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Neonatal Cardiology
Third Edition
Michael Artman, MD
Joyce C. Hall Eminent Scholar in Pediatrics
Senior Vice President, Pediatrician-in-Chief
Children’s Mercy Hospital
Chair, Department of Pediatrics
University of Missouri-Kansas City School of Medicine
University of Kansas School of Medicine
Kansas City, Missouri
Lynn Mahony, MD
Professor, Department of Pediatrics
University of Texas Southwestern Medical Center
Dallas, Texas
David F. Teitel, MD
Professor, Department of Pediatrics and the Cardiovascular Research Institute
University of California, San Francisco
San Francisco, California
New York Chicago San Francisco Athens London Madrid Mexico City
Milan New Delhi Singapore Sydney Toronto
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This book is dedicated to our families for their unwavering support, understanding, and sacrifices.
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Each of us continues to benefit from the wisdom of our mentors, who prepared us
so well for our lives, careers, and academic endeavors.

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Contents
Contributors ....................................................................vii Chapter 8
Foreword to the Second Edition.......................................ix Approach to the Infant With Inadequate
Foreword to the Third Edition.........................................xi Systemic Perfusion........................................ 137
Chapter 1 Chapter 9
Cardiac Morphogenesis: Implications for Cardiomyopathy and Other Causes of
Congenital Cardiovascular Diseases................... 1 Ventricular Dysfunction.................................. 155
Adriana C. Gittenberger-de Groot, PhD, Chapter 10
Robert E. Poelmann, PhD, Arrhythmias.................................................. 185
Margot M. Bartelings MD, PhD,
Marco C. DeRuiter, MD, PhD, Chapter 11
and Monique R. M. Jongbloed, MD, PhD Principles of Medical Management................. 217
Chapter 2 Chapter 12
Myocyte Contraction and Relaxation................. 19 Cardiovascular Drug Therapy.......................... 235
Perinatal Cardiovascular Physiology.................. 39 Care of the Postoperative Patient................... 255
Prenatal Evaluation and Management............... 55 Neurology of Congenital Cardiovascular Disease:
Brain Development, Acquired Injury,
Chapter 5 and Neurodevelopmental Outcome................. 267
Initial Evaluation of the Newborn With
Shabnam Peyvandi, MD
Suspected Cardiovascular Disease................... 67
and Patrick McQuillen, MD
Chapter 6
Approach to the Cyanotic Infant........................ 81
Chapter 15
Epidemiology, Etiology, and Genetics
Chapter 7 of Congenital Cardiovascular Disease............. 279
Approach to the Infant With Excessive
Pulmonary Blood Flow................................... 111 Index ..............................................................................291


Contributors
Margot M. Bartelings MD, PhD Patrick McQuillen, MD
Department of Anatomy and Embryology Departments of Pediatrics and Neurology
Leiden University Medical Center University of California, San Francisco
Leiden, Netherlands San Francisco, California
Marco C. DeRuiter, MD, PhD Shabnam Peyvandi, MD

Department of Anatomy and Embryology Department of Pediatrics
Leiden University Medical Center University of California, San Francisco
Leiden, Netherlands San Francisco, California
Adriana C. Gittenberger-de Groot, PhD Robert E. Poelmann, PhD

Department of Anatomy and Embryology Department of Anatomy and Embryology
Leiden University Medical Center Leiden University Medical Center
Leiden, Netherlands Leiden, Netherlands
Monique R. M. Jongbloed, MD, PhD

Department of Anatomy and Embryology
Leiden University Medical Center
Leiden, Netherlands
vii


Foreword to the Second Edition
During the 8 years since the publication of the first edi- Their importance in development of congenital cardio-
tion of Neonatal Cardiology in 2002, many remarkable vascular malformations is now being explored.
advances in our understanding of normal cardiovascular The association of neurological abnormalities with
development and of mechanisms, resulting in congenital congenital cardiovascular malformations has been recog-
cardiovascular malformations, have been achieved. nized for many years; in many genetic syndromes, both
The concept that these malformations had little impact developmental delay and cardiac defects are encountered.
on normal fetal development was widely accepted; the In recent years, concern has been raised regarding intel-
influence of congenital cardiovascular malformations lectual and behavioral impairment in children with several
on fetal blood flow patterns and oxygenation, as well as congenital cardiac anomalies. The possibility that this was
their effect on fetal cardiac and vascular development, is related to surgical procedures during infancy was consid-
increasingly being recognized. Furthermore, the potential ered, but recent evidence suggests interference with brain
effects of these defects on other organ systems, particu- development occurs during fetal life. In a most interesting
larly the brain, has engendered great interest and study. new chapter, authored by Dr. Patrick McQuillen, neuro-
In this second edition, Drs. Michael Artman, Lynn logical development and mechanisms by which congenital
Mahony, and David Teitel have continued the general phi- cardiovascular malformations could affect it are presented.
losophy of the first edition; they have presented clinical and This topic is of great importance, because it is suggested
hemodynamic manifestations of congenital and acquired that in some infants with these cardiac lesions, correction
cardiovascular disturbances, based on biological informa- during the neonatal period may not improve the neuro-
tion regarding development and function. All chapters have logical deficit. This would support the concept of interven-
been significantly modified to address the increased under- tion to correct the circulatory disturbance during fetal life.
standing of basic biology and factors affecting normal devel- The use of nonsurgical approaches to cardiac lesions
opment and performance. As in the first edition, the graphic has become standard practice over the past decade. Many
material largely presents diagrams that help to explain basic of these procedures are not yet applicable to neonates, but
physiological concepts and pathophysiology. The quality of as discussed in this edition, interventions to relieve aortic
the diagrams has been greatly improved, making the infor- and pulmonary stenoses by balloon valvuloplasty have
mation presented more readily assimilable. now become standard practice, thus avoiding the high
The first chapter, on cardiac embryology, contrib- risks of surgery in critically ill infants.
uted by Dr. Kathleen Ruppel, reviews the advances in the This edition of Neonatal Cardiology continues to provide
understanding of genetic pathways involved in cardiac pediatric cardiologists, neonatologists, and obstetricians
morphogenesis. Also, the revolutionary changes in our with an invaluable resource for the differential diagnosis
appreciation of the embryology of the heart and great ves- of cardiovascular disturbances and their management in
sels are presented. It was widely accepted that all struc- newborn infants. The symptom-complex approach is par-
tures developed from the primitive heart tube; it is now ticularly helpful to students and residents in understanding
recognized that other primitive cells from the anterior the mechanisms responsible for clinical manifestations.
or secondary heart field, as well as neural crest cells, are
major contributors to cardiac and great vessel formation. Abraham M. Rudolph, MD
ix


Foreword to the Third Edition
Congenital heart disease is the most common serious con- genetics. In addition, they have enlisted Dr. Gittenberger
genital defect. It occurs in ~1% of all live births, and annually de Groot and her colleagues to discuss current concepts of
about 1.5 million children are born with congenital heart cardiac embryology. Understanding embryology not only
disease. (A similar number have bicuspid aortic valves, but helps us understand how the anomaly formed but some-
these seldom cause problems in childhood.) Given the high day also will be integrated with genetics and perhaps lead
potential early mortality and morbidity of these diseases, to prevention of an anomaly. Furthermore, knowing how
any book such as this one that improves the effectiveness of anomalies such as aortic atresia develop gives a guide to the
treatment will make a major contribution to world health. best time for intrauterine treatment. In another chapter,
Neonatal cardiology is concerned mainly with congeni- Drs. McQuillen and Peyvandi discuss the relation between
tal heart disease. The period of transition from fetus to neo- cardiac malformations and neurodevelopment. Now that
nate is often difficult, and congenital or acquired disease at most forms of congenital heart disease are treatable with
this age may, for many reasons, be more difficult to manage low mortality, our concentration must be on the quality of
than at older ages. It is not surprising, therefore, that the life that results. Chief among these is neurological function,
highest mortality in children with congenital heart disease and recent studies have shown that fetuses with congenital
who are not treated occurs in the neonatal period. What is heart disease often have neurological abnormalities before
surprising is that so few books have concentrated on this birth. Whether these changes are due to abnormal brain
critical period. This third edition of Neonatal Cardiology has blood flow secondary to the congenital heart disease (and
gone a long way to correcting the deficiency. thus potentially amenable to treatment) or due to the same
With the advances in imaging methods, diagnos- disturbance that has altered cardiac development remains
tic cardiac catheterization has been replaced by echocar- to be determined.
diography, CT, and MRI. As a result, the emphasis today Included in this book are discussions of arrhythmias
is placed on anatomic abnormalities rather than on their and pharmacological treatment as they relate to congenital
physiological consequences, even though it is these conse- heart disease. Because pharmacology is used to manipulate
quences that often determine the outcome. The authors of physiology for the patient’s benefit, knowing the basis of the
this book, basing their work on the groundbreaking studies physiological disturbance leads to more effective therapy.
by Dr. Abraham Rudolph of abnormal fetal development Although knowledge of pathological anatomy is impor-
and the physiological changes due to congenital heart dis- tant in understanding congenital heart disease, knowledge
ease, have shown how understanding the physiology as well of the associated pathophysiology is mandatory if we wish
as the anatomy of these lesions improves our ability to treat to provide optimal care. This book is one of the few to com-
these patients. bine both aspects and represents a hallmark in the treatment
In this third edition, Drs. Teitel, Mahony, and Artman of congenital heart disease.
have updated and expanded what was in the second edition
with added information about myocytes, arrhythmias, and Julien I.E. Hoffman, MD
xi


CH APT ER
Cardiac Morphogenesis:
1
Implications for Congenital
Cardiovascular Diseases
■■ INTRODUCTION Incorporation of the Sinus Venosus, Atrial
■■ CARDIAC PROGENITORS AND THE CONCEPTS OF Septation, and Pulmonary Vein Development
FIRST AND SECOND HEART FIELD Ventricular Inflow and Outflow Tract Septation
Pharyngeal Arch Development
■■ THE NEURAL CREST
Valvulogenesis
■■ THE EPICARDIUM Conduction System Development
■■ BREAKING SYMMETRY Development of the Epicardium, Myocardium,
■■ CRITICAL DEVELOPMENTAL TIME WINDOWS and Coronary Arteries
■■ CARDIAC MORPHOGENESIS AND ■■ SUGGESTED READINGS
DYSMORPHOGENESIS
■■ INTRODUCTION understanding of mutations in humans that lead to con-

genital cardiovascular disease.
Knowledge of the role of cardiac-specific genes and their
This chapter summarizes the initial phases of cardiac
modulating factors has increased tremendously over the
development. We then describe in more detail how cardiac
last decade, although 85% of human congenital cardio-
morphogenesis leads to formation of the four-chambered
vascular disease is still considered to be multifactorial in
heart and how abnormal cardiogenesis contributes to
origin. Advances in the molecular biology of the develop-
congenital cardiovascular disease.
ing heart have greatly contributed to our understanding
of cardiac morphogenesis. Manipulation of conserved
■■ CARDIAC PROGENITORS AND THE
genes from a variety of model organisms has increased
CONCEPTS OF FIRST AND SECOND
our understanding of how genetic factors and cellular
HEART FIELD
interactions contribute to cardiac development. Trans-
genic mouse models have allowed time-specific tracing Heart development starts with two cardiogenic plates
of cells and their role in heart formation. The problem derived from the lateral splanchnic mesoderm. These
of embryo-lethality after manipulating “cardiac-specific” plates fuse in the midline in the anterior (cranial) region
genes has been overcome by inducible knockout strategies. of the embryo. The crescent of the cardiogenic plates is
Whole genome sequencing programs have also increased referred to as the first heart field (FHF) and is flanked
Artman-Ch01_p001_018.indd 1 2/10/17 6:27 PM

