and automaticity the heart with the splanchnopleuric mesenchyme around the develop-
ing lung buds and with the septum transversum mesenchyme, which
will give rise to the liver. The dorsal mesocardium is the site of early
Cardiac myocytes share a number of characteristic features that distin-
mediastinal mesenchyme production. It disappears as a mesenteric
guish them from other cells. All cardiac myocytes have sarcomeres and
entity during the third week of development, when the embryo has
a sarcoplasmic reticulum; in principle, they share the capacity for pro-
from 4 to 12 somites; at the same time, the endocardial heart tube
ducing an intrinsic cycle of electrical activity resulting in contraction.
becomes entirely surrounded by the myocardium and enclosed within
This phenomenon is called automaticity, or pacemaker activity. An
the pericardial cavity. The breakdown of the dorsal mesocardium estab-
absolute requirement for effective pacemaking is poor electrical cou-
lishes a passage across the pericardial cavity, from side to side and dorsal
pling of the cells, which also implies slow conduction. It allows the cells
to the heart, which persists as the transverse sinus of the pericardium.
to build up sufficient electrical charge, which is then propagated through
After folding and rupture of the dorsal mesocardium, the second heart
the surrounding myocardium. Thus ‘a small node can drive a large
field contributes cells to both the arterial and the venous poles of the
heart’.
heart.
Varying degrees of differentiation are seen in early populations of
At this stage, the heart is bilaterally symmetrical and has the form
cardiac myocytes, which can be categorized as forming working, nodal,
of an inverted ‘Y’. The legs of the Y are positioned caudal to each side
conducting and primary myocardium (Table 52.1). Cells of the atrial
of the cranial intestinal portal, where they form the venous pole of the
and ventricular working myocardium display virtually no automaticity,
heart (Fig. 52.8A–B). The stem of the Y connects cranially with the great
but are well coupled and have well-developed sarcomeres and sarco-
arteries, forming the arterial pole of the heart. From the outset, both


plasmic reticular structures. The development of the synchronously
poles are connected with the systemic vessels running from the embryo,
(fast) contracting working myocardium requires fast conduction of the
the yolk sac and the placenta. The pulmonary veins form later, during
depolarizing impulse, and so the cells possess well-developed gap junc-
the fifth week of development, the initial venous primordium becom-
tions. In marked contrast, the cells forming the nodes of the cardiac
ing evident in the mesenchyme derived from the dorsal mesocardium
conduction system have the opposite phenotype, and resemble the
caudally. Also at this site, mediastinal myocardium continues to be
myocytes that are found initially in the primary heart tube. The cells of
added to the heart, forming the smooth dorsal wall of the left atrium,
the putative atrioventricular and peripheral ventricular conduction
and providing the site of formation of the primary atrial septum.
system have an ambiguous phenotype: the cells are well coupled, thus
Recent genetic fate map studies have shown that the primary heart
allowing fast conduction of the depolarizing impulse, but otherwise
tube contains cell lines that will contribute to only two compartments.
retain an embryonic phenotype. The division does not imply that the
The myocardium of the stem of the inverted Y contains only precursor
cells belonging to one group are identical, but rather that they share
cells of the left ventricle, and both legs of the inverted Y contain precur-
distinguishing features developed to variable degrees.
sor cells of the atrioventricular canal and parts of both atrial chambers.
Automaticity and slow conduction are features of the myocardium
The atrioventricular canal, in turn, provides the precursors for the left
of the primary heart tube (see Video 52.1). The slow conduction of the
ventricular free wall, whereas the cells of the original embryonic left
depolarizing impulse over the heart tube causes a peristaltic wave of
ventricle largely end up in the ventricular septum. The embryonic
contraction, by means of which the blood is pushed towards the arterial
outflow tract contributes to the right ventricle. There is no evidence to
pole. During the waves of contraction, the accumulated cardiac extracel-
support the previous, traditional, concept of heart development, i.e.


lular matrix closes the endocardial tube and prevents the backward flow
that all the putative cardiac segments are already present in the straight
of blood. Unambiguous morphological markers are often lacking in the
heart tube and develop to contribute to the various parts of the defini-
early embryonic heart, which means that it is not possible to distinguish
tive cardiac chambers. This hypothesis has now been disproved by
the various cells phenotypically; automaticity and the speed of conduc-
elegant experimental studies that have shown that the definitive cardiac
tion have, therefore, become important functional parameters by which
chambers are formed by local differentiation and expansion, or ‘bal-
to describe the development of the different parts of the heart.
looning’, of the myocardial walls of the primary heart tube.
HEART TUBE
Looping of the heart tube
During the process of embryonic folding, the midline splanchnopleuric
Cranial and caudal recruitment of myocardium and endocardium pro-
coelomic epithelium, which is derived from the primary heart field
duces considerable lengthening of the primary heart tube. Recent
(cardiac crescent), becomes positioned ventral to the foregut. The coe-
studies of the mechanism of proliferation in the avian, mouse and
lomic epithelium is highly proliferative and gives rise to mesenchymal
human heart have shown that cardiac myocytes stop dividing after overt
populations. The early cardiac myocytes arise from the coelomic wall
differentiation. The tube continues to elongate, largely as a result of the
adjacent to the endoderm of the foregut (see Fig. 52.7). The cells
recruitment of additional myocytes to the tube, as shown by studies
of both morphology and molecular lineages, and, to a lesser extent,
Table 52.1 Basic phenotypes of cardiac myocytes because of an increase in the size of the myocytes that form the walls
of the tube. The lengthening heart tube bends ventrally and rightwards,
Feature Type of myocardium
concomitant with the breakdown of the dorsal mesocardium. The bend
‘Primary’ ‘Nodal’ ‘Conducting’ ‘Working’ is called the ventricular loop, since the left ventricle subsequently bal-
loons and expands at its outer curvature, which is the original ventral


Automaticity High High High Low
side of the straight tube. The inner curvature of this loop was originally
Conduction velocity Low Low High High
its dorsal side.
Contractility Low Low Low High
It is often stated that looping of the tube is the first visual evidence
Sarcoplasmic Low Low Low High
of asymmetry in the embryo, although careful examination reveals that
reticulum
the atrioventricular canal has become asymmetric prior to the start of


heart and great vessels
911
25
retpahC
A B C nents are separated one from another by the atrioventricular canal,
which, at this stage, has significant length. The systemic venous tributar-
ies drain directly to the atrial cavity.
The sinus venosus with right and left sinus horns, which forms at
the confluence of the systemic venous tributaries, is a prominent struc-
ture in lower vertebrates. In mammals, it does not become recognizable
as a morphological entity until the systemic veins have excavated them-
selves from the mesenchyme of the body and been surrounded by
myocardium. It then becomes incorporated into the pericardial cavity
so that the sinus horns become part of the heart. All of these processes
occur up to the twenty-fifth day of development in humans; only after
this stage is it possible to consider development of the definitive atrial
and ventricular chambers.
D E
INFLOW TRACT
Right The working myocardium of the atrium differentiates locally at the
ventricle dorsolateral sides of the heart tube (see Fig. 52.8D–G). The developing
atrium then expands enormously, in dorsal, lateral and, most promi-
nently, cranial directions. The cranial expansion is seen as pouches,
which become the left and right atrial appendages (see Fig. 52.9A–B).
Left
ventricle The floor of the atrium, including the sinus venosus, and the atrioven-
tricular canal are made of primary myocardium. Less cellular prolifera-
tion occurs in these parts than in the expanding atrial chambers;
the primary myocardium marks the inflow to, and the outflow from,
the initial atrial chambers as ‘rings’, which are also associated with the
formation of the conduction system. The ring at the inflow defines
the sinuatrial junction, whilst the atrioventricular canal, which forms
Developing atrium the atrial outlet during development, will eventually be incorporated
into the definitive right and left atrial chambers as the atrial vestibules.
Although it is possible to recognize the forming left and right atrial
F G
appendages at this stage, the right being more extensive than the left,
the atrium itself has a single cavity and there is no evidence of septum


formation. The myocardium of the sinus venosus and the newly forming
mediastinal myocardium are smooth-walled, whereas the myocardium
of the appendages shows ridges, the pectinate muscles, on the inner
surface. The formation of the different appendages is under control of
the Pitx2 signalling pathway. The myocardium of the appendages has a
chamber phenotype, or is working myocardium; it expresses atrial natri-
uretic factor and connexin40, among other markers.
Right atrium
The further development of the right atrium is characterized by the
Fig. 52.8 Local expansion of the myocardial wall of the early heart tube incorporation of the sinus venosus into the right part of the primary
and heart tube looping. A, A ventral view. B, The ventral wall has been
atrium. This process is under control of the T-box transcription factor
removed to show the inner aspect of the early heart tube. C, A left lateral
Tbx18. At about 4 weeks of development, the sinuatrial junction of the
view. The early heart tube is shaped like an inverted ‘Y’. The legs of the Y
looping primary heart tube is positioned symmetrically in the midline
pass caudal to each side of the cranial intestinal portal. In the early heart
(Fig. 52.10; see also Figs 13.1, 60.9). The left and right common cardi-
tube, the myocardium of the stem of the Y (purple) contains only
nal veins drain directly into the cavity of the primary atrium. The atrial
precursor cells for the left ventricle. The remaining myocardium (grey)
myocardium extends to the margins of the pericardial cavity and, strictly
contains only precursor cells for the atrioventricular canal and atria. The
speaking, the sinus venosus is not yet formed because the systemic
precursor left ventricular cells expand first. D–G, The later heart tube,
showing looping. D, A ventral view. E, The ventral wall has been removed venous tributaries are embedded within the mesenchyme of the septum
to show the inner aspect of the folding heart tube. F, A left lateral view. transversum.


