutes of Health
ral-crest cells, the cells arising from a second (U01 HL100405), a DeHaan Cardiac Myogenesis Award from the
heart field, and epicardial cells. The full devel- American Heart Association, and the W.W. Smith endowed chair
for cardiovascular research.
opmental potential and unique defining charac- Disclosure forms provided by the author are available with the
teristics of various cardiac progenitor cells are full text of this article at NEJM.org.

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Review article

franklin h. epstein lecture

Cardiac Development and Implications

L ine age R e s t r ic t ion

1638 n engl j med 363;17 nejm.org october 21, 2010

The New England Journal of Medicine

Figure 1. Overview of Cardiac Development.

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Figure 2. Progressive Lineage Restriction.

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The New England Journal of Medicine

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Figure 3. Development and Derivatives of the Epicardium.

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The New England Journal of Medicine

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C a r diova scul a r M at ur at ion transcribed loci); it also represses gene transcrip-

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The New England Journal of Medicine

Figure 4. MicroRNA-Mediated Regulation of Myosin Heavy-Chain Gene Isoform Expression.

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