2 Chapter 1
medially by the second heart field (SHF) mesoderm toward various parts of the embryo, including the heart.
(Figure 1A). Upon fusion in the midline, the FHF forms Cardiac neural crest cells differentiate into cells of the
the two-layered primary heart tube with myocardium autonomic nervous system and into vascular smooth
on the outside lined by endocardium on the inside. muscle cells of the pharyngeal arch arteries and contrib-
The myocardium secretes a glycoprotein-rich layer, the ute to the arterial pole of the heart entering the endo-
cardiac jelly, toward the endocardium. The primary heart cardial outflow tract cushions (Figure 1-1E). Neural
tube connects to the arterial pole cranially and to the crest cells within the heart are involved in modulation
venous pole caudally (Figure 1-1B) but does not contain and induction of semilunar valve formation and genera-
all segments of the four-chambered heart. Venous tribu- tion of the myocardial component of the outflow tract
taries abut on the small atrial component, followed down- septum. At the venous pole, where their contribution is
stream by the future atrioventricular canal and a primitive less important, a similar effect is observed in the atrio-
left ventricle. Finally, the outflow tract connects to the ventricular cushions. More recently, cardiac neural crest
aortic sac at the arterial pole (Figure 1-1C). The various cells contributing smooth muscle cells to the coronary
components can be distinguished soon after, as both the arteries have been identified.
AV canal and the outflow tract contain an increasing
amount of cardiac jelly that forms the endocardial cush- ■■ THE EPICARDIUM
ions. The cushions become even more prominent as they
acquire mesenchymal cells, derived from the endocardial The epicardium (splanchnic mesodermal lining of the
lining as a result of endocardial-mesenchymal transition. pericardial cavity) is a secondary layer covering the
Subsequently, the primary heart tube starts the develop- myocardial tube and the intrapericardial part of the arte-
mentally determined rightward looping. rial pole. During embryonic development, the epicar-
At the same time, the SHF adds progenitor cells to dium originates from both the venous and the arterial
both the venous and the arterial poles, which ultimately poles (Figure 1-1E–G). The larger epicardial population
form the essential components of the right ventricle (RV) derives from a protrusion of the coelomic wall, covering
and at least a part of the right side of the interventricu- the sinus venosus and liver primordium (Figure 1-1F).
lar septum (Figure 1-1D). At the venous pole, the SHF The cells of the proepicardium spread along the outer
forms cardiomyocytes encapsulating the sinus venosus wall of the ventricles and atria to the border of the myo-
and its tributaries. The sinus venosus is incorporated cardium at the arterial pole. Here, they join the arte-
subsequently into the wall of the right and left atrium. rial epicardium, which is derived from a much smaller
Likewise, the walls of the great arteries, the embryonic arterial proepicardium exhibiting a slightly different
pharyngeal arch arteries that connect to the aortic sac, are phenotype (Figure 1-1G). On activation, the epithelial
partly built from SHF-originating cells. Neural crest cells epicardium undergoes endocardial-mesenchymal tran-
also contribute to formation of the great arteries, as will sition, and the resulting mesenchymal cells fill the sub-
be explained below in this chapter. epicardial space as epicardium-derived cells. These cells
Multiple specific transcription factors and signaling migrate between the myocardial cells of the heart tube,
molecules are essential to the early stages of cardiogenesis. the atrioventricular cushions, and the future fibrous
These include the earliest markers of the precardiac meso- annulus. These epicardium-derived cells, in contrast
derm, including the homeobox-containing gene Nkx2.5 to neural crest cells, differentiate into several cell lines
and the zinc-finger-containing GATA4/5/6 subfamily. including the majority of the cardiac fibroblasts and the
Members of the T-box family, TBx1/5/18/20, also have vascular smooth muscle cells of the coronary vascular
essential roles in SHF differentiation. Myocardial differ- system (Figure 1-2).The endothelial lining of the coro-
entiation is regulated by several myocyte-specific genes, nary vascular system is derived from the endothelium
including myosin light and heavy chain, alpha-cardiac of the sinus venosus/liver primordium adjacent to the
actin, and cardiac troponin I. proepicardium (Figures 1-1F, 1-2).
■■ THE NEURAL CREST ■■ BREAKING SYMMETRY

The neural crest cells are an ecto-mesodermal deriva- Starting with the developmentally determined rightward
tive arising from the crest of the neural tube, migrating looping, it is clear that the heart and its connections to the

CARDIAC MORPHOGENESIS: IMPLICATIONS FOR CONGENITAL CARDIOVASCULAR DISEASES 3
Arterial pole RVV LVV

First heart RCV PV LVC DA
field Second heart SVC
field AoS Ao
RVV
Cardiac jelly PT
A
LA
OFT
EC ∗ AVC EC RA
LV
RV LV
RV
Venous pole
IVC
A B C D
NH18 HH17
PAA
Anterior SHF
SV OFT
aPEO
NCC
PC
Posterior SHF
PC
vPEO
vPEO
CV L
F G
E
FIGURE 1-1. Cardiac development. A. Schematic depiction of the precardiac mesoderm in the primi-
tive plate. The brown area reflects the mesoderm of the FHF, whereas the yellow area corresponds
to the putative SHF mesoderm. B. Primary heart tube derived of FHF mesoderm. The tube consists of
myocardium, lined by cardiac jelly. C. Heart tube after looping. The yellow areas reflect SHF-derived
contributions. The SHF contributions to the outflow tract have not been depicted. Note that in this
stage the atria are still positioned entirely above the primitive left ventricle, whereas the outflow tract
is positioned above the primitive right ventricle. D. Advanced stage of heart development. Septation
has now occurred at the level of the atria, ventricles, and outflow tract. E. Sagittal view of an embryo.
The (anterior and posterior) SHF mesoderm and its derivatives are depicted in yellow. Contributions
from neural crest cells are depicted in blue. A proepicardial organ can be distinguished at the venous
pole as well as a smaller proepicardial organ at the arterial pole. F. Scanning electronic microscopic
section at the level of the venous pole in a chick embryo, showing the venous pole of the proepicardial
organ. G. Scanning electronic microscopic section at the level of the outflow tract in a chick embryo,
showing the arterial pole of the proepicardial organ (arrowheads, asterisk). Abbreviations: A, atrium;
Ao, aorta; AoS, aortic sac; aPEO, atrial pole of proepicardial organ; AVC, atrioventricular canal; EC,
endocardial cushions; FHF, first heart field; HH, Hamburger and Hamilton; IVC, inferior vena cava;
LA, left atrium; L, liver; LCV, left cardinal vein; LV, left ventricle; LVV, left venous valve; PAA, pharyn-
geal arch artery; PC, pericardial cavity; PT, pulmonary trunk; PV, pulmonary vein; RA, right atrium;
RCV, right cardinal vein; RV, right ventricle; RVV, right venous valve; SHF, second heart field; SV, sinus
venosus; SVC, superior vena cava; VPEO, venous pole of proepicardial organ. B–E: Adapted from:
Gittenberger-de Groot AC et al. Ann Med. 2014;46(8):640-652. F and G: Adapted from: Gittenberger-de
Groot AC et al. Differentiation. 2012;84(1):41-53.

4 Chapter 1
Development Congenital/disease Stem cells
Compact myocardium
Spongious
myocardium
Infarction
Myocardium
CMPCs
Cardiomyocyte
precursor
Conduction
anomalies
Cardiac jelly
Trabeculae
∗ Purkinje fibres
Endocardium Endocardial cushions Cardiac

valves
Interstitial fibroblats Annulus fibrosis
Meso-
derm Valvulopathies
∗ EPDCs
Fibroelastosis
PEO epithelium Epicardium EPDCs
Fistulae
Sinus VSMCs fibroblasts
ECs
venosus/
liver Pattern anomalies
Endothelial Coronary capillaries Coronary
precursor vessels
Myocyte line Endocardial line

∗
Reactivation Composite
EPDC line Endothelial line in adults structures
FIGURE 1-2. Cell lines contributing to the developing heart. Schematic representation of cardiac
cell lines (cardiomyocytes, endocardium, epicardium, and endothelium) that are derived from the first
and second heart field mesoderm and are the main contributors to the definitive heart and vessels.
Epicardium-derived cells (in yellow) as well as inadequate interaction with other cardiac cell types may
play a role in some cardiac malformations (green boxes). The second heart field and neural crest cell
contribution to the great vessels is not represented. Abbreviations: CMPCs, cardiomyocyte progenitor
cells; EPDCs, epicardium-derived cells; ECs, endothelial cells; VSMCs, vascular smooth muscle cells.
Adapted from: Gittenberger-de Groot AC et al. Differentiation. 2012;84(1):41-53.
lungs are not symmetric. Situs inversus and heterotaxy abnormal cardiac development and even early embryo-
occur in humans; several mouse models have increased lethality. This results in early spontaneous abortion in
our knowledge on essential signaling factors related to humans. In homozygous mouse strains, 50% of spontane-
determination of situs. It is remarkable that only the ous early embryo-lethality related to mutations is caused
atrial situs and its contributing posterior SHF seem to be by cardiovascular abnormalities. In the usually non-
influenced by these factors, while right ventricle and left homozygous human, the percent of spontaneous abor-
ventricle with their specific morphologies do not copy the tions caused by congenital cardiovascular disease cannot
atrial situs anomalies (eg, inversus or ambiguous). be determined unequivocally. The FHF lesions are consid-
ered to be the most critical for embryonic demise. Most
of the cardiac malformations that clinicians encounter
■■ CRITICAL DEVELOPMENTAL
in the perinatal period occur during looping and events
TIME WINDOWS
mediated by the SHF. Spontaneous abortion in the second
In the preceding paragraphs, the cellular building blocks trimester caused by congenital cardiovascular disease is
of the cardiovascular system have been presented. Serious less common, as most forms of cardiac malformations are
disturbances of one or more cell populations can lead to compatible with intrauterine survival.

■■ CARDIAC MORPHOGENESIS AND incorporated into the posterior wall of both the right and
DYSMORPHOGENESIS the left atria. The atrial appendages are probably related
to the FHF.
In the human embryo, the formation of the four-
The left and right cardinal veins (the embryonic supe-
chambered heart occurs by about 8 weeks’ gestation.
rior and inferior caval veins) are incorporated into the
Thereafter, maturation and remodeling of, eg, the pha-
right atrium and are flanked by the folds of the embry-
ryngeal arch arteries and valves are essential for ensuing
onic right and left venous valves (Figure 1-1C, D). The
proper functioning and postnatal survival. The most
left inferior cardinal vein (future coronary sinus) and the
important elements of cardiac morphogenesis (summa-
left superior cardinal vein (regressing in the human heart
rized in Figure 1-3), including septation, valve formation,
as the ligament of Marshall) all drain into the cavity of
conduction system maturation, and coronary vascular
the right atrium. A splanchnic vascular plexus surrounds
development, will be presented.
the developing lung buds. During early developmental
stages, the primary route of pulmonary drainage from this
Incorporation of the Sinus Venosus, Atrial plexus is toward the systemic veins; a direct connection of
Septation, and Pulmonary Vein Development the primitive pulmonary veins to the heart is achieved
The precardiac mesoderm of the SHF at the venous pole from different tissue later during development. The
develops uniquely from an Nkx2.5-negative but myo- anlage of the primitive pulmonary vein, the so-called
sin light chain positive cell population, surrounding the mid-pharyngeal endothelial strand, initially does not
lumen of the sinus venosus. This myocardial cell lineage is have a lumen and is connected to the sinus venosus.
Heart tube
Heart loop
Atrial septation
Ventricular septation
Conduction system
Valve formation
Pulmonary veins
Aortic arch/
pulmonary artery
Ductus arteriosus
Coronary vasculature
Ovulation in days 18 24 26 28 29 31 33 35 37 39 41 43
Crown-rump length in mm 1-5 2-3 3-5 4-5 6-7 7-8 9-10 11-1414-1617-20 22-2425-26
Horizons IX XI XII XIII XIV XV XVI XVII XVIII XIX XXI XXII
chicken/mouse: sequence overlap identical
FIGURE 1-3. Cardiac morphogenesis. Schematic representation focusing on the time line and the
major events during cardiac morphogenesis. Many processes essential to heart formation overlap dur-
ing the 7 to 8 weeks of development, making it difficult to determine the separate molecular pathways
or the primary insult that leads to congenital cardiovascular malformations, either isolated or complex.
Valvulogenesis occurs relatively late in heart formation, while completion of atrial septation (closure
of the foramen ovale) and ductus arteriosus differentiation (closure of the ductus arteriosus) naturally
occur after birth because of the unique requirements of the fetal circulation. Source: Jongbloed MRM,
et al. Development of the Cardiac Conduction System and the Possible Relation to Predilection Sites
of Arrhythmogenesis, TheScientificWorldJOURNAL, vol. 8, pp. 239-269, 2008.