G, The lateral wall has been removed to show the inner aspect of the During subsequent development, the pericardial cavity expands to
heart from the left. In D and E, the expansion of the right ventricle can be enclose the terminal segments of the systemic venous tributaries; at the
seen and the heart tube has elongated to the right. The developing atrium same time, their walls differentiate as myocardium. They can now be
can be seen dorsolaterally in D–G. termed the left and right horns of the sinus venosus; each horn receives
the union of the corresponding umbilical vein, vitelline radicles and
common cardinal vein (see Figs 52.10, 60.9). Concomitantly, the con-
looping. Although the sense of laterality of the developing organs of striction between the left horn and the atrium becomes more pro-
the body, including the atrial appendages, develops during gastrulation, nounced. As the dorsal wall of the left atrium is formed from additions
the pathway of signalling that governs rightward looping of the heart of mediastinal myocardium, the left horn becomes incorporated into
tube remains unknown. However, it is now well established that signal- the developing left atrioventricular junction, its orifice draining to the
ling pathways, including Pitx2, nodal, lefty and cited-2, determine the newly formed right atrium. At the same time, the left-sided venous
formation of the morphologically left-sided or right-sided features seen tributaries diminish in size; the left common cardinal vein forms the
in organs such as the lungs, bronchial tree, liver and spleen, and atrial oblique vein of the left atrium, and the left sinus horn forms the coro-
appendages. nary sinus (see Fig. 52.10C), maintaining its own myocardial wall as it
By the time the primary heart tube has formed its ventricular loop, becomes incorporated into the atrioventricular junction.
it is possible to distinguish the atrial and ventricular components of the The right sinus horn increases rapidly in size with growth of the liver
developing heart (Figs 52.8D–G, 52.9), and to recognize an outflow (see Figs 60.9–60.10). The vitello-umbilical blood flow enters the right


tract connected with the aortic sac and developing pharyngeal arch horn through a wide but short hepatocardiac channel, which becomes
arteries. The cells that, at this stage, make up the outflow tract, will, at the cranial end of the inferior vena cava. The right horn also receives
later stages, be found within the right ventricle. At the proximal side of the right common cardinal vein, draining the blood from the right side
the outflow tract, cells are recruited to the developing right ventricle of the body. Later, when transverse connections are established between
and, contemporaneously, new cells are recruited to the outflow tract the cardinal veins, the blood from the left side of the body also reaches
from the second heart-forming field. The atrial and ventricular compo- the heart via the veins draining the right side (see Fig. 13.4). As these


Development of the thorax
912
7
noItCeS
A B C
Right atrium Left atrium
Left third
aortic arch
artery
Left second
Right aortic arch
atrium artery
Truncus
arteriosus
Primary
heart Left atrium
tube
Atrioventricular
junction
100 µ Right Left ventricle
ventricle Left ventricle Right ventricle
Fig. 52.9 A, A scanning electron micrograph of an early developing human heart, showing the external appearance of the myocardium of the right and
left ventricles and the right and left atrial appendages. The truncus arteriosus passes between the atria. B, A reconstruction of the heart tube at stage
13, showing the endocardium. In the left and right ventricles, the endocardium interdigitates with the myocardium and appears trabeculated; elsewhere,
it is separated from the myocardium by the cardiac extracellular matrix. C, The heart at stage 13 with the truncus arteriosus reflected to the right. The
opening of the sinus venosus into the right atrium can be seen (yellow). The region of the primary heart tube is indicated by a yellow interventricular ring.
(A, With permission from Oostra RJ, Steding G, Lamers WH, Moorman AFM. Steding’s and Virágh’s Scanning Electron Microscopy Atlas of the
Developing Human Heart. New York: Springer-Verlag, 2006. B, Modified from O’Rahilly and Müller. Developmental Stages in Human Embryos 1987
Carnegie Institution of Washington. Pub 637.)
A B
Atrium
Right horn of
Ventricle sinus venosus
Left horn of
sinus venosus
Atrium Precardinal vein
Relative movement of
dorsal region of heart
Common
cardinal vein
Vitelline veins Vitelline veins
Umbilical veins Common cardinal vein Umbilical veins
Left bulbar ridge Right bulbar ridge
C Veins D Superior vena cava
from head
Venous Left atrium
Atrium mesocardium
Pulmonary vein Left valve of
sinus venosus
Left horn of
sinus venosus Right valve of
sinus venosus
Right horn of Atrioventricular canal Cut edge of


sinus venosus inferior vena cava
is absorbed
into atrium Left ventricle Right horn of
Left horn of sinus sinus venosus
venosus attenuates
and becomes Right atrium
coronary sinus Right hepatocardiac channel
Right ventricle
Fig. 52.10 The changes to the sinus venosus. A, A dorsal view of the early heart tube shown in Figure 52.8D. B, Changes to the circulation bring the
venous circulation to the right, causing enlargement of the right horn of the sinus venosus and atrium, and attenuation of the left horn of the sinus
venosus. C, The right horn of the sinus venosus becomes absorbed into the atrium. The left horn of the sinus venosus becomes the coronary sinus.
D, A dorsal view of the embryonic heart, showing the relative changes to the sinus venosus.


heart and great vessels
913
25
retpahC
changes take place, the right sinus horn, including the proximal parts
of the superior and inferior cardinal veins, becomes incorporated into
the right atrium, forming the smooth-walled systemic venous sinus, P
also known as the sinus venarum.
The right sinus horn opens into the right atrium through its dorsal
and caudal walls (see Figs 52.10, 52.14). The sinuatrial orifice becomes
elongated and slit-like, guarded by two muscular folds: the left and right
sinuatrial (venous) valves. These two valves meet cranially and become
continuous with a fold that projects from the atrial roof: the septum
spurium. The valves also meet caudally, and merge with the inferior
atrioventricular cushion. With ongoing development, the cranial part
of the right sinuatrial valve loses its fold-like form, but its position is
V
indicated in the adult heart by the site of the crista terminalis of the
O
right atrium. Its caudal part forms the valve of the coronary sinus, also
known as the Thebesian valve, and most of the valve of the inferior vena
cava (Eustachian valve). The union of the two valvular remnants then
passes through the tissue that separates the orifice of the coronary sinus
E
from the fossa ovalis. This area is known as the ‘sinus septum’ but, in
reality, this ‘septum’ is no more than a muscular fold in the dorsal wall
of the right atrium. The continuation of the venous valves persists as
the tendon of Todaro, an important landmark for the location of the
atrioventricular node in the definitive heart. The left venous valve Fig. 52.11 A scanning electron micrograph of a human heart at 42 days’
blends with the right side of the atrial septum; there is usually no trace gestation. The right lateral wall of the right atrium, the right ventricle and
of it in the postnatal heart. the outflow tract have been removed. The valve of the sinus venosus (V)
is prominent. There is no septal cusp of the tricuspid valve guarding the


inlet portion of the right ventricle. The parietal cusp has been removed.
Left atrium The atrioventricular cushions are fused. Note the adjacent right lateral
tubercles (O). A small interventricular foramen (foramen secundum,
Following the formation of the primary atrium and the left atrial p. 915) is indicated (arrowhead). There is a well-developed right
ventricular outflow tract (curved arrow). Other abbreviations: E, embryonic
appendage, the left atrium takes shape by the formation and incorpora-
trabeculae; P, pulmonary trunk.
tion of mediastinal myocardium. While the tributaries of the sinus
venosus approach the atrium caudally, the differentiating pulmonary
veins gain their entrance to the atrial cavity through the dorsal meso- the signalling pathways that determine caudocranial differentiation.
cardium (see Fig. 52.7). The topographical relationships seen in the Retinoic acid and its downstream transcription factor, Tbx5, play a
postnatal heart are, thus, established as soon as differentiation of the crucial role in this process.
pulmonary venous portal occurs. The myocardium at the inner curvature, the original dorsal side of
Early in the development of the atrium, the pulmonary vein devel- the cardiac tube, remains smooth-walled and maintains its molecular
ops as a solitary channel from angiogenic cells derived from the dorsal phenotype, whereas the myocardium at the outer curvature of the myo-
mesocardium, and establishes continuity with the vascular plexus cardial tube displays trabeculations in the fifth week of development;
formed in the mediastinal mesenchyme around the developing lung the original primary heart tube is represented by an interventricular ring
buds. The solitary pulmonary vein opens into the caudo-dorsal wall of (see Fig. 52.9C). By stage 17, the trabeculations have achieved a typical
the atrium adjacent to the developing atrioventricular junction, its atrial spatial orientation, giving a sponge-like appearance to the internal
orifice being flanked by two prominent ridges. The primary atrial aspect of both ventricles (Fig. 52.11). The definitive trabeculations,
septum develops from the right ridge, following incorporation of the coarse in the right ventricle but much finer in the left, are first observed


left sinus horn into the right side of the primary atrium, thus confining around the fortieth day of gestation; they appear initially in the walls
the pulmonary venous orifice to the developing left atrium (see Fig. of both ventricles at the level of the atrioventricular junction and
52.14). The pulmonary vein initially branches within the dorsal media- develop towards the apex of the heart. By the time the fetus is 10 weeks
stinal mesenchyme, its tributaries draining blood from the developing old, the trabeculations are much sparser, and are confined to the apical
lung. With continuing development, the walls of the venous channels regions. This process of remodelling is accomplished without the inter-
become surrounded by myocardium, this process occurring to the level vention of macrophages or inflammatory cells in the immediate inter-
of the second bifurcation. The veins then expand and are incorporated stitium. The ventricular myocardium, encompassing the trabeculations
into the roof of the left atrium, eventually forming the greater part of and exterior wall, possesses a chamber phenotype, the myocytes express-
its cavity. However, all four pulmonary veins do not achieve their sepa- ing, among other proteins, the fast-conducting gap-junctional proteins
rate opening into the atrial roof until well after the completion of atrial connexin 40 (Cx40) and 43, and atrial natriuretic peptide. This myo-
septation, and probably not until the tenth or eleventh week of develop- cardium stops proliferating and differentiates into the fast-conducting
ment. Variations in the precise pattern of pulmonary venous drainage peripheral ventricular conduction system, whereas the outer layer
are quite common. With these changes, the left half of the primary becomes highly proliferative and forms the compact layer of the ven-
atrium becomes progressively restricted to the mature appendage. The tricular wall, no longer expressing Cx40 and atrial natriuretic peptide,
myocardial sleeves surrounding the pulmonary orifices taper off and but still expressing Cx43.
become intermingled with fibrous tissue. In later life, it is likely that
this intermingling of myocardial and fibrous tissues forms the substrate
for some forms of atrial fibrillation. The opening of the solitary pulmo- OUTFLOW TRACT


nary vein to the left of the right pulmonary ridge is a prerequisite for
atrial septation. Initially, the outflow tract possesses myocardial walls up to the pericar-
dial reflections. It displays a characteristic bend, which has a proximal
part arising from the developing right ventricle, and a distal part that
VENTRICLES becomes continuous with the aortic sac beyond the pericardial reflec-
tions. Although this bend is a conspicuous morphological feature, it is
The ventricles develop at the ventral side of the looping primary heart highly unlikely that the cells to either side of it retain their position
tube during the fourth week of development (see Figs 52.8–52.9). The during subsequent development. Instead, it seems probable that cells
left ventricle develops from the stem of the Y-shaped heart; the right are recruited from the second heart-forming field, and pass through the
ventricle develops later, downstream relative to the left ventricle, when outflow tract to contribute to the definitive right ventricle. Subsequently,
more myocardium has been added to the cardiac tube. As a result of still more cells are recruited from pharyngeal mesenchyme, passing
the looping of the heart tube, the right ventricle is positioned at the proximal to the pericardial reflections and forming the intrapericardial
right of the left ventricle, which is a prerequisite for the appropriate components of the arterial trunks. There remains much disagreement
connection with the expanding atrial component of the heart. Unlike as to how best to describe these morphological parts of the outflow
the atrial chambers, the morphological differences between the right tract. Some authors have labelled the proximal myocardial part the
and left ventricles are not part of the general asymmetry between the conus, calling the distal part the truncus, and the intrapericardial
right- and left-sided organs of the body, but rather are under control of portion of the outflow tract the aortic sac. Others have called the entire


Development of the thorax
914
7
noItCeS
myocardial outflow tract the bulbus, since the myocardial outflow tract hearts, the leading pacemaker is always found at the venous pole (Fig.
of primitive vertebrates, called the conus arteriosus in primitive fish and 52.12). Thus, it is the most recently recruited cells at the venous pole
the bulbus cordis in amphibia, is presumed to develop into the right that always have the highest pacemaking activity. All regions of the early
ventricle in higher vertebrates. Because the terms conus and truncus embryonic heart tube possess poorly coupled cells and display intrinsic
have been inconsistently used in literature, we prefer simply to describe automaticity, thus permitting slow propagation of the depolarizing
proximal and distal parts of the myocardial outflow tract, and to impulses along the cardiac tube, and producing matching peristaltic
describe, when it appears, an intrapericardial arterial portion of the waves of contraction that push the blood in an antegrade direction. The
outflow tract, this part interposing between the muscular component myocytes of a developing heart do not have well-developed sarcomeric
and the ventral aorta, the distal junction occurring at the pericardial structures, and have a poorly developed sarcoplasmic reticulum. This
reflections. tissue has been called primary myocardium, distinguishing it from the
Given that different authors use different terminologies, it is not rapidly conducting and well-developed working myocardium of the
surprising that formation of the outflow tract remains one of the most atrial and ventricular chambers.
confusing areas of cardiac development. The recent finding that the As development proceeds, the ventricular chambers develop in the
stem of the heart tube contains precursor cells exclusively for the left cranial part of the heart tube, by ventral expansion, and the atrial cham-
ventricle makes it essential to adopt descriptions that follow dynamic bers in the caudal part by dorsolateral expansion (see Fig. 52.8). An
events, rather than continuing to use static names. Thus, as soon as the adult type of electrocardiogram can be recorded from such hearts,
primary heart tube bends to produce its ventral ventricular expansion, showing rapid atrial depolarization, a period of atrioventricular delay,


by definition, the developing ventricle achieves inlet and outlet com- and rapid ventricular depolarization. The electrocardiographic tracings
ponents, even though these structures are not the definitive ventricular reflect the development of fast-conducting components within a slowly
inlets and outlets. Cells that, initially, are found in the ventricular conducting heart tube, i.e. the development of a morphological conduc-
outflow tract subsequently become cells of the right ventricle. Further- tion system. The newly developed working myocardium expresses atrial
more, working myocytes can easily be distinguished from the primary natriuretic factor, along with the gap junctional proteins Cx40 and
myocytes of the straight heart tube. The primary myocardium is smooth- Cx43, which permit fast conduction.
walled, whereas the developing myocardium of the ventricles is trabecu- Like the early peristaltic heart, flow through the developing cham-
lated, and expresses specific markers such as atrial natriuretic peptide bered heart remains directional because the dominant pacemaking
and Cx40 and Cx43. Thus, that part of the primary heart tube down- activity is still at the inlet of the heart (see Fig. 52.12). Peristaltic hearts
stream of the developing ventricular loop is termed the outflow tract, do not need valves, whereas chambered hearts require the presence of
irrespective of the fact that, eventually, it will largely become incorpo- one-way valves at the inlets to, and the outlets from, the chambers. The
rated within the definitive right ventricle (see Figs 52.8–52.9). More- slowly conducting atrioventricular canal, interposed between the atrium
over, within the inner curvature of the ventricular loop, the walls of the and the ventricle, and the outflow tract positioned between the ventricle
outflow tract and atrioventricular canal fade into one another without and the great arteries, are the parts that contain the endocardial cush-
a clear boundary. Indeed, ventricular working myocardium never devel- ions. These are able to function as sphincteric valves, as a result of their
ops at the inner curvature. It is within this ventricular part of the prolonged duration of contraction. These components retain their func-


primary heart tube that the cushions of the atrioventricular canal and tion until the definitive leaflets of the one-way valves have been sculpted
the outflow tract must achieve appropriate connections with the mus- from the cushions. The primary myocardium of the outflow tract does
cular ventricular septum in order to divide this part of the tube into left not regress until the arterial valves have been formed, and does not
and right compartments. The cavity of the tube within which these disappear in its entirety until around the twelfth week of human devel-
events take place has been called the ‘interventricular foramen’. This is opment. The primary myocardium of the atrioventricular canal is even-
incorrect, since it is, rather, the region between adjacent parts of the tually incorporated into the atrial vestibules at the same time as the
primary heart tube. It is, none the less, the remodelling of this inner formation of the atrioventricular valves, becoming sequestrated on the
curvature that sets the scene for the completion of cardiac septation. atrial side of the atrioventricular junctions between 6 and 12 weeks
of development. An important part of the canal persists dorsally, where
it differentiates into the slowly conducting atrioventricular node (see
CARDIAC FUNCTION AND THE
Fig. 52.12).
CONDUCTION SYSTEM Considerable progress has been made over recent years in decipher-
ing the pathways involved in establishing the building plan of the heart
Although only mammalian hearts have a well-defined conduction (Fig. 52.13). The combined action of the transcription factors Tbx5 and
system, an essentially similar electrocardiogram can be recorded from Nkx2–5 is required for the formation of the myocardium of the atrial
animals as diverse as fish and humans, indicating that the electrical and ventricular chambers. Tbx5 is expressed in a gradient over the heart
connections between the cardiac components, along with the underly- tube, decreasing in concentration from caudal to cranial, and may
ing gene-regulatory networks, have been conserved during vertebrate impose positional information. However, its pattern cannot explain the
evolution. Indeed, the development of the conduction system of the localized formation of the chambers and the conduction system. Local-