6 Chapter 1
During atrial septation it connects to the dorsal wall of left atria. It partially disintegrates forming the ostium
the left atrium. The splanchnic pulmonary venous con- secundum, which is required for the formation of the
nections with the systemic cardinal (putative caval) veins embryonic foramen ovale (Figure 1-4A, B), the essential
gradually disappear during normal development. communication between the right and left atria during
During atrial septation, four components deserve fetal life. Fusion of a mesenchymal cap on the free rim of
attention: the primary septum, the dorsal mesenchymal the primary atrial septum with the atrioventricular endo-
protrusion, the septum secundum, and the endocar- cardial cushion mass and with the dorsal mesenchymal
dial cushions. The initially two-layered myocardial pri- protrusion closes the ostium primum. This structure is
mary atrial septum is positioned between the right and found at the right side of the primary atrial septum
SVC
SVC
DM OS DM PV
SAS PAS MC
DM
PV
RA RA
OP
LA LA
IVC
TO MO
AVC IVC
A B
FIGURE 1-4. Atrial septation. A. Early development of the dorsal and cranial wall of the right and
left atria. The gold indicates the contribution of the SHF to the incorporated sinus venosus myocar-
dium. The appendages are not depicted. Both the inferior and the superior vena caval veins enter in
the right atrium as well as the coronary sinus, which is derived from the left superior cardinal vein.
A mesenchymal cap (green) under the rim of the primary atrial septum borders the ostium primum,
which connects the right and left atria. The entrance of the primitive pulmonary vein is seen in the left
atrium. The infolding of the superior wall of the right atrium that will form the secundum atrial septum
is already seen merging with the dorsal mesenchymal protrusion. B. After completion of septation,
the ostium primum is closed by fusion of the mesenchymal cap with the atrioventricular cushions,
which have now divided the atrioventricular canal into a tricuspid and a mitral orifice. The perforations
in the primary atrial septum have enlarged to form an ostium secundum that in combination with the
free rim of the secundum atrial septum is part of the foramen ovale (arrow) that closes after birth.
Abbreviations: AVC, atrioventricular canal; DM, dorsal mesocardium; IVC, inferior vena cava; LA, left
atrium; MC, mesenchymal cap; MO, mitral orifice; OP, ostium primum; OS, ostium secundum; PAS,
primary atrial septum; PV, pulmonary vein; RA, right atrium; SAS, secundum atrial septum; SVC, supe-
rior vena cava; TO, tricuspid orifice. Used with permission from Gittenberger-de Groot AC, et al., (2011).
Normal and Abnormal Cardiac Development. In: Pediatric Cardiovascular Medicine, Second Edition
(eds JH Moller and JIE Hoffman), Wiley-Blackwell, Oxford, UK.

as a thick mesenchymal mass (Figure 1-4A, B) and caval vein. Mutations in genes involved in posterior SHF
will develop into the muscular base of the atrial sep- differentiation, such as TBx5 and NKx2.5, are linked to
tum. At the right side of the primary septum and usu- this relatively common group of malformations.
ally incorporating the left venous valve, a folding process
of the atrial myocardial wall forms the crescent ridge Atrioventricular septal defects. Data from animal mod-
of the atrial septum secundum (the limbus). Dur- els and humans suggest that most cases of atrioventricu-
ing development, the free edge of the primary atrial lar septal defect (atrioventricular canal) are caused by a
septum (the valve of the foramen ovale) and the rim of deficiency in the base of the atrial septum resulting from
the septum secundum (the limbus) will overlap, allowing underdevelopment of the dorsal mesenchymal protru-
blood to pass via the foramen ovale (Figure 1-4B). At a sion. Additionally, the posterior inlet ventricular septum
variable time after birth, these two rims often fuse, result- is shorter than normal; in combination, this results in
ing in the closure of the foramen ovale, although this partial fusion to absence of the atrioventricular cushions,
structure remains patent in up to 20% of normal adults. resulting in a common valve with either one- or two-valve
ostia (depending on the amount of fusion). Portions of
Implications for Congenital Cardiovascular Disease the atrioventricular cushions develop into the character-
istic atrioventricular valve leaflets observed in atrioven-
Abnormal pulmonary venous return. As described
tricular septal defects (ie, superior and inferior bridging
above, pulmonary drainage is initially via an extensive
leaflets and left and right-sided mural leaflets).
midsagittal splanchnic vascular network. Disturbance
of the SHF can lead to misalignment and faulty incorpo-
ration of the primitive pulmonary veins into the dorsal Ventricular Inflow and Outflow Tract Septation
left atrial wall. In case of absence or atresia of the mid- Viewed from the right, the ventricular septum is divided
pharyngeal endothelial strand, either the early pulmo- into several components, including the ventricular inlet
nary to systemic connections will persist or abnormal septum, an apical trabeculated component, and an ante-
connections will develop, leading to abnormal drainage rior (“infolding”) component (Figure 1-6A, B). The out-
of the pulmonary venous blood to three levels: subdia- flow tract septum (Figure 1-6C) develops as a separate
phragmatic (eg, scimitar syndrome; Figure 1-5A), car- structure. The different components with their specific
diac, and supracardiac (Figure 1-5B). The drainage of all developmental history, boundaries, and origin are asso-
the pulmonary veins can be abnormal (total anomalous ciated with varying congenital malformations of the ven-
pulmonary venous connection) or partial, with some pul- tricular septum.
monary veins entering in into left atrium and some into To understand the process of ventricular septation
either systemic veins (Figure 1-5B) or the right atrium. and the aberrations in development that lead to the most
The few known genetic causes are linked to abnormalities common septal defects, it is helpful to first review several
of left/right asymmetry (heterotaxy) caused by mutations novel findings concerning the contribution of both the
of the transcription factor PITx2 or by more downstream anterior SHF and the neural crest cells to the outflow tract
signaling abnormalities (eg, PDGFRα). septum and the trabecular portion of the right ventricle.
Several tracing studies in mouse embryos employing
Atrial septal defects. Several types of atrial septal surrogate markers for SHF-derived cells have shown an
defects occur. A primum atrial septal defect is caused by asymmetric contribution to both the myocardium and the
a deficient connection of the primary interatrial septum vascular wall of the right ventricular outflow tract and the
with the atrioventricular cushion complex. This anomaly pulmonary trunk. In this process, which we have termed
is often seen in conjunction with an atrioventricular sep- the “pulmonary push,” the embryonic left (pulmonary)
tal defect (see below) in which the dorsal mesenchymal side of the outflow tract is expanded by a relatively
protrusion is also underdeveloped. The most common large contribution of the SHF as compared to the right
anomaly of the atrial septum is a secundum atrial septal (aortic) side, eventually bringing the pulmonary orifice
defect, in which there is deficiency of an atrial septal com- to its normal anterior and cranial position with respect
ponent. More rarely, a sinus venosus type of atrial septal to the aorta. This pulmonary push is responsible for the
defect is seen, which is related to the superior or inferior so-called rotation of the outflow tract and great arteries

8 Chapter 1
BV
VV
RPA
SVC RPV LPV
LPA
RSPV SVC Ao
PT LSPV
LIPV
RA LA
RA LA
RAA
LV LAA
RV
RIPV
IVC IVC
A B
FIGURE 1-5. Anomalous pulmonary venous connection. A. Scimitar syndrome is characterized by a

partial or complete right-sided anomalous venous connection to the inferior vena cava. In this case,
the right inferior pulmonary vein has an anomalous connection to inferior vena cava. The other veins
depicted all drain normally to the left atrium. Other characteristics of Scimitar syndrome include
hypoplasia of the right pulmonary artery and lung, resulting in dextroposition of the heart. B. Total
anomalous pulmonary venous connection, extracardiac type. The right and left pulmonary veins drain
via a vertical vein into a systemic vein (eg, the left innominate vein, which drains into the superior
vena cava). The absence of pulmonary venous connections and incorporation into the left atrium lead
to a small left atrium that does not contain vessel wall tissue. Abbreviations: Ao, aorta; BV, brachio-
cephalic vein; IVC, inferior vena cava; LA, left atrium; LAA, left atrial appendage; LPA, left pulmonary
artery; LIPV, left inferior pulmonary vein; LPV, left pulmonary vein; LSPV, left superior pulmonary
vein; LV, left ventricle; PT, pulmonary trunk; RA, right atrium; RAA, right atrial appendage; RIPV, right
inferior pulmonary vein; RPA, right pulmonary artery; RPV, right pulmonary vein; RSPV, right superior
pulmonary vein; RV, right ventricle; SVC, superior vena cava; VV, vertical vein. Panel B is Adapted
from Douglas YL et al. Int J Cardiol. 2009;134:302-312.
and also explains the relatively deep position of the aortic left ventricular outflow tracts. This outflow tract separa-
orifice in the crux of the heart. tion complex (distinguishable only as an outflow tract
During this process, neural crest cells are incor- septum in specific cardiac anomalies) fuses by bringing
porated by ingression into the aortic sac, creating the together the septal and parietal cushion with the merged
aorto-pulmonary septum, which separates the aorta and atrioventricular cushions, thereby closing the embryonic
pulmonary artery. The aorto-pulmonary septum forms interventricular foramen and completing ventricular
the central condensed mesenchyme, as well as two prongs septation. During this process, an anterior folding sep-
extending into the septal and parietal endocardial cushions tum is formed resulting from the expansion of the right
present in the outflow tract (Figure 1-6C). The neural crest and left ventricles, pushing the two outer faces of both
cells have an induction effect on the outflow tract, recruit- ventricles together and trapping epicardium in between.
ing myocardial cells into the cushions that form the pos- Of note, the epicardium serves a similar function as the
terior wall of the subpulmonary infundibulum, which also endocardial cushions inside the heart, bringing two myo-
forms the septum between the right ventricular and the cardial faces together. The trapped epicardial cells will

PT Ao
APS
D
Ao PT
OTS SB MB P
RV
∗ IS TS
SB AFS
IS
MB TS
A B C
FIGURE 1-6. Ventricular septal components. A. Schematic representation showing the components
of the interventricular septum including the inlet septum, the anterior folding septum, and the tra-
becular (apical) septum. The septal band that continues into the moderator band is related devel-
opmentally to the inlet septum. The posterior wall of the subpulmonary infundibulum contains the
small outflow tract septum (asterisk). B. Postmortem specimen with the above-mentioned septal
components. C. Scanning electron microscopic picture of the outflow tract of a chicken embryo. The
aorto-pulmonary septum at the level between the aortic and pulmonary trunk orifices, which consists
at this stage of condensed mesenchyme of neural crest cell origin, will merge with the distal endo-
cardial outflow tract cushion and extend into the proximal outflow tract cushion. The distal level will
remodel into the semilunar valves of the great arteries, while the proximal endocardial cushion will,
by induction through the neural crest cell population, transform into myocardium and eventually form
the small outflow tract septum. Abbreviations: AFS, anterior folding septum; Ao, aorta; APS, aorto-
pulmonary septum; D, distal (endocardial outflow tract cushion); IS, inlet septum; MB, moderator
band; OTS, outflow tract septum; P, proximal (outflow tract cushion); PT, pulmonary trunk; SB, septal
band; TS, trabecular septum. A: Adapted from Gittenberger-de Groot, AC, et al., (2012). Normal and
Abnormal Cardiac Development, in Pediatric Cardiovascular Medicine, Second Edition (eds JH Moller and
JIE Hoffman), Wiley-Blackwell, Oxford, UK. B and C: Used with persimmon from Gittenberger-de Groot, AC,
et al., (2012). Normal and Abnormal Cardiac Development, in Pediatric Cardiovascular Medicine, Second
Edition (eds JH Moller and JIE Hoffman), Wiley-Blackwell, Oxford, UK.
differentiate into epicardium-derived cells, bringing these cushion mass. Since the fibrous connection between the
cells deep into the core of the septum. tricuspid and mitral orifice and valves derives mainly
from atrioventricular and outflow tract endocardial
Implications for Congenital Cardiovascular Disease cushions, the ventricular septal defect will in part be
Ventricular septal defects. Muscular ventricular septal flanked by fibrous tissue; hence, the term “perimembra-
defects can be found within the anterior folding septum, nous” is often used to describe these defects. The defect
within the inlet septum, and on the border of the septal can extend more posteriorly toward the inlet septum or,
band with the anterior folding septum, ie, central muscu- in case of a malaligned or shortened outflow tract sep-
lar ventricular septal defect. tum, toward the orifices of the great arteries. These are
generally referred to as subarterial, but more specifically
Perimembranous ventricular septal defects and they are subaortic in tetralogy of Fallot and subpul-
malalignment defects, tetralogy of Fallot, and double- monary in Taussig-Bing malformation. From a devel-
outlet right ventricle. These malformations are caused opmental point of view, a double muscular subarterial
primarily by an abnormal extension and malalignment of infundibulum or conus has been proposed to be essen-
the outflow tract septal complex with the atrioventricular tial for the anomaly called double-outlet right ventricle.