heart is inextricably associated with the development of the basic build- ized expression of the transcriptional repressors Tbx2 and Tbx3 in the
ing plan for the heart. The conduction system is best defined as the inflow tract, the floor of the atrium, the atrioventricular canal, the inner
system that initiates and conducts the sinus impulse. In mammals, it curvature of the ventricular region, and the outflow tract prevents the
encompasses the sinuatrial node, the atrioventricular node, the atrio- differentiation of primary into working myocardium. Tbx2 and Tbx3
ventricular bundle, the bundle branches and their terminal ramifica- effectively compete for binding to the promoters of the chamber-
tions. The nodes and the atrioventricular bundle can be considered the specific genes, such as atrial natriuretic factor, Cx40 and Cx43. The
central conduction system, while the bundle branches and their rami- remaining primary myocardium of these regions initially induces the
fications represent the peripheral ventricular conduction system. The endocardium to undergo epithelial to mesenchymal transition, by
sinus impulse is generated in the sinus node; from here, it is rapidly which process the cardiac cushions become filled with mesenchyme.
propagated through the atrial myocardium towards the atrioventricular The myocardium also participates in the alignment of the atrial and
node, where propagation is delayed. After an essential period of atrio- ventricular chambers (which is essential for proper cardiac septation,
ventricular delay, the impulse travels rapidly through the atrioventricu- and is guided by the fusing cardiac cushions); it forms the conduction
lar conduction axis and the peripheral ramifications to reach the system, including the sinus and atrioventricular nodes, the atrioven-
ventricular myocardium, which is then rapidly depolarized. Following tricular bundle, the floor of the developing right atrium (the internodal
repolarization, the sequence recurs in endless fashion throughout the region), and the entirety of the atrioventricular canal. In the early
life of the individual. The term ‘conduction system’, as opposed to the chamber-forming heart of the mouse, Tbx3 is expressed in the atriov-


working myocardium of the chambers, may suggest that the working entricular canal, the floor of the atrium and around the orifices of the
myocardium does not conduct, while the conduction system conducts systemic venous tributaries, but not in the dorsal mesocardium sur-
rapidly. In order to produce powerful synchronous contractions, the rounding the entrance of the pulmonary vein. During subsequent devel-
working myocardium of the chambers must also, of necessity, conduct opment, the domain of expression of Tbx3 expands from the
rapidly, whereas to act as a pacemaker, the cells of the nodes need to atrioventricular canal to form a crescent on the crest of the ventricular
be poorly coupled, and hence display slow conduction. septum. The dorsal aspect of this crescent develops into the atrioven-
The vertebrate heart is myogenic, implying that all cardiomyocytes tricular bundle, while the atrioventricular node is formed at the dorsal
have the capacity to generate and conduct the depolarizing impulse. junction with the atrioventricular canal. The ventral parts subsequently
Because cardiac myocytes are electrically coupled, the cells with the disappear during development.
highest pacemaking activity take the lead. In the formed normal heart, The fact that the ventricular conducting system originates from
the leading pacemaker is always within the sinus node. In embryonic a single primary ring provides a solid base for understanding the


heart and great vessels
915
25
retpahC
A B C
Right Aorta
Truncus atrium Left atrium
arteriosus Right atrium Left
atrium
Pulmonary
Sinuatrial
trunk
node
Position of the original
interventricular ring in
the fully formed heart
Interventricular
ring
Right
ventricle
Left ventricle Right ventricle Developing Left
ventricular ventricle
septum
Atrioventricular node
Bundle of His Bundle branches
Fig. 52.12 Development of the conduction system of the heart. A, At stage 13 with the truncus arteriosus reflected to the right, the interventricular ring
marks the region of the primary heart tube. The purple part of the interventricular ring will give rise to the atrioventricular bundle and bundle branches,
whereas the yellow part of the interventricular ring will not participate in the formation of the adult conducting system. B, The truncus arteriosus, now
divided into the pulmonary trunk and aorta, is presented between the right and left atria, which expand lateral to it. The right atrium is now positioned
entirely above the right ventricle, and the outflow tract has expanded to the left; the left ventricle has access to the aorta. C, The position of the original
primary heart tube ring indicated in the formed heart. The pulmonary trunk has been removed.
genated blood. Prior to birth, the lungs are not functioning and blood
flow to them is small. Even so, normal development of the heart
requires that all cardiac compartments receive an adequate amount of
blood. To this end, even before birth, the systemic blood of the right
atrium is guided to the left atrium so that the left half of the heart and
Outflow tract (OFT)
the brain is provided with a normal flow of blood. The right ventricle,
in contrast, drains to the dorsal aorta via the ductus arteriosus (see Fig.
Right ventricle (RV)
Inner curvature of heart tube (IC) 36.9B). The walls that separate the right and left sides of the heart are
largely formed in the fourth and fifth weeks of development. Some time
Left ventricle (LV)
later, not only the components of the primary heart tube – specifically,


Atrial roof (A roof)
Atrioventricular canal (AVC) the atrioventricular canal and the outflow tract – but also the atrial and
ventricular chambers, must be separated physically into right and left
Atrial floor (A floor) Inflow tract (IFT) halves. However, each compartment is separated in markedly different
fashion.
Septation of the atrial chambers
IFT A roof A floor AVC IC LV RV OFT
As a prelude to atrial septation, the right horn of the sinus venosus is
Tbx1 – – – – – – – + incorporated into the right part of the atrium, and the pulmonary vein
arises as a midline structure within the dorsal mesocardium. Internal
Tbx2 + – + + + – – + separation into right and left atria is mainly effected by growth of two
Tbx3 – – + + + – – – septa, coupled with remodelling of the venous compartments. At the
end of the fourth week of development, a crescentic fold, the primary
Tbx5 + + + + + + +/– – atrial septum or septum primum, grows by active proliferation from the
dorsocranial atrial roof into the direction of the atrioventricular canal,
Tbx18 + – – – – – – –
extending downwards just to the right of the entrance of the pulmonary
Tbx20 + + + + + + + + vein (Fig. 52.14A,D). It is separated from the left sinuatrial valve by the
interseptovalvular space. The leading edge of the septum primum is
Fig. 52.13 The early heart: distribution of the T-box transcription factors covered by a mesenchymal cap in continuity dorsally with extracardiac
involved in patterning the heart. mesenchyme (mediastinal mesenchyme) derived from the dorsal meso-
cardium which forms the vestibular spine, or spina vestibule, also called
the dorsal mesenchymal protrusion. The ventral horn of the septum
disposition of the conducting system in a number of congenital anoma- primum reaches the ventral (cranial) atrioventricular cushion, while the


lies. The concept accounts particularly well for the morphology and dorsal horn reaches the dorsal (caudal) cushion. Thus the primary atrial
disposition of the atrioventricular node and bundle in hearts with strad- foramen, the foramen or ostium primum, is entirely surrounded by
dling tricuspid valves, with double inlet left ventricles, and with con- mesenchyme derived from endocardium. Ventral and caudal to the
genitally corrected transposition. advancing edge of the septum primum, the developing atrial chambers
communicate through the foramen primum (see Fig. 52.14A,D).
As the foramen primum diminishes in size, the upper margin of the
SEPTATION OF THE EMBRYONIC
septum primum perforates by apoptosis and, thus, right to left shunt-
CARDIAC COMPARTMENTS ing of blood continues through a secondary foramen, the foramen or
ostium secundum. The latter is formed before the end of the fifth week
The flow of blood on the right and left sides does not intermingle, even of development. Initially, it lacks an upper rim, since its upper border
in the developing heart, because flow is laminar, and the pressures are is the atrial roof. The foramen primum is finally occluded in the
similar at the right and left sides. It is only after birth that the pressures median plane, as the edge of the septum primum merges with the
in the ‘left’ systemic circulation become higher than those in the ‘right’ fusing atrioventricular cushions (Fig. 52.14B,E). The foramen secun-
pulmonary circulation; therefore, the different flows have to be sepa- dum then enlarges to permit free passage of blood from the right to the
rated physically in order to prevent admixture of oxygenated and deoxy- left atrium.


Development of the thorax
916
7
noItCeS
A B C
Septum primum grows
toward atrioventricular cushions Pulmonary veins form atrial roof
R sii ng uh st h veo nrn o so uf s S puo ll mita or ny a o rp y e vn ei in ng – of S pre impt uu mm A int ir ti ia al l lyro io nf f on ldo et d I sn et pe tr ua mtri a sl e f co uld n dfo ur mms
adjacent to AV canal
Crista
Breakdown of terminalis
septum primum
produces foramen
secundum
Foramen Incorporation
primum of pulmonary
veins
Atrioventricular
(AV) canal
Foramen
ovale
Dorsal (AV)
atrioventricular cushion Mediastinal mesenchyme reinforces fusion
of AV cushions and mesenchymal cap Muscularized Flap valve formed
AV cushion mass by septum primum
D Opening of right horn of sinus venosus E F Interatrial fold forms septum secundum
Growth of septum primum Coalescing holes form Foramen ovale
and mesenchymal cap foramen secundum SVC
Septum primum
SVC
Foramen
primum
IVC
IVC and
valve
Coronary
sinus and valve
Primary ventricular foramen Muscular septum fused
Solitary opening of pulmonary vein Fused AV cushions Interventricular foramen Right ventricle with AV cushions
Dorsal (inferior) Ventral (superior) Mediastinal mesenchyme Mesenchymal cap
AV cushion AV cushion (spina vestibuli) on septum primum
Fig. 52.14 Three representative stages in the development of the atrial septum. A–C, Coronal views from the front. D–F, Lateral views from the right
side. A and D, The septum primum has not yet obliterated the original communication between the two atria (foramen primum) and the atrioventricular
endocardial cushions have not yet fused. B and E, The atrioventricular endocardial cushions have fused with each other and with the septum primum,


which has broken down in its dorsal part to form the foramen secundum. C and F, The septum secundum is forming on the right side of the foramen
secundum from an interatrial fold. Abbreviations: AV, atrioventricular; IVC, inferior vena cava; SVC, superior vena cava.
The solitary opening of the pulmonary vein into the roof of the left of the process, these regions are called the atrioventricular canal and
atrium, which is originally adjacent to the atrioventricular junction, the outflow tract, or conotruncus. The dorsal or inferior atrioventricular
becomes incorporated into the atrial wall, ultimately forming four sepa- cushion continues into the floor of the atrium, which is made of
rate orifices at the corners of the atrial roof. As this development con- primary myocardium. As the cushion extends dorsally, it meets the
tinues, the muscular atrial roof itself invaginates on the right side of the mediastinal mesenchyme in the region initially termed the spina vesti-
primary atrial septum (see Fig. 52.14B,E), the invaginated fold consti- buli, where it continues as a mesenchymal cap running along the
tuting the septum secundum. The free edge of the septum secundum leading edge of the septum primum until it meets the ventral, or cranial,
overlaps the foramen secundum. When left atrial pressure exceeds right atrioventricular cushion (see Figs 52.14, 52.16). The dorsal cushion also
atrial pressure in postnatal life, the septum primum closes against the has a significant ventricular extension in the inner curvature of the heart
septum secundum as a flap-valve (Fig. 52.14C,F). The passage taken by tube, which comes to lie on top of the developing muscular ventricular
blood as it passes from the right atrium – under the crescentic edge of septum. The two atrioventricular cushions fuse in the sixth week of
the septum secundum, then obliquely towards and through the foramen development, dividing the atrioventricular canal into its right and left
secundum to the left atrium – persists throughout intrauterine life as components. The cushions are very large relative to the canal, leaving


the foramen ovale. At first, the foramen ovale is sited craniodorsally narrow right and left slits, which increase markedly in size during
relative to the atrial septum, but with remoulding of the venous com- further development.
ponents, it achieves a cranioventral position. At the start of stage 10, the venous pole, the atrioventricular canal,
the developing left ventricle and the outflow tract are all positioned
symmetrically around the midline (Fig. 52.15A). As a result of the
Septation and appropriate positioning of the
subsequent rapid growth of the cardiac tube, the atrioventricular canal
atrioventricular canal
moves in its entirety to the left (Fig. 52.15B) as the ventricular part of
the heart tube loops to the right, thus placing the developing left ven-
Extracellular matrix accumulates between the endocardium and myo- tricle on the left and the forming right ventricle on the right (see Fig.
cardium of the primary heart tube. However, it mostly disappears in the 52.9). This ventricular loop is conspicuous throughout the fourth and
regions of ballooning of the chamber myocardium of the developing fifth weeks of development, and it is at this stage that a deep interven-
atria and ventricles. The matrix becomes filled with mesenchyme in the tricular groove appears externally. Over this period, the atrial floor,
persisting regions of the primary heart tube. In conventional accounts including the developing systemic venous sinus (sinus venosus) and the


heart and great vessels
917
25
retpahC
right ventricle passes in through the right atrial vestibule and exits
through the muscular subpulmonary infundibulum, while blood enter-
ing the left ventricle passes in through the left atrial vestibule, and exits
through the aortic root. The changes needed to produce the definitive
connections between the cardiac components are complex. Three dis-
tinct structures contribute to the formation of the postnatal ventricular
septum: the muscular ventricular septum, the proximal parts of the
outflow cushions and the atrioventricular endocardial cushions. The
latter two components separate those parts of the primary heart tube
that are committed to the right and left ventricles, as opposed to the
ballooned apical ventricular components. Inappropriate formation and
connection of the cushions with the muscular ventricular septum
underscores deficiencies of the definitive ventricular septum; such
lesions account for about two-thirds of all cardiac septal defects.
Separation between the right and left ventricles is initially heralded
by the appearance of a caudal crescentic ridge within the ventricular
loop. The trabeculated parts of the ventricles contain less extracellular
matrix than the walls of the primary heart tube, and it is these parts of
the chambers that expand on each side of the ridge that remains
between them. The crest of the developing septum, therefore, is its
oldest portion. The more apical parts are added concomitant with
enlargement of the chambers, as if they were expanding like balloons.
The impression can be gained that the dorsal and ventral horns of the
Stage 10 ventricular septum grow along the ventricular walls, meeting and fusing
early week 4 week 5 with the right extremities of the dorsal and ventral cushions of the
atrioventricular canal. In reality, the crest of the septum marks the posi-
tion of the original primary heart tube and becomes the atrioventricular
bundle. The septum has a free, sickle-shaped margin that, together with
the fused caudal surface of the endocardial cushions, bounds an ovoid
foramen. Previously, this foramen has erroneously been termed the
interventricular, or bulboventricular foramen; it is no more than a locus
within the cavity of the primary heart tube. The apical trabecular com-


ponents of the ventricles balloon from the ventral side of the primary
heart tube. At the dorsal side, or the inner curvature, there is no chamber
myocardium, only the smooth walls of the primary heart tube. There-
fore, from the outset of the process, the forming apical parts of the
ventricles are separated by a muscular septum. The foramen marked
caudally by the crest of the ventricular septum provides the initial inlet
to the developing right ventricle, and the outlet for the developing left
ventricle. Completion of ventricular septation requires division of this
primary foramen, rather than its closure. It also demands appropriate
connection between the muscular septum and the divided atrioven-
tricular canal, including its cushions, and with the divided outflow tract,
along with its cushions (see Fig. 52.16).
Use of inappropriate terminology means that the entire region
upstream relative to the foramen has previously been called the primi-
tive ventricle, the entire downstream region the bulbus, and the junc-
tion between them the bulboventricular junction. In the account
presented here, the area is termed the primary junction, initially marked
by a distinct notch on the outside of the heart, and inside by the cor-
responding ridge of the developing ventricular septum. The ridge is
Fig. 52.15 Movements of the atrioventricular canal relative to the midline positioned between the atrioventricular orifice, which is initially a
during development. common structure, and the caudal part of the forming right ventricle.
ebut
traeH
noitces-ssorC
atrioventricular canal, moves to the right (Fig. 52.15C). The developing
pulmonary vein remains anchored in the midline and, subsequent to
these manœuvres, the atrioventricular canal once more becomes posi-
tioned in the midline; this process facilitates the appropriate connec-
tions of the developing muscular septum with the atrioventricular and
outflow cushions. The orifice of the sinus venosus is, by now, positioned
to the right. From the outset, the muscular ventricular septum develops
in line with the right side of the dorsal (inferior) atrioventricular
cushion (Fig. 52.16), so that the separating right atrium always has


direct access to the developing right ventricle. The process also ensures
that space remains ventrally for incorporation of the subaortic compo-
nent of the outflow tract into the left ventricle.
Septation of the ventricles
After the looping of the heart tube, it is easy to gain the impression that
the atrioventricular canal communicates exclusively with the develop-
ing left ventricle, while the outflow tract is supported exclusively by the
developing right ventricle. In the definitive heart, blood entering the
A B C
Systemic blood (caudal entry)
Midline
Pulmonary blood (dorsal entry)
Dorsal mesocardium Arterial pole
Primary atrial septum
Venous pole
Working myocardium
Primary myocardium Atrioventricular canal
A B
Foramen
secundum Dorsal (inferior)
atrioventricular cushion
Dorsal
Ventral (superior)
mesocardium
atrioventricular cushion
Septal spiral outflow tract cushion
Outflow tract
cushions Parietal spiral outflow tract cushion
Dorsal mesocardium giving rise
Atrioventricular
to mediastinal mesenchyme
cushions
Fig. 52.16 Septation of the ventricles and outflow tract. A, A frontal view of the heart at stage 13, with the outflow tract reflected to the right. Lines show
the level of transverse sections of the atrioventricular cushions and outflow tract. Note that blood from both atria passes through the embryonic
interventricular foramen at this stage. B, A sagittal section of heart along the dotted line in A, showing the atrioventricular junctional region, seen from the
right side. The atrioventricular cushions extend on to the leading edge of the septum primum (although the mesenchymal cap on the atrial septum – see
Figure 52.14 – probably has a different developmental origin).