10 Chapter 1
Given that the “pulmonary push” is an essential element aortic sac with the bilateral dorsal aortae (Figure 1-7A–D).
of rotation and extension of the right ventricular outflow Stability of the vasculature is provided by a smooth muscle
tract, anomalies of this region are better understood as cell layer that is derived from several sources, including the
resulting from unbalanced contributions from SHF and SHF splanchnic mesoderm and cardiac neural crest cells.
neural crest cells. Remodeling of this system requires a balanced interaction
of the SHF and neural crest–derived cells (Figure 1-7E)
Pharyngeal Arch Development and differs among species. In fish, five or more branchial
The pharyngeal arches develop as a bilaterally symmetric arches persist and feed the pairs of gills. In reptiles, pairs of
system harboring skeletal, muscular, glandular, and vas- the third (carotid), fourth (aorta), and sixth (pulmonary)
cular elements of the face and neck region. The six pairs pharyngeal arch arteries persist, but in birds and mam-
of pharyngeal arch arteries begin their development as a mals, the arterial system becomes asymmetric. In birds, the
cranio-caudal series of endothelial tubes that connect the right fourth becomes the aortic arch, whereas the left one
RCA LCA RCA LCA

LSA
RSA DAo
III γ
IV
RSA β
VI AAo DA
LSA PT
AoSac PA DA
α LDAo
CoA Ao
RDAo PT
a
DesAo
A B C D E
Right arch Left arch
RDA
III
Chicken Mouse Human
F G H I
FIGURE 1-7. Remodeling of the pharyngeal arterial arch system. A–D. Schematic representation
of the remodeling of the pharyngeal arterial arch system during development. The left arch with
principal fourth arch segment becomes dominant, and right-sided structures disappear. The color
coding refers to the arterial segments derived from the pharyngeal arches (blue, third arch; pur-
ple, fourth arch; green, sixth arch). E. Relative contribution of neural crest cells (blue) in the wall
of the great arteries showing that there are mixed wall structures as well as sharp boundaries.
F and H. Species variation in pharyngeal arch remodeling in the chicken (right arch), and the mouse
and human (left arches). I. Development of a right-sided anomalous subclavian artery occurs when
the right fourth arch segment disappears (asterisk) and the right dorsal aortic segment persists.
Abbreviations: AoSac, aortic sac; Ao, ascending aorta; CoA, aortic coarctation; DesAo, descending
aorta; DA, ductus arteriosus; PA, pulmonary artery; PT, pulmonary trunk; RCA/LCA, right/left carotid
artery; RDA, right dorsal aorta; RDAo/LDAo, right/left descending aorta, RSA/LSA, right/left subclavian
artery. Adpated from: A–D: From Molin DG, et al. Cardiovasc Res. 2002; 56(2):312-22, by permission of
Oxford University Press. Reprinted with permission from Molin DG, et al. Birth Defects Res A Clin Mol
Teratol. 2004; 70(12):927-38.

degenerates during development (Figure 1-7F). In mam-

mals, including humans, the main part of the left fourth
develops into the B-segment of the aortic arch (between
the origins of the left carotid and left subclavian arteries;
Figure 1-7H), while the right fourth becomes part of the
right subclavian artery (Figure 1-7G, H). The remodeling
process involves apoptosis of the vascular segments that
disappear, probably combined with shear stress-invoked
signaling. The distal part of the left sixth pharyngeal arch DA
artery persists in mammals as the ductus arteriosus. The
proximal part, which can be very short, is connected to
the left pulmonary artery. On the right side, the distal part
of the sixth pharyngeal arch artery disappears together
with the right dorsal aortic segment, to which it joins cau- Ao
dally with the left dorsal aorta. The subclavian arteries are
thought to develop from the ipsilateral seventh interseg- PT
mental arteries, but how these arteries move superiorly dur-
ing development is poorly understood (Figure 1-7A–D). A
The contribution of SHF and neural crest cells to the
pharyngeal arch arterial system is mainly to the differen-
tiation of the smooth muscle layer, whereas the neural Vascular wall
crest cells also provide for the innervation of the various
segments. The contribution of SHF and neural crest cells Luman
differs within the aortic arch system, as there are precise
boundaries to the contributions of neural crest cells. The Ductal tissue
ascending aorta and pulmonary trunk, including their

roots, are of mixed origin. The ductus arteriosus is com- B
pletely derived from neural crest cells with a sharp bound-
ary to the descending part of the thoracic aorta that lacks FIGURE 1-8. Aortic coarctation. Schematic depiction of an
aortic coarctation involving muscle of the ductus arteriosus
neural crest cells (Figure 1-7E). The pulmonary and sub- A. Ductal tissue with thick intimal cushions (depicted in blue)
clavian arteries probably have a complete SHF origin. completely encircles the aortic arch. B. Histological section
showing the extension of ductal tissue covering most of the
Implications for Congenital Cardiovascular Disease endothelial surface of the aortic wall. Abbreviations: Ao,
aorta; DA, ductus arteriosus; PT, pulmonary trunk.
Coarctation and aortic arch malformations. A number
of abnormalities may occur during the extensive remodel-
ing of the aortic arch system. However, many are able to the aortic arch between the left subclavian and entrance
sustain the prenatal circulation. Based on variable SHF and of the ductus arteriosus or its ligament (Figure 1-7H), can
neural crest cell contribution and ensuing hemodynamic also be hypoplastic. The most common abnormality in this
alterations, some sites are especially vulnerable to develop segment is the localized aortic coarctation, in which the
abnormal anatomy. In humans, the most common site is contribution from the left-sided ductus arteriosus is obvi-
located in the fourth arch artery, leading to interruption ous. Normally, the ductus arteriosus closes after birth, but
or hypoplasia of the B-segment (Figure 1-7H) resulting if the ductal (muscular) tissue extends abnormally into the
in aortic interruption. The causal factor in this anomaly aortic arch, its constriction at birth can increase the sever-
is linked with the SHF and TBx1 disturbances, combined ity of the coarctation (Figure 1-8A, B).
with the resulting alterations in blood flow. Dominance
of the right-sided fourth arch artery may lead to a right Anomalous origin of the subclavian artery. A relatively
aortic arch with mirror image branching of the carotid and common abnormality is seen when the right subclavian
subclavian arteries. The A-segment, or isthmus, located in artery does not reach its proper cranial position before

12 Chapter 1
the right dorsal aortic segment disappears. Rather than (anterior, posterior, and septal), while the mitral valve
arising from the right innominate artery, it arises from has two leaflets (aortic and lateral leaflet). The atrioven-
the descending aorta, distal to the left subclavian artery. In tricular cushions initially adhere to the myocardium of
the presence of an abnormal right-sided aortic arch, the the atrioventricular canal (Figure 1-9A) but separate by a
left subclavian artery can arise anomalously (Figure 1-7I). process that is not well understood (Figure 1-9B). The free
rims of the developing leaflets remain connected by endo-
Valvulogenesis cardial cushion–derived chordae tendinae to the papillary
Both semilunar and atrioventricular valves derive from muscles of the respective ventricles. The mesenchymal
their respective endocardial cushions. This implies that content of the valves is derived by endocardial-mesenchy-
defective endocardial-mesenchymal transition, essential mal transformation from the underlying endocardium.
for proper valve differentiation, can be linked to abnormal Epicardium-derived cells also migrate from the surface
valve structure. However, both in humans and in animal of the heart to the area of the annulus fibrosis, separat-
models, only a few genes have been linked to deficient ing the atrial and ventricular myocardium, and into the
valve tissue (eg, NOTCH1, NFATC1). Since the origin endocardial valve tissue (Figure 1-9B). In the cushions,
of the semilunar and atrioventricular valves differs with epicardium-derived cells are found mainly in the develop-
respect to SHF and FHF and they receive different con- ing parietal (and not septal) leaflets, a pattern potentially
leading to the preferential distribution pattern of affected
tributions from neural crest cells and epicardium-derived
valve leaflets in anomalies like Ebstein malformation and
cells, the normal development of the respective valves is
mitral valve prolapse.
described below.
Atrioventricular Valves Semilunar Valves

The fibrous tissue of the atrioventricular valves derives Both the aortic and the pulmonary semilunar valves
from the endocardial cushions in the atrioventricular derive from the septal and parietal cushions of the out-
canal, including the superior and inferior cushion and a flow tract. Neural crest cells enter the endocardial cush-
small lateral atrioventricular cushion on each side. The ions at the border of the arterial wall and myocardium.
central portions of the superior and inferior atrioven- At the same time, endocardial-mesenchymal transforma-
tricular cushions fuse, separating the tricuspid and mitral tion of the endocardial lining is essential to bring in the
orifices. The tricuspid valve consists of three leaflets mesenchymal cells containing the cushion. This process
ES AVCu AL
AVCu
RV
A B C
FIGURE 1-9. Atrioventricular valve formation. A. The atrioventricular valves develop form the atrio-
ventricular endocardial cushions (depicted in light blue). B. With dissociation of the embryonic atrial
and ventricular myocardium, the epicardium-derived cells from the atrioventricular epicardial sulcus
(depicted in dark blue) migrate into the endocardial cushions providing the fibroblasts for the annu-
lus fibrosis and a population within the cushions. The cushions form the definitive valve leaflets by
delamination from the wall as well as the chordae tendinae that are attached to the papillary muscles.
C. Ebstein anomaly of the tricuspid valve. The anterior tricuspid valve leaflet is rather well developed,
whereas the septal and posterior leaflets have not delaminated from the ventricular wall. Abbreviations:
AL, anterior (tricuspid valve leaflet); AVCu, atrioventricular endocardial cushion; ES, epicardial sulcus;
RV, right ventricle.

is more prominent in the cusp side facing the aorta. Arte- these emerge from the main cushions or whether there
rial epicardial cells have recently been identified in the are differential contributions of SHF, neural crest cells,
developing valve leaflets. Additionally, two intercalated and endocardium to the respective cushions and leaflets.
cushions develop each in the aortic and pulmonary part of The latter is important for understanding malformations
the outflow tract (Figure 1-10A). It is not known whether like bicuspid aortic valve (Figure 1-10B).
Implications for Congenital Cardiovascular Disease

Overriding and straddling atrioventricular valves and
double-inlet left ventricle. The tricuspid orifice becomes
positioned above the right ventricle during remodeling of
the inner curvature of the heart, which is closely linked
to the repositioning of the outflow tract. Initially, there
is only a slit-like inlet portion of the right ventricle, and
the right side of the atrioventricular cushions is contained
within this area. If the remodeling or shift of the tricuspid
orifice is incomplete, a ventricular septal defect remains.
IC
The valve overrides the septal defect; occasionally, there is
B actual straddling in which the tricuspid valve has chordal
EC
attachments into both ventricles. The ventricular septal
defect is characteristically in a posterior or inlet position.
EC
If more than 50% of the tricuspid valve remains connected
to the left ventricle, the resulting anomaly is called double-
inlet left ventricle, which a common form of physiologic
single ventricle. It is much less common for the mitral
IC
valve to straddle the ventricular septum. This is usually
associated with transposition of the great arteries, in which
case the ventricular septal defect is located anteriorly.
Stenosis or atresia of an atrioventricular valve. The

complete atrioventricular canal is originally connected to
NCCs the primitive left ventricle (Figure 1-1C). In the absence
of a connection of the atrium to the developing right ven-
tricle, the tricuspid orifice is atretic. It is seen as a myo-
cardial dimple in the right atrium. In these cases, the right
A ventricle has only trabecular and outflow tract portions,
lacking the inlet portion.
FIGURE 1-10. Outflow tract valve development. A. Sche-
matic representation of the two main outflow tract endocar-
dial cushions (light blue) that line the myocardial outflow Ebstein anomaly of the tricuspid valve. This anomaly
tract, showing a saddle-shaped border with the vascular is caused by deficient delamination of the valve leaflets.
wall of the aortic sac. As a result of inward migration of The amount of nondelamination is highly variable, from
neural crest cells (indicated as dark blue dots), the cush-
minimal inferior displacement of the hinge point of the
ions are separated into future aortic and pulmonary valve
leaflets. In both orifices, the third leaflet arises from an leaflet to severe displacement with almost complete atri-
intercalated cushion (green). This process results in two alization of the right ventricle. The displacement is mainly
facing coronary aortic leaflets and a nonfacing or noncoro- of the origins of septal and posterior tricuspid leaflets
nary leaflet. The pulmonary valve leaflets have the same from the atrioventricular junction toward the right ven-
configuration but lack the coronary orifices. B. Postmortem
tricular apex. The anterior tricuspid leaflet is usually not
specimen showing a bicuspid aortic valve. Abbreviations:
EC, endocardial cushions; IC, intercalated cushion; NCCs, displaced. Redundant tissues and fenestrations of the
neural crest cells. anterior leaflet are frequently observed.