Development of the thorax
918
7
noItCeS
Appropriate connection with the separating atrioventricular and Fig. 52.18A). The most proximal parts of the cushions remain unfused
arterial junctions is essential for the development of a four-chambered when the aorta and pulmonary trunk have gained their separate exist-
heart. The serendipitous discovery of the expression of a ‘neural’ antigen ence within the pericardial cavity. At this time, the proximal part of the
in the primary junctional myocardium, surrounding the so-called outflow tract, upstream to the intrapericardial arterial trunks, remains
primary interventricular foramen, has clarified the complex morpho- encased in a myocardial sleeve. The arterial valves and sinuses then
genic steps involved in the remodelling of this region at the inner develop within the more distal part of this myocardial outflow tract;
curvature and the final position of the original interventricular ring in the outer myocardial wall does not disappear completely until well after
the fully developed heart (see Fig. 52.12). the completion of septation. The most proximal parts of the cushions
are the last ones to fuse, and they then muscularize and join the mus-
Septation and appropriate positioning of the cular ventricular septum, thereby joining the aorta into the left ventricle.
outflow tract The dorsal atrioventricular cushion maintains its mesenchymal charac-
ter, becoming the membranous part of the interventricular septum in
the formed heart. Formation of its interventricular and atrioventricular
The length of the myocardial portion of the outflow tract decreases
components does not become evident until the septal leaflet of the
markedly between the fourth and eighth weeks of development. In
tricuspid valve delaminates from the surface of the ventricular septum.
part, the myocardium becomes incorporated into the ventricles; in
part, it disappears by apoptosis. In the definitive heart, there is no dis-
tinct myocardial outflow tract present within the left ventricle because NON-MYOCARDIAL COMPONENTS OF THE HEART
the myocardium that initially separated the developing mitral and
aortic valves disappears, leaving the fibrous aortic–mitral continuity
The non-myocardial components of the heart are the epicardium,


distinctive for the postnatal heart. In the right ventricle, the proximal
including the coronary vasculature, and the interstitial fibroblasts and
myocardial outflow tract persists as the smooth-walled muscular sub-
the valvular apparatus, which are formed, in their larger part, from
pulmonary infundibulum. Formation of the part adjacent to the aortic
endocardially derived mesenchyme. From the outset, the atrioventricu-
root requires muscularization of the most proximal parts of the outflow
lar valves, mitral and tricuspid, are formed at the site of the initial atrio-
cushions to form the greater part of the supraventricular crest, or crista
ventricular canal, whereas the aortic and pulmonary valves are initially
supraventricularis.
developed within the myocardial outflow tract, and only later achieve
Key to separation of the outflow tract is the appearance of the two
the semilunar attachments of the leaflets, which cross the anatomical
outflow ridges, or cushions, which spiral one round another as they run
ventriculo–arterial junctions. All of the leaflets form initially as internal
from the distal end of the right ventricle, where they are positioned
endocardial projections that enclose a myocardial basement mem-
septally and parietally, to the aortic sac (see Fig. 52.16; Fig. 52.17).
brane, matrix and mesenchymal cells. The precise mechanisms involved
Within the aortic sac, a transverse wedge of tissue, termed the aorto-
in the formation of these areas have still to be determined.
pulmonary septum, separates the origins of the arteries traversing
the fourth and sixth pharyngeal arteries. The septum is formed from
Development of the epicardium and the
dorsal mediastinal mesenchyme. Myocardial precursor cells and non-
coronary vasculature
myocardial cells are added to the outflow tract, the latter forming the
intrapericardial components of the arterial trunks. Neural crest cells
migrate from the pharyngeal mediastinal myocardium into the outflow The epicardium, coronary vascular bed and interstitial fibroblasts


cushions. They do not appear to populate the septum itself, but form develop from a mesothelially covered protrusion of mesenchymal cells,
the larger parts of the walls of the intrapericardial portions of the the pro-epicardium, which arises from the pericardium in the region of
truncus arteriosus. The precise relationship between the outflow cush- the sinus venosus during week 5. The base of the pro-epicardium
ions and the newly formed aortic arch arteries, which never possess a encompasses bi-potential pericardial cells, which are recruited either to
septum between them, has still to be assessed. the cardiac lineage to form the venous pole of the heart, or else to the
The spiral outflow ridges start to fuse from the sixth week onwards, epicardial lineage. The entire structure expresses Tbx18. Bone morpho-
initially in the distal part of the outflow tract, and fusions continue genetic proteins and fibroblast growth factors influence which lineage
gradually into the direction of the ventricular septum (see Fig. 52.17; is followed; the precise mechanism of specification is not yet clear. Cells
A B C
Intercalated cushion of
pulmonary valve
Ao
Distal margin of parietal cushion
RA LA of pulmonary valve
Distal margin of septal cushion
PT
of pulmonary valve
RV LV
Left ventricle
Right ventricle
200 mm 40 mm 4400 µmmm
Dorsal (inferior)
Septal spiral outflow tract cushion
atrioventricular cushion
Ventral (superior)
Parietal spiral outflow tract cushion
atrioventricular cushion
Fig. 52.17 Septation of the outflow tract. A, A scanning electron micrograph (SEM) of a human heart at stage 18. The pulmonary trunk is separate from
the aorta. B, An SEM of the human heart at stage 17, showing the luminal aspect of the right ventricle and the outflow tract. The anterior and parietal
walls of the outflow tract have been removed along the dotted line shown in A. C, An SEM with added colour to show the structures in B. The outflow


cushions are unfused. The distal margins of both outflow tract cushions are contributing to the developing pulmonary valve: the third leaflet and sinus of
this valve are derived from the intercalated cushion. The components of the aortic valve develop from the dorsal aspect of the outflow tract cushions.
Abbreviations: Ao, aorta; LA, left atrium; LV, left ventricle; PT, pulmonary trunk; RA, right atrium; RV, right ventricle. (Courtesy of Prof G Steding,
Göttingen, with permission from Oostra RJ, Steding G, Lamers WH, Moorman AFM. Steding’s and Virágh’s Scanning Electron Microscopy Atlas of the
Developing Human Heart. New York: Springer-Verlag, 2006.)


heart and great vessels
919
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The coronary arteries were previously assumed to form by means of
IV angiogenesis, or sprouting from the aortic root. However, recent studies
VI
have demonstrated that the vessels develop prior to the formation of
the arterial orifices in the aortic sinuses; it is now thought that the
vessels arise by vasculogenesis, and that mesenchymal cells in the sub-
epicardial space give rise to primitive vessels that invade the myocar-
dium and spread over the myocardial surface. Sprouts of this plexus
R
approach the base of the outflow tract and connect to the sinuses of the
aortic root. Ultimately, only solitary right and left coronary arteries
S V remain, although, in up to one-third of human hearts, small accessory
O E branches of the coronary arteries take origin directly from the coronary
sinuses. The vessels that remain acquire a medial wall and an adventitial
D I
covering, whereas those that do not form a medial wall are destined to
regress. The coronary veins develop by sprouting from the coronary
sinus, draining directly to the atrial chambers. The mature coronary
At vascular pattern is established by remodelling of the capillary plexuses
500 µm and reduction in the number of arteriovenous anastomoses.
A
Atrioventricular valves
Initially, the atrial myocardium is continuous with the ventricular myo-
C
cardium through the myocardium of the atrioventricular canal. The
LA
PV atrioventricular canal itself is characterized by the tissues of the atrio-
ventricular groove on the epicardial side, and those of the endocardial
AV cushions on the endocardial side. As the atrioventricular valves develop,
these tissues fuse at the ventricular margin of the canal, and so disrupt
C myocardial continuity. Although molecular lineage studies in the
mouse have demonstrated that the atrioventricular cushions are initially
entirely populated by endocardium-derived mesenchymal cells, they
RA
T receive a significant epicardial contribution during further develop-
ment, the fibroblasts making up the valvular leaflets, and their tendi-
nous cords in the formed heart are therefore derived from both the
endocardium and the epicardium.


The atrioventricular valves develop as shelf-like projections from the
margins of the atrioventricular orifices. They are directed as almost
complete conical sheets towards the ventricles, their advancing edges
continuing, initially as trabecular ridges, deep into the ventricular cavity.
B 500 µm With continued differential growth and excavation on their ventricular
aspects, each sheet develops major indentations forming the mitral and
Fig. 52.18 A, A scanning electron micrograph (SEM) of a human heart at tricuspid orifices and defining their principal leaflets. Minor marginal
32 days (stage 15). The right lateral wall of the right atrium, right ventricle indentations subdivide some leaflets into scallops. Each leaflet develops
and the outflow tract have been removed. The septum primum (S) and functionally significant regional variations in surface texture and its core
the developing valve of the sinus venosus (white arrow) are at a distance condenses as a collagenous fibrous lamina, supported either by the
from the unfused ventral (V) and dorsal (D) atrioventricular cushions. The
fibro-fatty tissue of the atrioventricular groove, or by a fibrous anulus.
interventricular foramen (primum) is open (O). Its lower margin is made up
The anterior leaflet of the tricuspid valve and the aortic and mural
by the developing interventricular septum (I). Note the left anterolateral
leaflets of the mitral valve all appear at about the time of fusion of the
ridge (R) and, at the distal margins of the truncus arteriosus, the valve
atrioventricular and outflow cushions. Delamination of the septal
swellings (*) of the putative aorta and pulmonary trunk. Other
leaflet of the tricuspid valve occurs after the completion of ventricular
abbreviations: At, atrium; E, embryonic trabeculae; IV, origin of fourth
septation, producing the interventricular and atrioventricular compo-
aortic arch; VI, origin of sixth aortic arch. B, The septal aspect of the right
nents of the membranous septum, and continuing until at least week


ventricle of a human heart at 8 weeks. Delamination of the septal cusp of
the tricuspid valve (T) is taking place. A cleft (black arrow) has appeared, 11 (Fig. 52.18B).
marking the posterior margin of the septal cusp. There are no clefts
delineating the anterior margins in the region adjacent to the Aortic and pulmonary valves
supraventricular crest (C), and the endocardium is continuous. No tension
apparatus (chordae tendinae and papillary muscles) is present. Other
The aortic and pulmonary valves form from endocardial cushions
abbreviations: AV, aortic valve; LA, left atrium; PV, pulmonary valve; RA,
within the distal end of the myocardial outflow tract and become popu-
right atrium.
lated by neural crest cells, in addition to endocardial- and pharyngeal-
derived mesenchyme. The fusing outflow cushions divide, providing
detach from the pro-epicardium and spread over the myocardial tube, two rudiments each for the developing aortic and pulmonary valves.
caudally to cranially and dorsally to ventrally. Thus, in successive stages, The remaining leaflet for each valve is then produced from the newly
the pro-epicardial cells approach the myocardial surface of the develop- appearing intercalated cushions (see Fig. 52.17). Each cushion-derived
ing atria, atrioventricular canal, ventricles and the proximal part of the intrusion grows, and is also excavated on its mural aspect to form a
outflow tract. The distal part of the outflow tract, as it becomes arterial- semilunar valvular leaflet. Similar events affect the adjacent wall. In this
ized with regression of the initial myocardial walls, is covered by an way, the pouches between the valves and the walls of the cushions
outgrowth of the pericardial mesothelium at the site of the initial peri- gradually enlarge, the mural aspect of each cushion forming the valvular
cardial reflections. After the formation of the epicardium, a space is sinuses. The core of each leaflet forms a collagenous fibrous lamina,
formed between the developing epicardium and the outer myocardial delicate and thin in each crescentic lunule, thick and compact in the


layer, which is particularly pronounced at the atrioventricular and central nodule, with marginal radiate and basal bands. The dynamic
outflow regions of the heart tube. This is the subepicardial space, or nature of cardiac development makes it difficult to describe the posi-
subepicardium; it is subsequently populated by mesenchymal cells that tions of the leaflets precisely in space; it is, therefore, best to describe
are largely derived from the epicardium and which play an important the right, left and non-coronary sinuses and leaflets of the aortic valve,
role in the formation of the coronary vasculature. The precursors of and the adjacent and non-adjacent leaflets of the pulmonary valve.
coronary fibroblasts, smooth muscle cells and endothelium are all
derived from these pluripotent cells, which possibly also play roles in
the development of non-vascular tissues, including the mesenchyme of FETAL CIRCULATION
the atrioventricular cushions and some myocardial elements. The rem-
nants of the pro-epicardium can be found in the area of the developing As the cardiovascular system develops, the embryonic circulation (Ch.
systemic venous tributaries up to stage 15. 13) is modified into a fetal circulation, which maintains a placental


Development of the thorax
920
7
noItCeS
circulation and is also able to establish the pulmonary circulation at
birth. Extensive remodelling of the early aortic arch arteries and (ini-
tially bilateral) dorsal aortae occurs (Ch. 36). The dorsal aortae persist
on the cranial side of the third aortic arches as continuations of the
internal carotid arteries (see Fig. 36.9). The dorsal aorta between the
third and fourth aortic arches, the carotid duct, diminishes and finally
Superior
disappears. From the fourth arch to the origin of the seventh interseg- vena cava Arch of aorta
mental artery, the right dorsal aorta becomes part of the right subclavian
Ductus
artery, and caudal to the seventh intersegmental artery, the right dorsal Right lung arteriosus
aorta disappears as far as the locus of fusion of the thoracic aortae. After
disappearance of the left carotid duct, the remainder persists to form Foramen ovale Pulmonary trunk
the descending part of the arch of the aorta. The fused right and left
embryonic dorsal aortae persist as the definitive descending thoracic Left lung
Right atrium
and abdominal aorta. A constriction, the aortic isthmus, is sometimes
Left atrium
present in the aorta between the final site of origin of the left subclavian
artery and the orifice of the arterial duct.
Left ventricle
Concomitant changes also occur in the early venous system. The
precardinal veins enlarge as the head and brain develop. They are Right lobe
further augmented by the subclavian veins from the upper limb buds, of liver Right ventricle
which become the chief tributaries of the common cardinal veins,
gradually assuming an almost vertical position as the heart descends Left lobe of liver
into the thorax (see Fig. 13.4). That part of the original precardinal Portal vein
vein rostral to the subclavian vein is now the internal jugular vein,
and their confluence is the brachiocephalic vein of each side. The right Persistent left
and left common cardinal veins are originally of the same diameter; umbilical vein Ductus venosus
by the development of a large oblique transverse connection, the left


brachiocephalic vein carries blood across from the left to the right. Inferior vena cava
The part of the original right precardinal vein between the junction of
Umbilical
the two brachiocephalic veins and the azygos veins forms the upper vein
part of the superior vena cava. The caudal part of this vessel, below Aorta
the entrance of the azygos vein, is formed by the right common cardi-
nal vein. The left precardinal and left common cardinal veins caudal
to the transverse branching of the left brachiocephalic vein largely
atrophy; the precardinal constitutes the terminal part of the left supe- Left Bladder
rior intercostal vein, while the common cardinal is represented by the umbilical
ligament of the left superior vena cava and the oblique vein of the left artery
atrium. The remainder of the left superior intercostal vein is devel-
oped from the cranial end of the postcardinal vein and drains the
second, third and, on occasion, the fourth intercostal veins. The
oblique vein passes downwards across the back of the left atrium to Placenta
open into the coronary sinus, which represents the persistent left horn
of the systemic venous sinus. Fig. 52.19 A plan of the fetal circulation. The arrows indicate the direction
The fetal circulation contains a number of relatively large vessels that of blood flow. The placenta is drawn to a greatly reduced scale.
permit the majority of the blood flow to bypass the liver and lungs. The
placenta serves as the organ for fetal nutrition and excretion, receiving
deoxygenated fetal blood and returning it oxygenated and detoxified.
Fetal blood reaches the placenta via two umbilical arteries and, in early Blood from the head and upper limbs returns to the right atrium via
fetal life, returns by two umbilical veins (Fig. 52.19). The right umbili- the superior vena cava, flows through the right atrioventricular orifice
cal vein later disappears, whereas the persisting left umbilical vein into the right ventricle (together with the small amount of blood that
enters the abdomen at the umbilicus, traverses the edge of the falciform is returned via the inferior vena cava), and then passes into the pulmo-


ligament to reach the hepatic surface, and then joins the left branch of nary trunk. However, because the fetal lungs are largely inactive, only a
the portal vein at the hepatic portal. Opposite the junction, a large little of the blood from the right ventricle flows through the right and
vessel, the ductus venosus, arises and ascends posterior to the liver to left pulmonary arteries and returns to the left atrium via the pulmonary
join the left hepatic vein near its termination in the inferior vena cava. veins. The greater part of the outflow through the pulmonary trunk is
(For a detailed developmental account of the circumhepatic veins, see carried by the ductus arteriosus directly to the aorta, where it mixes with
Figs 60.8–60.11.) The portal vein is small in the fetus compared to the the small quantity of blood that passes from the left ventricle into this
size of the umbilical vein. Parts of the left branch of the umbilical vein, part of the aorta. The mixture descends in the aorta and most is returned
proximal and distal to their junctions, function as branches of the portal via the umbilical arteries to the placenta; some is distributed to the
vein, carrying oxygenated blood to the right and left parts of the liver. lower limbs and the organs of the abdomen and pelvis.
Blood in the left umbilical vein, therefore, reaches the inferior vena cava
by three routes: some enters the liver directly and reaches the vena cava
CHANGES IN THE FETAL CIRCULATION AND
via the hepatic veins; a considerable quantity circulates through the liver
with portal venous blood before also entering by the hepatic veins; and OCCLUSION OF FETAL VESSELS AFTER BIRTH
the remainder is bypassed into the inferior vena cava by the ductus
venosus. At birth, as pulmonary respiration begins, increased amounts of blood
The refreshed placental blood passes almost directly to the aorta for from the pulmonary trunk flow through the pulmonary arteries to the
distribution to the head and upper limbs. Blood from the ductus lungs and return by the pulmonary veins to the left atrium; pressure
venosus and hepatic veins mixes in the inferior vena cava with blood therefore increases within the left atrium. A decrease in pressure also