14 Chapter 1
Bicuspid and unicuspid semilunar valves. A bicuspid contributions or deficient epicardial-myocardial signal-
aortic valve (Figure 1-10) is the most common congenital ing during development.
cardiovascular malformation, encountered in about 1%
to 3% of the human population. The valve often functions evelopment of the Epicardium, Myocardium,
D
normally at younger ages. In some cases, this malforma- and Coronary Arteries
tion, as well as a unicuspid valve, may also present in the Initially, the ventricular myocardium is oxygenated by
neonatal period because of significant aortic valve dys- diffusion from the ventricular lumen. A separate structure
function (usually stenosis). for gas exchange becomes necessary as the myocardium
grows. In early development, an epicardial covering over
Conduction System Development the myocardium is essential for normal coronary vascu-
The atrioventricular conduction system differenti- lar development. However, the epicardium-derived cells
ates from a cardiomyocyte origin. The atrial part of the also fulfill an important role in driving compaction of the
conduction system is derived from the posterior SHF– outer myocardial layers of the ventricle, specifically the
derived myocardium, which is devoid of Nkx2.5 expres- anterior part of the folding septum. The coronary endo-
sion. This includes a transient left sino-atrial node and thelial cells arising from the sinus venosus spread in the
the definitive right sinus node. Expression of markers subepicardial space and invade the compacting myocar-
reflecting a pacemaker phenotype (eg, Tbx3, Podoplanin, dium. In the peritruncal area, they form an endothelial
and Shox2), as well as histological features, indicates that ring surrounding the aorta and pulmonary orifice. The
the developing cardiac conduction system covers the endothelial cells also invade the aortic wall and form
entire sinus venosus area during early embryonic stages, the main stems and orifices of the coronary arteries in
including the internodal myocardium as well as the the pulmonary artery-facing (left and right) sinuses of
myocardium surrounding the pulmonary veins. During Valsalva. The factors guiding this process as well as those
later development stages, expression is restricted to the that repel them from entry into the pulmonary wall and
definitive elements of the conduction system. The FHF from the noncoronary aortic cusp remain to be defined.
(atrioventricular canal myocardium) and the primitive
(left) ventricle appear to contribute to the compact part Implications for Congenital Cardiovascular Disease
of the atrioventricular node and the main parts of the Myocardial thinning and noncompaction. The myo-
ventricular conduction system, including the common cardial thinning based on deficient epicardial-myocardial
bundle of His and the left and right bundle branches. interaction resembles noncompaction cardiomyopathies.
Animal models have shown that proper development of Experiments in both avian and mouse models in which the
the fibrous annulus requires the presence of epicardium- epicardial cell population has been limited in its outgrowth
derived cells. If the epicardial outgrowth is inhibited, a and endocardial-mesenchymal transition lead to severe
phenotype with accessory pathways and pre-excitation thinning of the compact myocardium and a spongy inter-
occurs. ventricular septum. Whether the basis of these malforma-
tions is epicardial or myocardial in humans is unknown.
Implications for Arrhythmias
Embryonic conduction pathways that normally disap- Coronary vascular anomalies. In anomalies such as
pear may persist both in structure and in function. This transposition of the great arteries, the main coronary stems
leads to abnormal atrial automaticity at specific sites, take the shortest course to the facing sinus of Valsalva,
including the terminal crest (formerly the right venous explaining the observed variation in patterning. When
valve), the pulmonary venous myocardium, and the cor- epicardial outgrowth and spreading is inhibited, single
onary sinus. The occurrence of congenital cardiovascular or pinpoint arterial orifices are observed, suggesting that
disease with a combination of nondelamination of the epicardium-derived cells are necessary for proper con-
tricuspid valve, noncompaction cardiomyopathy, and nection of the coronary arteries to the aorta. Ventricular-
accessory pathways with pre-excitation, as is observed coronary artery connections (Figure 1-11A) or fistulae
in Ebstein anomaly and transposition-transposed develop if there is no connection of the coronary arteries
great arteries, could be related to abnormal epicardial to the aorta. In human congenital cardiovascular disease

M RV
RV
VCAC
VCAC CA
CA
SEP
SEP
B C
VCAC
FIGURE 1-11. Ventricular-coronary arterial communications. A. Schematic representation of a heart

with pulmonary atresia with intact ventricular septum. The right coronary artery has a pinpoint orifice
(arrowhead), and the main subepicardial coronary branches are severely thickened and in part obliter-
ated (arrows). There are ventricular-coronary arterial communications between the diseased coronary
arteries and the hypoplastic right ventricular lumen, which is common in this condition. B and C.
Sections of a human fetal heart with pulmonary atresia and intact ventricular septum showing that
the severe coronary arterial pathology in the subepicardial region is already present in the fetus. The
ventriculo-coronary arterial communications are primarily a coronary arterial (epicardium derived) dis-
turbance and not primarily of myocardial origin. Magnifications: Bars, B and C: 1 mm. Abbreviations:
CA, coronary artery; SEP, subepicardial region; VCAC, ventriculo-coronary arterial communications.
Adapted from Gittenberger-de Groot AC et al. Prog Pediatr Cardiol. 2010;29(1):3-9.
that includes coronary abnormalities, an epigenetic cause Wamstad JA, Alexander JM, Truty RM, et al. Dynamic and
of the supposed link between disturbed epicardium and coordinated epigenetic regulation of developmental transi-
ventricular-coronary arterial connection is still missing. It tions in the cardiac lineage. Cell. 2012;151(1):206-220.
has been suggested that the occurrence of connections and Neural Crest
coronary orifice pathology in a subgroup of the patients
Arima Y, Miyagawa-Tomita S, Maeda K, et al. Preotic neu-
with pulmonary atresia and intact ventricular septum is of
ral crest cells contribute to coronary artery smooth muscle
epicardial origin (Figure 1-11B, C). involving endothelin signalling. Nat Commun. 2012;3:1267.
Kirby ML, Hutson MR. Factors controlling cardiac neural
SUGGESTED READINGS crest cell migration. Cell Adh Migr. 2010;4(4):609-621.
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Chen L, Fulcoli FG, Tang S, Baldini A. Tbx1 regulates pro-
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Kathiriya IS, Nora EP, Bruneau BG. Investigating the Epicardium and Coronary Vasculature
transcriptional control of cardiovascular development. Gittenberger-de Groot AC, Vrancken Peeters MP, Mentink
Circ Res. 2015;116(4):700-714. MM, Gourdie RG, Poelmann RE. Epicardium-derived cells
Kelly RG. The second heart field. Curr Top Dev Biol. contribute a novel population to the myocardial wall and the
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16 Chapter 1
Gittenberger-de Groot AC, Winter EM, Bartelings MM, Ebels T, Anderson RH, Devine WA, et al. Anomalies of the
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Lie-Venema H, van den Akker NM, Bax NA, et al. Origin, Cardiovasc Surg. 1990;99(2):299-307.
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in normal and abnormal cardiac development. Scientific drome: a European Congenital Heart Surgeons Association
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lial cells contribute to proximal coronary artery stems Development
and their aortic orifices in the mouse heart. PLoS One. Bajolle F, Zaffran S, Kelly RG, et al. Rotation of the
2013;8(11):e80857. myocardial wall of the outflow tract is implicated in
Tian X, Hu T, Zhang H, et al. Subepicardial endothelial the normal positioning of the great arteries. Circ Res.
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Winter EM, Grauss RW, Hogers B, et al. Preservation of R, et al. Evolution and development of ventricular septa-
left ventricular function and attenuation of remodeling tion in the amniote heart. PLoS One. 2014;9(9):e106569.
after transplantation of human epicardium-derived cells Scherptong RW, Jongbloed MR, Wisse LJ, et al. Mor-
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Breaking Symmetry
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Another random document with
no related content on Scribd:
haperend wat te zèggen, met wegsmoring van tranen, als om zich te
verantwoorden voor hem, dat kereltje.
—Wim.… jonge.… je voader suip nie.… hep gain [131]geld.… hai hep
niks.… hai wil werreke, d’r is gain proat ván.… moar sullie wille
nie.… sullie wille nie.… hai mo f’rrekke.…
En Wimpie, met beefstemmetje, huil-bibberend:
—Neenet foader, nie f’rrekke.… ikke sel bidde.… bidde.—
Snik-scheurend, viel ie half flauw van inspanning terug in z’n

peluwtje.—De kindertjes begonnen weer uit hun schrik-hoekje te
praten, zacht, in schuwe fluister-klankjes. Ant, die woordstameling
van d’r Wimpie had gehoord,—niet wist, dat Wimpie’s smeek-kijk ’r
behoed had van ’n drift-slag op ’r hoofd, zooals Wimpie niet wist, dat
ie met z’n kijk z’n moeder redde en Kees nauw begreep, dat ie ’t liet
uit besef voor Wim’s oogenangst,—Ant was weer in furie gevlamd.
Ze voelde, dat Kees ’n demonische macht had op Wimpie, die o
zooveel hield van z’n ruwen vader; dat ie haar schat, haar kind
behekste. En tòch, al het goed-aardige, innig-zachte in Wimpie,
voelde ze aan, als ingegrift in z’n zieltje, zag ze, als sprak z’n mond,
omdat ie moest spreken, door Satan bewogen. In haar klein-dwazen
maar fel-blinden geloofshaat, opgehitst door biechtvader en d’r
moeder, was uitgemaakt, vast, dat Wimpie behekst werd door Kees.
Daar boven uit nog zag zij, dat Wimpie worstelde tegen die
beheksing. Zoo leed ze dubbel. Wat echt-innig leefde in Wimpie,
voelde zij áán als vreeselijk gemartel. Trok ie Kees voor, dan zei ze
in zich zelf: arme stumper nou sit de duufel weer op se lijfie, nou is ie
behekst.… Nou mot ie dinge segge, die ie heelegoar nie wil
segge.… wat ’n gemartel.—En zoenend zei ze ’m dan: stil moar
jonge, ikke wêe wel da je’t mot zegge.… dat de duufel je weer te
pakke hep.… Dan huilde Wimpie verschrikkelijk, hartverscheurend
en stamelde, dat ’t niet waar was.… dat ie van voader soo veul
hield.… En weer zoende Ant hem ’r dwars tegen in, opgewarmd nog
door d’r moeder.… ja jonge da wee ’k wel.… seg moar da je ’t
meent.… je mó’t segge.… ik weut wel.… main jongelief, main
skat.… onse Heer sel je t’met wel verlosse van die duufel.… [132]
Vol van ingelepelde gebeden, vroom en kinderlijk, soms wèg in

godsdienstige zielsverrukking, viel Wimpie half in zwijm, begreep ie
z’n moeder niet meer, bleef ie stil zitten zonder woord. Zoo was
helsch, bij elkaar komen van Kees en Ant door Wimpie, onmogelijk
geworden, omdat zij wel voelde dat Kees van Wim hield, maar vast
wist, Wim niet van z’n vader, dien vuilen ketter en godskimper; vast
wist dat ie behekst praatte. Zoo was ze ook nu weer naar achterend
gehold, nog vol haat en woede, en toch met bang meelij voor
Wimpie, die nu weer niet goed begreep, wat ze wou, z’n moeder.
Dientje en Jansje zaten in ’t achterend, op ’n rot toonbankje. Met

gilstem krijschte Ant naar ze toe:
—Paa’s op f’r je foar.… hai hep main en-wille f’rmoorde.. hai hep
main en wille f’rmoorde.… t’met snait ie jullie allegoar an rieme.…
die skafuit.… die godskimper.… die ketter.… Op ’t erf hollend, schold
ze door nog, naar binnen, tegen de kinders, die van de bank
gesprongen waren.
Kees zat naast Wimpie, z’n vuile reuzehand over ’t doodskopje te

strijken, zoo zacht, dat ie ’t hoofdje bijna niet raakte, niks zeggend.
En Wimpie, lag stil met smartgroeven om z’n breeën mond, waarom
iets lachen wilde maar niet kon. En over-wijs, als van bijna dood
kind, staarden z’n oogen, groot in den schemerhoek.
De ouë Rams had zich niet verroerd. Sneller alleen sisten door de
stilte, pruimstraaltjes tegen gloeienden konkelpot op, en grom-zwaar,
strompelde van z’n lippen:
—Swaineboel.… swaineboel.
Vroeger had ie veel kranten ingekeken, maar, oproerige kerel als

Rams geweest was, hadden de geestelijken ’m verboden te lezen.
Nou, op ouën dag versuft, mocht ie alleen nog doorzien roomsch
advertentieblaadje uit de streek. Ouë Rams had gehoorzaamd, eerst
grimmig, later al toeschietelijker, gromde ie alleen nog maar, zonder
nader te zeggen wie en wat ie bedoelde: swaineboel.… swaineboel.
[133]
[Inhoud]
II.
Om twaalf uur luidde in vromen galm, Engel des Heeren. Wim sloeg
’n kruisje. Met beverig schrikstemmetje nog, zette hij plots in, toch
plechtig z’n toon:
—De Engel des Heere hep an minse geboodskapt.… en sai hep

ontvange van de hailige geest.…
Ant was strak naar z’n bed geloopen en met ’n wenk aan de kinders
zette ze mee in, zangerig-plechtig, ’n wees-gegroet, in extatische
bidhouding.
Even stem-stilte, en zacht uit ’t half donkere hoekje, vibreerde

Wimpie weer:
—Sien de dienstmoagde des Heere, main geskiede noar u woord.…

—Wees gegroet, dreunde weer in, Maria vol genoàde.… de Heer is
mit u.…
Zacht even weer bidstilte en Wimpie weer vooruitschietend:
—En ’t woord is vleesch geworde—en ’t hep onder ons gewoond.…
—Wees gegroet, plechtigden weer in psalmdeun de

kinderstemmetjes, met Ant er boven uit, schel:
—Bid f’r ons hailige moeder Gods, op da wai de belofte van Kristus
woardig worde.
Alle sloegen, in ooge-dichte strakheid, ’n kruis, murmelden zacht iets

nà.
Met rooie huiloogen nog, mond, stijf-nijdig dicht weer, begon Ant op
klein vuil vierkante tafel, naar ’t raam geschoven, ’n paar borden,
dof-bonsend van barsten, neer te rammelen. Geen woord had ze
meer gezegd nà kijfpartij. Onrustig stommelde ’t steenen geluid door
de gezonken ruziestilte. Door Dien en Jans was nog wat
eigengemaakt brood, groenige schimmelkorstjes en vuile bonkjes
deeg, bijeengesnord en tusschen smerige plasjes, op tafel
uitgegooid.
De ijzeren pot met gebedelde en gekregen krieltjes was

aangesjouwd van de schouw, met ’n vuil pannetje nattige rijst. Ouë
[134]Rams sjokkerde z’n stoel, zonder uit zitstand te buigen,
langzaam naar tafeltje, met z’n rug, haard-hitte onderscheppend.
De kinders hielpen elkaar één-voor-één op ’n oud-brok

waschstelling. Dien en Jans wiebelden wippig op ’n plank, over ’n
paar onttakelde stoelen gelegd. En naaktbeenig, morsig stelletje van
twee, drie en vier jaar, krullebolden aschblondig, rood-sproetig, met
hun gore snuitjes naast elkaar, in gulzige eetloering. Ant, op laag
krukje, verzakt tegen tafelrand, keek dreigend naar de kinders, die
wachtten, gulzig wachtten, opgedrongen in eng ruimtetje. Dien van
negen, paste op Jans van acht; Jans op Annie van zeven. Maar
Grietje van zes wilde niet, dat Annie van zeven op d’r paste. Die
voelde zich te slim. Met Dien van negen moest zij de kinderzorg
deelen. De kleintjes kregen ’n bonk deeg en beschimmelde korst
ieder, in ’n hoopje op naakte tafel vóór zich, met wat groen-glazige
krieltjes, die Ant uit de pot naar hen toerolde. Dien aan ’t hoekje,
stilde stemmenruzie tusschen drie kleintjes, deelde moederlijk
broodhomp, met inspanning van magere handjes afbrokkelend, wat
krieltjes en gekookte aardappelschillen, gedoopt in ranzige olie. En
allen ooge-gulzigden, met vertrokken mondjes, zonder aan maaltje
te raken. Voor Wimpie alleen was er altijd wat extra. Voor hèm werd
uitgezuinigd door Ant, maar hij at ’t minst. Dokter Troost had gezegd,
dat ie vleesch, heel veel vleesch, melk en eieren moest hebben.
Anders zou ie kraken. Maar koemelk kon Wim niet doorkrijgen. Toen
had Kees ergens ’n klein geitje weten los te krijgen voor ’n paar
centen. Dàt had ie opgefokt en ’n paar kippetjes. Nou had Wimpie
ten minste altijd wàt. Van afval en wandelingen op buur-erfjes vraten
de kippen; van schillen, gras en groentebrokken gulzigde ’t geitje.
Dá’ gong.… dá’ gong, vredigde Kees. En als ’t erg benauwd was,
toch nog altijd wat reuzel en ’n kaantje spek voor Wimpie.…
Ouë Rams begon, kromgebukt met z’n handen in de natte rijst en

krieltjes te grijpen, slangde een dik straaltje olie uit oorloos grove,
steenpuisterige ronde kom, er overheen. Kees schudde uit den pot
z’n bord vol, perste met handeplat de aardappels [135]fijn door de
bewaterde, half rauwe rijstkorrels, bezaaide de groenige krieltjespap
zwart, met gemeene peper.… Want soo.… neenet.… da gong nie.…
da kan nie bokkeme!.. da’ zoetige flauwe goedje.… Nou bràndde er
nog wat op z’n tong. Met z’n handen grabbelde ie in z’n bord, zich
haastig den mond volproppend, in afsluiting van licht-rochelende
ademhaalgeluidjes. Ant was ’n paar maal weer opgestaan. Plots
baste haar huilerige stem uit naar hongerige, gedresseerde
kinderstoetje:
—Nie te veul d’r afbreke Dién.… d’r mó’ f’r f’noàf’nd blaive.…
Kinders schokten van schrik. Als d’r nou maar gebeden kon worden,
gulzigden hun hongeroogen. Plots gaf moeder, na plechtig ’n kruisje
geslagen te hebben, dat de kinders extatischstrak, in licht
lipgemurmel, op hun lijfjes natrokken,—àchteruit naar bedje van
Wimpie, met stroef gezicht, ’n vroom-stillen wenk, en heilig-rustig,
klankte òp uit schemer-hoekje, zangerig z’n kinderstemmetje:
—Onse foader die in de hemele sait.… g’hailigt sai uufe noam.…

loat toekomme U raik.… U wil geskiede op oarde aa’s in de
hemel.…,—waar schel, in stemgedrang op inviel hongerend stoetje
met krasgeluid van Ant er boven uit:
—Gaif ons hede ons doàgelijksch brood.… en vergaif ons onse

skulde.… g’laik wai vergefe an onse skuldenoare.… Laid ons niet in
bekoring.… moar verlos ons van de kwoade.. O-amen.…
—Oâmen, dreunden de kinders, vrouw Hassel en ouë Rams, en

stilgevouwen, in sober gebaar, hun handen tegen borst ingehaakt,
oogen dicht, met vroomstrakke gezichten, zaten allen in het
schamele krotlicht tot de kleinste van twee, die gedresseerd staarde
in plechtig bidhoudinkje. En zacht, innig-bedeesd, met vibratie van
rust en diepe gemeendheid klankte uit ’t hoekje weer op:
—Wais gegroet Meria.., vol van genàode.… de Heer is mit u.…

Gesegend sait gai boofe alle andere frouwe.… En gesegend is de
vrucht uufs lichoams.… Jesus.—
Weer invielen de schelle stemmetjes, woord-duikelend snel, [136]in

toom gehouden tòch en achtervolgd door langzaam-rekkende stem
van Ant, die geen haast had:
—Hailige Meria.… moeder Gods.… bid f’r ons sondoare.. nou en in ’t

uur van onse dood.… Oàmen!
—Oâmen, plechtigden de stemmen na. Nog eens ging stil gemurmel

door het groepje, ieder voor zich uit; dàn oogjes openden zich van
de jongsten, die sluwig opgluurden maar gauw ze weer dichtknepen,
toen ze vrouw Hassel’s mager-fijn gezicht nog naprevelen zagen in
bid-stillen ernst, met ’t schuwe donkere licht van cel-hoog raam op ’r
extatisch-verzèngde trekken. Kees had slonkerend in rochelende
afsnijding van luchthaaltjes z’n peper-zwarte krieltjes verorberd. Te
gloeien en been-schudden zat ie van ergernis. Elken keer als ’t
stemmetje van Wimpie opklankte, vergrauwde en vertrok er iets
zenuw-wilds in z’n gezicht.
De kinders konden beginnen, gulzigden in, met oogen en handen.

Ouë Rams zat te smakkauwen met diepe inrimpeling van z’n oud-
geel gezicht, dat vellig-slap meetrok, bij iedere kauwbeweging.—Z’n
blauwdiepe oogwallen hobbelden zakkerig boven z’n kauw-kaken.
Kees had nog ’n restje aardappels uit den pot geschud. Van ’t bidden
zei ie maar niks meer. Elken dag had ie ’r om gevochten en
geschreeuwd, maar ’t gaf geen zier.… Wimpie dee ’t uit zichzelf.…
—’t Was ze ingelepeld.. Hoe meer ie vloekte, hoe fijner Ant werd.
Wimpie moest vóórbidden, wat vroeger nooit gebeurde. Ze had
gezien, hoe ’t hem hinderde; dat deed ’r goed. Ant at bijna niet.
Loom pikte ze nu en dan ’n kriel uit den pot, met ’r handen telkens ’n
duw àfstootend op ’r buik als had ze ’t benauwd daar. De kinderen,
die korrels napikten en tafelreten uitplukten met d’r nageltjes, ooge-
gulzigden rond naar vader, die nog krieltjes slikte, tusschen ’n
broodbonk door. Kees voelde ’t éven.
—Wie mô nog oàrepel?

—Je sel niks gaife, bitste Ant.… wat’r blaift is f’r morge.. se freete mi-
sonder end.…
—He moe?.… eintje moar, bedelde Grietje.…
Kees woedend weer op z’n woest-nijdig wijf, rolde naar eindkant

[137]van tafel ’n paar gaterige aardappeltjes. De smerige
kinderhandjes grepen en wrongen tusschen pot en nattige plasjes,
schreeuwend door elkaar:
—Van main.… ikke.… van.…
—Blaif d’r af.
—O! gemein.… moeder se knaipt!.… se bait!
Ant sloeg woest met d’r vuist op tafel.
—Hou je bekke skorum.… je moakt puur de klaine wakker.. Griet! sé’

jai de fles d’r is in de konkel.… moar suig d’r nie an ’t pijpie,
ongeluk!.…
Griet luisterde niet. Wild stoof Ant op, kletste ’n draai om ’r ooren,
rukte Annie die met d’r vuil bovenlijfje, en bebreide knuistjes over de
tafel kroop, terug naar d’r zitplaats, dat de anderen waggelden op
hun waschstelling en gilden van schrik. Aan ’r vingertjes had Grietje
’n paar fijngeknepen krieltjes kledderen, en gulzig, ongevoelig voor
snauwen, likte en zoog ze ’r handjes af, onder oogengetril toch voor
ransel-angst. Weer kletsten er draaien en bonkten er boffen tegen
ruggetjes en hoofdjes, grienden ’n paar in stikkend-stillen stuiphuil,
die langzaam uitbarstte in schreiend gebler. Rustiger na de
rammeling was ’t geworden. Nou moest Wim nog wat slikkerbikken.
Weekzacht sprak Ant ’r lieveling, ’r jongen aan, ’n beetje als klein
kindje.
—Wil Wimpie nou s’n aitje? Kom, laa’k sàin nou effe op main skoot
neme.… hee?
—Hee joà!.… moe.… effe moar, lachte Wim vroolijk nù hij den kring
inkwam.—Zeer voorzichtig, overal door Wimpie gewaarschuwd,
waar ze ’m niet mocht aanraken, schoof ze banden van z’n beentjes.
Touw door ledekantgat heen geboord, waaraan zware zandzakken
als vracht schommelden tegen vergroeing, knoopte ze los. Zacht
beurde ze ’m op, bij voeten en ingeslonken ziekte-nekje, dat mager
boven z’n hempje uitspalkte. Ingebukt liep ze, voetje voor voetje met
’m naar tafel, ’m schokloos op d’r schoot zettend. Kees, die
onverschillig gekeken en nog geen stom woord tot Ant, na de ruzie
gezegd had, kwam nu bij z’n vrouw staan, gluiperig bijdraaiend.
[138]En terwijl de kinders om kruimels morden, muschjesachtig
pikkerig en nijdig elkaar bevochten, schillen van geitje elkaar uit de
handen trekkend en kijvend om bord van grootvader, die gemorst
had, staaroogden Kees en Ant naar zieke Wimpie, als leefde alleen
hij. Jammerlijk vaalgroen bleekte z’n kopje in ’t schuwe val-licht.
Uitgemergeld, als ademend geraamtetje, wrakte broos z’n beenig,
puntig zwaar hoofdje op ’t slappe nekje, als zou ’t breken bij lichtste
wending; bleekten de steen-witte ooren, angstig-groot, ooren van
een doodzieke, mager, uitgedroogd, stil-alleen sprekend voor heel
het geteisterde kopje. Om z’n puntigen neus holden diepe
oogwallen, paarsig, lijkig bleek-groen, ’t gezichtje akelig versmallend
nog. Z’n vuile hansop liet z’n beentjes uitspaken, latjesplat, recht uit.
Om moeders schoot was als een kring getrokken waar binnen de

kinders niet genaakten. Wim’s voetjes dwarsten verkromd en
ingeduwd van liggewoonte en ’t bleeke vel zwabberde geel-plooiïg
om de slappe spieren.
Uit de schouw sloeg roetdampige rook neer van takbossen, die

nattig knetterden in het walm-mistige vuur. Niemand klaagde van
rotstank, rook, valeriaan en ziektebenauwing, in het donkere hok.
Ant liet den rommel vervuilen uit woede en uit geaardheid. ’t Kon er
niks schelen of in d’r ellende de boel verrotte. Niemand zei wat. Ze
was afgetobd met ’r kroost. Stank moest maar stank blijven.
Kees had, vóór dat Ant ’t Dientje kon zeggen, ’t eitje verzorgd en
klaargemaakt voor Wimpie.—Op ’n boterham had ie ’t voor ’m in
kleine stukjes gehapt en weer brokje aan brokje voorzichtig uit z’n
mond op ’t brood geduwd. Hij was blij, dat er nog meer voor Wimpie
stond, in ’t achterend. Menschen uit Wiereland, die meelij met
Wimpie hadden, brachten wel ereis wat voor ’m mee. En als Kees
zelf iets voor ’m klaarmaakte, had ie hoop, dat Wim nog beteren kon,
al trok de dokter met den dag zuurder gezicht. Met kleine hapjes
duwde Ant telkens stukjes ei in Wim’s mond, die hij traag
verkauwde. Heel hoog op ’n teststoof steunden haar beenen in
schoot, wijd-uit, en met inspanning nog, zocht ze ’m goed tegen ’r
aan [139]te houden dat ie nergens pijn zou hebben. Soms klonk éven
’n pijnkreetje op. Schrikangstig zei ze dan iets, niet wetend waar ze
’m geraakt had. Vandaag vond Kees ’m al vreeselijk zwak uitzien. Er
kwam lamte in z’n hart en benauwing, want twijfel spande weer in
’m, of ie wel ooit beter kon worden, z’n jonge, z’n eenige jonge!
Wimpie was klaar met eten. De kinders klonterden weer bijeen. Heel
zacht droeg Ant Wim in z’n bed, rommelde ze weer bangelijk-tastend
langs z’n lijfje, de bandjes van zandzak over z’n voetjes schuivend.
Plots knielden, op sein van Ant, allen weer voor de tafel, die in ’t
midden geschoven was neer, en oogendicht, met handjes
ineengeprangd, gezichten naar duisterend kruisbeeld op de schouw,
begon zwaar van allen kant tegelijk gebed te ratelen, met rauwe
kuch-stem van ouë Rams, hoestscheurend soms, en ’t schelle wilde
extaze-gebed van Ant er doorheen. In het scheemrig donker knielde
het bidgroepje, midden in duisterende kamer, aan alle zij omwalmd
van rook, die zwart-dampig uit schouw trok. Wimpie alleen bad in z’n
bedje, met rozekransje schuifelend door z’n magere handjes, ’n
extra tientje, de twaalf artikelen des geloofs,—en zacht dreunde door
de stilte, onze-vaders en wees-gegroets, z’n plechtig stemmetje:
—Ik g’loof in God.… d’almachtige voàder.… skepper van hemel en

oarde.… en in Jesus Kristus.… s’n eenige soon.…
Kees kende die dolle vertooning, zooals ie schold, was machteloos ’t

erf opgehold. Voor Wimpie wou ie niet heelemaal laten zien hoe
gloeiend ’t land ie had, hoe vreemd en miserabel mal hij zich in z’n
eigen gezin voelde.
Eens toen Wim nog gezond leek, had ie hem woest, in drift, gezegd,
dat ’t uit most sijn, maar toen had ’t kind zoo gesnikt dat ’t in drie
uren niet tot bedaren te brengen was; had hij liggen zoenen ’t
kruisje, dat om z’n halsje, op z’n bloote lijfje hing. Nou zei ie niets
meer, ook niet tegen d’anderen. Daar stond ie nou, op ’t erfje, in de
kou, zich suf te staren naar den modderig besneeuwden rommel,
naar de ingesneeuwde assen en wielen van ’n brok geradbraakte
handkar.—In verlegenheid [140]schopte ie ’n bezem tegen de put,
sloeg ie de deur van ’t pleehok nijdig dicht.
Toen ie, huiverig van guurte ’n kwartier op ’t erf rondgescharreld had,

wel dacht, dat ’t bidden nou gedaan zou zijn, kwam ie weer in.
Dadelijk bitste z’n vrouw ’m toe, dat ze morgen de wasch had bij
Henkels in Wiereland.
—Dan he’k de wasch op de ploas.… aa’s jai nou moàr hier en-blaif
bai sain.…
Driftig-stram draaide de hoestende ouë Rams zich plots weer naar

de schouw, de geit in touwkronkels om z’n stoelpoot meesleurend.
Met z’n stompige, afgesleten voeten zocht ie buik van konkelpot,
ging pruimpje van mondhoek tot mondhoek, en spatte ie z’n
sisstraaltjes weer door de stilte heen. Kees had wat gegromd.
—Murge mo’k meskien noa bosch.… raize loàje.… d’r is gister een
van de ponder donderd.… half dood.… nou mo’k feur sain.…
—Meskien!.… meskien!.… huildrensde Ant’s stem, en plots in ’n

schreeuw opspringend greep ze rood-sproetige Mietje van twee, die
op den grond zat vuil te doen, bij den arm. ’t Kind spartelde in ’r
hand, en zwaar ranselde ze ’t meisje in drift-rammeling.
—Jou varke.… mo je nou hier skaite.… ka je nie vroàge..

beesteboel.… woar sit je.… Dien!?.… f’r wa holp je da merakel nie
op de pot.… hier pak an!.… furt jai!.…—En toen weer in een tot
Kees—nou, ikke mo main wasch bereddere.…
—En je moeder dan, ken die nie blaife, meskien is d’r feur main
wa.…
—Koue larie, da seg ikke.… hai je t’met ’n afsproakie mit ’n lel.…

Kees smoorde weer. ’t Taai dóórtartende kijfheete van z’n vrouw
kende ie.…
De kinders zaten weer te spelen, met hun bloote lijfjes en flodderige

rokjes op steen-killen vloer. Plots toen ze hoorden, éven, dat vader
en moeder tegelijk wegwouen, kregen ze ’t doodelijk benauwd. Want
dan moest grootmoe Rams op ze passen, ’n [141]heks voor ieder, die
hen sloeg, gromde in haar halve blindheid.—Vandaag was ’t feest
voor hen, nou grootmoe d’r uit was, naar den polder, bij d’r ouwere
dochter. En nou kwam dàt, midden in. Wel wisten ze, dat moeder op
Donderdag ’n wasch had in den polder, maar dan bleef Dientje van
school en vader altijd thuis. Nou Woensdag ook.—Wimpie was
geschrokken. Als vrouw Rams d’r dochter opjoeg en vuilligheidjes
vertelde van Kees, schreeuwde Wimpie dat ze loog. Daarop wreekte
ze zich als ze alleen in huis regeerde. Als d’r lui bij waren, kon ze
vrindelijk zijn, poezig-lief tegen Wim. Maar dat was hevige huichel,
dat voelde hij zelf heel diep. Ze had gloeienden hekel aan ’m, omdat
ie van z’n vader hield.
Toch vertelde Wimpie nooit wat van d’r geniepigheid als zij alleen
thuis de baas was. In z’n ziekelijk lijfje zat vroom, innig-simpel zieltje
en diep onwetend was ie van al die vroomheid en innigheid. Soms
vertelden de kinders Ant wel eens, dat Wimpie zoo gegild en gehuild
had. Dan in onrust, niet begrijpend, vroeg Ant hem, maar Wim
schudde z’n bleek kopje voelde zich héél sterk, wou vergeven, nu ie
toch gehoord had van den kapelaan, dat ie gauw bij den Heere zou
zijn. Vreemd lachte in droeve, zalige trekjes, z’n mond breeër,
rimpelde z’n doodskopje, leek ie ouer in z’n kijk dan ’t groote mensch
dat ’m ondervroeg, liefhad. Maar toch had ie angst voor zoo’n dag
met grootmoe alleen, om de pijn en ’t gesar. Ant had doorgekeven
op Kees’ vraag:
—Main moeder?.… gun je ’r nie daa’s ’n poar uur te freete hep in de

polder.…
—Gunne?.… f’r main blaift s’r veur de eefighait.…
—Joa, jai ken d’r aa’sem nie ruike.… moar soo meroakel.…
—Hou je nou moar koest.… ik blaif bij kinders.… je moer sel ’k nie
roepe.…
Ant was blij, maar wou niks laten merken.… Driftig riep ze Dien en
Jans van ’t erf, die juist met touwtjes, aan ’t kalefateren waren, hun
doorbeten modderzware mansschoenen, uit vullesbakken opgediept,
voor en achter verbaggerd in gaten, [142]rooig van kleur, wijdmannig
slobberend om teer-kleine meisjesvoetjes.
—Hei skorum.… kom jullie.… goan jai stookie soeke.… furt.… d’r is
vast niks meer.… murge.… furt!.… kwak de vullesbakke òm-end.…
moar paa’s op in de Waik da’ de pelisie je nie sien.… En jai Jans.…
àn de bel.… la je nie wègsture.… pakt an wat t’r te kraige kompt.
De twee kinders luisterden met koppige drift in d’r gezichtjes van

verzet. Maar ze durfden niks zeggen. Dien had nou al twee
ochtenden achtereen den heelen polderweg afgeslenterd, doodop,
en gegrabbeld op de stinkaschbelt naar uitgebrande kokes, naar
rotte beentjes, houtstompies; had paardevuil langs het pad
bijeengeschoffeld op klein gebrekkig wagentje. Maar niks naar zin
van Ant.… ’t Kind had gegriend, dat ze naar school wou, maar Ant
had ’r woedend gemept.… en ’r gevraagd waar ze dan van freete
moste en dat ze tog gain klompe an d’r poote vond.…—En Jansje
zocht al de heele week hout in bosch, onder den sneeuwmodder uit,
loerde ook op stookies. Met ’r gebarsten blauw-kleumrige
winterhandjes, knakte ze in jachtige onrust, takken van de
padstruiken, bang voor tuinders en veldwachters, die lol hadden in ’t
snappen van bedelvolk. En alles in ’n grooten zak stoppend,
sjouwde ze op ’r mager kinderruggetje zware houtvrachten, in regen
en windguurte, die onder ’r vodrokjes op ’r bloote lijf striemde. Dien
droeg tenminste nog ’n jongensbroekie onder ’r stinkende vaal-rooie
rokje.… maar Jans had nog niks. Nou mosten ze ’r weer op uit, in
die nattigheid. Ze vloekten, harde vloekjes van haat en wrevel, tegen
elkaar, die ze gehoord hadden, nauw verstonden, maar opluchtten
toch hun verkropte woede. Want ze haatten, met afgetobde
hongerlijfjes, zwerftochten in den winter, hoe lekker ze die ’s zomers
ook vonden, dàn rondstoeiden op zonneplekken en gras, onder den
bedel door. [143]
[Inhoud]
VIJFDE HOOFDSTUK.
Kees was met ’n nijdigen deurslag ’t pad opgegaan. Rammelen van

flauwigheid voelde ie zich nog, en als ie dacht aan wat vleesch, liep
’m ’t water over de tanden. Toch, de lucht deed ’m goed. Alle weeren
joegen en sloegen om z’n karkas, die er steviger tegen hardde. Z’n
armoe had ’m sober gemaakt en gezond bleef ie, sterk, door zuivere
lucht, ruimte, duingeur van zomers en al z’n grondwerk. Alleen z’n
kinders niet; zwakkelijk geslacht, bang en zenuwachtig. Dat had ie
nou sien bij veul tuinders, allegoar bijna beverige sukkels, mit
hoofdpain, angst, slecht sloape.… da was nooit soo in sain tait.
De oogenglans van Wim, dat hij thuisblijven zou morgen had ie niet
gezien, in woede nog om z’n kijfwijf en schoonmoeder.
Van god-verlaten, in oneindige eenzaamheid, lag de sombere weg

naar zee, in groezeligen sneeuwmiddag, zwaar van grauwte. Vroeg-
decemberend vaalde stilte-schemer over lage akkers, waartegen
heuvelige duinbulten paarsig en grauwig in verte vernevelden. Nou
was ’t al te laat voor ’m om nog ruigte te zoeken. Waar nou heen?
Nattige mistigheid en guurte zoog tusschen z’n kleeren en huid.…
Wacht, aa’s tie effe bai Klaos Grint gong. Meskien had die nog wat
boompies te moake.… Verduufeld, datie selfers nog gain luis had om
wa tieme te koope.… Op den reutel kreeg ie niks.… Wat
skoremzoodje toch tegen sàin.… Die lamme Kloas, die gluupert!
Zwaar loomde z’n gang langs ’t sneeuwmodderpad. Telkens tuurden

z’n oogen even op de grauwe wijdte van akkers en paarse
duinnevels. Rustig toch voelde ie zich in de eeuwig-geheime stilte
die er trilde en sloop boven ’t verre middagland. [144]Vóór ’t huisje
van Grint bleef ie staan, trapte ie even tegen de deur. Gouïg
lichtschuim glansreepte langs kozijnen, achter rood gordijntje, en stil,
in schem’rige middag-donkering, lag daar ’n sneeuw-bevracht huisje,
blank-stil, op ’t duinpad geduwd met z’n bloedend raamrood, fèl-
glanzend tegen ’t wit. Dadelijk achter z’n huis had Klaas Grint àl z’n
grond, z’n bessen, frambozen- en aardbeienakkers ’t meest. Grint
was de knapste en sluwste tuinder-kleinpachter uit de buurt, ’s
Winters, zes maanden dóór, zat ie in z’n huiskamer met vier
dochters en ’n zoon, aardbei-mandjes te vlechten, uitzuigend en
afbeulend z’n kinderen, om te sparen, te spàren. Vrouw Grint maakte
Kees open, lachte.
—Kaik?.… daa’s Kees!.… Piet is t’r ook, en je neef Hassel van de

Kuil.…
Al de niet-katholieke vrouwen uit de streek hielden van Kees om z’n

reuzig lijf, z’n guitige grijze oogen. Kees bromde wat, recht uit ’t
gangetje doorloopend naar ’t hok, waar gewerkt werd. Vier meisjes
hurkten op den grond, naast elkaar, met ruggen tegen den muur
gestut, beenen dàn rechtuit, dan opgetrokken. Dwars over hen, aan
kortere muurzij hurkte Klaas Grint, de tuinderpachter; en bijna op de
kachel gedrongen, met z’n beenen tegen z’n vader aan, zat Jan,
zoon van Grint, lange bleuïge kerel van achttien. Lui-hangerig stond
Piet, naast hurkende Geertje Grint, mooie donkere tuindersmeid met
prachtige gloeiende bruine oogen, vol lichtrumoer. Als ze uit ’r
bukwerk naar ’m òpkeek, sterden ’r uit ’r appels rooie vonkjes,
aanhalig en stoei-levendig. Achter Piet weggeduwd in benauwing,
stond Jan Hassel, zoon van Dirk Hassel, Gerrits broer, tusschen wie
al twintig jaar hevige vijandschap broeide. De neven kenden elkaar
bijna niet. Toch werkten ze zomers soms akker aan akker, in duin op
Wiereland en loerden ze op dezelfde mooie meiden van Grint. Het
vlechthok van Klaas was voor alle soort bloemkweekersknechten,
tuinders en losse werkers ’n inloop ’s winters, ’n honk waar de
kachel brandde, en allicht ’n kop heete leut te slobberen viel.—
Kees, reuzig boven allen uit, was stil in den hurkenden werkkring
[145]gestapt, zacht groetend, met z’n hoofd de bakzoldering net
rakend. ’n Klein groen glaslampje hing aan ’n spijker tegen bruin-vuil
beschot, boven den kop van Klaas, rood-fel beschijnend, lankaster
gordijntje van achterraampje, zwak-naar groezellicht
neerschemerend over den grond en laagzittend werkgroepje in ’t
hok. Spraakloos bij Kees’ komst zaten ze in arbeid verbukt te
vlechten, elk afgevlochten mandje in ’n hoek kwakkend, tot
groezelbruinen hoop bijéén. Telkens verbukten ze even van beschot
àf, naar kachelkant, greep-grabbelend in de vooruit klaargemaakte
bodems, die met hun uitpriemende, dun slingerige teenen-enden, als
groote donkere spinnen over den grond dooréénwriemelden, in het
zuinige lampjes-licht. De kachel pafte zwaar-gloeiend in ’t lage hokje
en Jan Grint, die broeiing in z’n rug opving, zat telkens te blazen en
zweet met z’n mouw vol houtsplinters, in z’n gezicht te strijken. In het
bruindoffe schijnsel van muur, donkerden de gezichten, nekgebukt,
naar den grond, òver de mandjes heen en in wilde bewegelijkheid
dàn duisterden weg, dàn lichtten òp vlechtende handenparen, de
buigzame teenen verschakelend tot mandjes.
Van ’t achter-end uit stem-vroolijkte vrouw Grint naar Kees.
—Drink je nog Kees, ’n bakkie leut? D’r is d’r nog van ’t grondje.…
—Dankkie.
—Leut? lachte schamper Klaas Grint,—gaif sain de fles.. verdomd

Kees, aa’s ’k je nooit nog mi stuk in je kroag sien en-hep.… en nou
segge alderlei, da je suipt aa’s ’n spons.…, wa heppe sullie d’r an.…
da moakt moar swart.… wâ ken hoarlui bokkeme.… verdomd!—
Kees antwoordde niet, haalde schimpig z’n schouders op. Hij wist
wel, dat Grint ’t zelf vertelde, die skorem, en aa’s ie ’t meende, vond
ie ’t nog lammer, want hij had ’t land door zoo’n beroerling
beschermd te worden. Gesprek wou niet vlotten. Piet Hassel stond
stil en Jan Hassel de neef, was bij Kees’ inkomen nog bescheidener
in z’n achterafje teruggetrokken. De meisjes keken maar òp naar
Kees, den langen [146]Kees, den gevaarlijken Strooper, met z’n
guitige oogen en z’n stillen loer op hun handen. Dat was nou Kees,
over wien ze altijd den mond vol hadden, Kees met z’n streken!—
Achter dun hokjesbeschot bonsde dreunwrijf op waschplank van de
meid, in schuimtobben. En klagelijk huilde ’r stem ’n smertelijk liedje,
zoeterig-sentimenteel, plechtig zangsleepend door werkgroepje:
A.. àn ’t be e.. edje fan d’r krà-à-à-’n-ke liefelinggg..

Si.. i.. t moe-der neer, in sti.. il.. ge.. waieen..
—Jessis poà, wa ken die maid seure, lachte kwaad mooie Geert,
daa’s nou puur ieder Dinsdag krek soo.… an de tobbe.
—Is dat nou seure? klapte Trijn, vurige jongensmeid, ’t is prêchtig.…

mô je moar wachte.… tweede komplot.… aa’s God d’r kind loat
stèrrèfe.… en sai ken d’r in ’t klooster goan.… prêchtig! En ’t
Treurelied van de jongelingg.… ses komplotte.… aàs hai se’n maisie
f’rmoord uit jeloersighait.. en van de Skeepsjonge!.…
—Nou, ik wou moar da se d’r snoàter hield, driftte Jan Grint, is me

da.… da singe!.… daa’s griene!.… da gemeine kreng!.… die hep
nou twee hufters.… en d’r gelant is d’r van deur.… Teun de
kweeker.… en nou singt sai in d’r eeuwighait van d’r liefelinge, die se
t’met thuis lam ranselt.…
Piet voelde ook weer zeglust:
—Nou, jullie benne ook soo got-vergete stommetje.… segge jullie d’r
is wat.… gong tug gain paop f’rbij.… seg erais wá’, jai Trien, jai
Geert, lach d’rais.… effetjes!.…
—Stil d’r ’s;.… hoor nou d’r ’s.… zei met gespannen luistergezicht
Trijntje in armgebaar Piet tegenhoudend.
Nog nimmer f’r.. i.. in d’ laik ’t so.. on licht ske.. een..

Gebukt goan se onder smart en sorrege!
Dreun-dof bonsde langs richels van waschborden rhytmisch [147]’t

goed-gewrijf, en klagelijk huilde d’r weemoeds-stem dóór, gedempt
achter beschot uitklinkend. Dat was te veel voor Piet. Zwaar
opdonderend tegen ’t huilig gezang, in stem-davering, barstte ie uit,
met beenporren tegen Geert en Cor:
—Bommelebom, bommelebom.. làange Jaàn mit skeele Piet!.…

mottige Toon en laànge Griet.… Alle goane wai op rais.… Jào, mi
selfers de dikke Gais.… En elleke jonge hep ’n maid.…
bommelebom.… bommelebom!
Met voetdreun trapte ie maat en Jan opwindend er tegen in, onder

stuipgelach van meisjes die met hun hoofden naar elkaar toe-
neigden.
—Deesie.… Deeeesie!.…
’k Wait daa’t êe blom in main hart ontbloei.. i.. it!
Deeeessie!!.… Deeee.… esie!!.…
—F’rjenne, jullie werke nie.… och Piet sing sooveul aa’s je lust
hep.… moar la’ hoarlie d’r gangetje.… hee?.…, schreeuwde Klaas
rood-driftig boven gezang uit. Niet zien kon ie, dat met ’t mirakelsche
lachen, d’rlui handen stilstonden.
—Nou poà.… u is t’r ook een!.… bitste kwaadaardig Geert, nou

magge wai nie lache.…
—Wel neenet, da mist nie.… lach sooveul jullie wille.… moar d’r mó’
werkt-en worde.

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Marco C. DeRuiter, MD, PhD Shabnam Peyvandi, MD

Adriana C. Gittenberger-de Groot, PhD Robert E. Poelmann, PhD

Monique R. M. Jongbloed, MD, PhD

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■■ INTRODUCTION understanding of mutations in humans that lead to con-

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■■ THE NEURAL CREST ■■ BREAKING SYMMETRY

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Arterial pole RVV LVV

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Development Congenital/disease Stem cells

Endocardium Endocardial cushions Cardiac

Myocyte line Endocardial line

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FIGURE 1-5. Anomalous pulmonary venous connection. A. Scimitar syndrome is characterized by a

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RCA LCA RCA LCA

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degenerates during development (Figure 1-7F). In mam-

ascending aorta and pulmonary trunk, including their

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Atrioventricular Valves Semilunar Valves

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Implications for Congenital Cardiovascular Disease

Stenosis or atresia of an atrioventricular valve. The

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FIGURE 1-11. Ventricular-coronary arterial communications. A. Schematic representation of a heart

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En Wimpie, met beefstemmetje, huil-bibberend:

—Neenet foader, nie f’rrekke.… ikke sel bidde.… bidde.—

Snik-scheurend, viel ie half flauw van inspanning terug in z’n

Vol van ingelepelde gebeden, vroom en kinderlijk, soms wèg in

Dientje en Jansje zaten in ’t achterend, op ’n rot toonbankje. Met

Kees zat naast Wimpie, z’n vuile reuzehand over ’t doodskopje te

Vroeger had ie veel kranten ingekeken, maar, oproerige kerel als

—De Engel des Heere hep an minse geboodskapt.… en sai hep

Even stem-stilte, en zacht uit ’t half donkere hoekje, vibreerde