from the lower limbs and abdominal wall, and enters the right atrium. occurs in the inferior vena cava as a result of the reduction of venous
Because right atrial pressure is much greater than left atrial pressure, it return concomitant with occlusion of the umbilical vein and ductus
forces the flap-like valve of the septum primum to the left, which venosus. Atrial pressures become equal and the valvular foramen ovale
permits passage of blood from the right to the left atrium. The valve of is closed by apposition, and subsequent fusion, of the septum primum
the inferior vena cava is so placed as to direct 75% of the richly oxygen- to the rims of the foramen. Contraction of the atrial septal muscle,
ated blood from the umbilical vein to the foramen ovale and left synchronized with that in the superior vena cava, may assist this closure,
atrium, where it mingles with the limited venous return from the pul- which occurs after functional closure of the ductus arteriosus. Although
monary veins. From the left atrium, blood enters the left ventricle and the foramen ovale closes functionally after pulmonary respiration is
from there flows to the aorta; from here, it is probably distributed established, it does not become structurally closed until some time
almost entirely to the heart, head and upper limbs, which means that later. It is obliterated in fewer than 3% of infants 2 weeks after birth,
little reaches the descending aorta. and in 87% by 4 months after birth. Fusion is sometimes incomplete


heart and great vessels
921
25
retpahC
and a potential atrial communication (atrial septal defect) persists the ductus arteriosus, and is also a potent inhibitor of contraction of
throughout life. Almost always, this has no functional effect because the the pulmonary vessels.
inequality of atrial pressures and the valve-like arrangement of the
opening do not favour passage of blood.
Ductus arteriosus
Soon after birth, a number of fetal vessels occlude, although the
majority remain patent. This differential constriction suggests that the
walls of a population of fetal vessels are different to those of the remain- The ductus arteriosus shunts blood from the pulmonary trunk to the
ing vessels. Bradykinin, one of the kinin polypeptide hormones that arch of the aorta, bypassing the fetal lungs (see Fig. 52.19; Fig. 52.20).
induce contraction or relaxation of smooth muscle, forms in the blood It arises as a direct continuation of the pulmonary trunk at the point
of the umbilical cord when the temperature of the cord decreases at or where it divides into right and left pulmonary arteries. It is 8–12 mm
shortly after birth. It is also formed and released by granular leukocytes long, and joins the aorta at an angle of 30–35° on the left side, antero-
in the lungs of the neonate after exposure to adequate oxygen. Brady- laterally, below the origin of the left subclavian artery. The opening of
kinin is a potent constrictor of the umbilical arteries and veins, and of the ductus arteriosus into the aorta is greatly elongated. Its diameter at
Right recurrent laryngeal nerve
Trachea Oesophagus
Right common Brachiocephalic trunk
carotid artery
Left recurrent laryngeal nerve
Ansa subclavia Left common carotid artery
Right vagus nerve Superior cervical cardiac nerve (passing to
superficial part of cardiac plexus)
Right phrenic nerve
Left vagus nerve
Right subclavian artery
Ansa subclavia
Right and left
brachiocephalic veins Left subclavian artery
Internal thoracic artery Left phrenic nerve
Internal thoracic artery
Pericardiacophrenic artery
Fibrous pericardium
Pericardiacophrenic artery


Superior vena cava
Inferior cardiac nerve; branch
of vagus nerve (passing
Pulmonary trunk to superficial part of
cardiac plexus)
Ascending aorta
Ductus arteriosus
Pulmonary plexus
Right pulmonary
artery and veins
Left pulmonary artery
Pulmonary plexus and veins
Hilum of right lung
Conus arteriosus Hilum of left lung
Right auricle
Left auricle
Right coronary artery
(in coronary sulcus)
Great cardiac vein
Anterior cardiac veins Left coronary
nerve plexus
Left ventricle
Oblique fissure
of right lung
Oblique fissure
Marginal arterial and of left lung
venous branches
Anterior interventricular
(descending) branch of
left coronary artery
Visceral layer of serous Right coronary Parietal layer of serous pericardium lining fibrous
pericardium (epicardium) plexus pericardium that is fused to diaphragm
Fig. 52.20 An anterior view of the heart and great vessels in a full-term neonate. The lungs have been displaced to expose the heart, and the epicardium
has been dissected off the heart and the roots of the great vessels. Note that, after birth, blood flow reverses through the ductus arteriosus prior to its
closure. (After Crelin ES 1969 Anatomy of the Newborn. Philadelphia: Lea and Febiger.)


Development of the thorax
922
7
noItCeS
Arch of cricoid cartilage Destruction of the endothelium and proliferation of the intima subse-
quently occur, and lead to permanent closure. Diverse factors that may
Oesophagus
promote ductal closure have been identified, and include increased
oxygen tension; increased plasma catecholamine concentrations; sup-
Trachea Left recurrent
pression of prostaglandin I production; switching off prostaglandin E
laryngeal nerve 2
receptors; a synergistic role of prostaglandin Fa and oxygen concentra-
Tracheal lymph nodes 2
Aortic arch tions; and a decrease in plasma adenosine concentration. After birth,
these interrelated events result in the closure of the ductus arteriosus.
Superior tracheobronchial Left vagus nerve It has been proposed that the high oxygen tension of the reversed blood
lymph nodes flow through the ductus initiates the synthesis of a hydroperoxy fatty
Ductus arteriosus acid that suppresses prostacyclin production, thus exposing the ductus
Azygos vein (becomes ligamentum to the contractile effects of prostaglandin endoperoxide. After closure,
arteriosum) the duct becomes the ligamentum arteriosum, which connects the left
Tracheal bifurcation pulmonary artery (near its origin) with the aortic arch.
Bronchopulmonary
lymph node
Right main bronchus
Left main bronchus FETAL AND NEONATAL HEART
Right bronchial artery Upper left bronchial
artery At full term, the heart is situated midway between the crown of the head
Inferior tracheobronchial and the lower level of the buttocks (see Fig. 14.6). The anterior surface
lymph node Lower left bronchial is formed mainly by the right atrium and right ventricle, as it is in the
artery
adult. This surface is usually covered by the thymus, which may extend
Oesophageal arteries over the base of the right ventricle. The heart is relatively large at birth,
Oesophagus weighing around 20 g. The cardiac output is around 550 ml per minute
and the blood pressure is 80/46 mmHg. The heart rate during fetal life,
Diaphragm as term approaches, is around 150 beats per minute (bpm). It increases
Descending thoracic


at birth to around 180 bpm, decreases over the first 10 minutes after
aorta
birth to 170 bpm, and reaches 120–140 bpm from 15 minutes to 1
hour after birth. Any signs of fetal distress will increase this general basic
level. The heart rate decreases further with increasing age: it is normally
113–127 bpm from 6 months to 1 year, and settles to around 100 bpm
by the end of the first year.
Fig. 52.21 An anterior view with the heart removed to show the
Considered relative to the thoracic landmarks, the foramen ovale lies
relationship between the left primary bronchus, the aortic arch and the
at the level of the third intercostal space, with its long axis in the median
ductus arteriosus in a full-term fetus. (After Crelin ES 1969 Anatomy of
plane. It is 4–6 mm in vertical length and 3–4 mm wide (see Fig. 14.6).
the Newborn. Philadelphia: Lea and Febiger.)
It is almost exactly in the coronal plane of the body, so that blood passes
from the anterior, or ventral, right atrium posteriorly and upwards to
reach the upper and posterior part of the left atrium. After birth, the
its origin from the pulmonary trunk, when distended with blood, is intra-atrial pressures are equalized, and the free edge of the flap valve
4–5 mm, which is nearly equal to the diameter of the adjacent ascend- formed by the primary atrial septum is kept in contact with the left side
ing aorta (5–6 mm). Both arteries taper to a smaller diameter as they of the rims of the fossa, promoting subsequent anatomical fusion,
pass inferiorly and the aorta remains slightly larger (4 mm) (Fig. despite the fact that the foramen remains probe-patent in up to one-
52.21). In the neonate, the ductus arteriosus is closely related to the left third of all individuals. The initially free crescentic margin of the
primary bronchus inferiorly and the thymus gland anteriorly. infolded superior interatrial fold forms the border of the fossa after
The ductus arteriosus differs from the other great vessels that arise fusion; the flap valve formed by the primary septum accounts for its


from the heart because its tunica media contains smooth muscle rather floor in the adult heart.
than layers of elastin. It has been suggested that the relationship Functionally, the ventricular septum is often considered to be part
between the recurrent laryngeal branch of the vagus nerve and the of the left ventricle; while this is certainly true in terms of the orienta-
developing ductus arteriosus is responsible for this histological differ- tion of the myocardial aggregates that make up the ventricular walls, it
ence on the grounds that the left recurrent laryngeal nerve (which, in a is not correct from a cellular lineage perspective. The ratio of cardiac
stage 16 embryo, is very large in relation to the aortic arch system) sup- weight is usually expressed as the weight of the right ventricle relative
ports the ductus arteriosus as it enwraps it, thereby permitting the to that of the left ventricle and the septum. Calculated in this fashion,
ductus to develop as a muscular, and not an elastic, artery. the left ventricle at birth weighs about 25% more than the right ventri-
It is essential that the ductus arteriosus remains patent during intra- cle. However, the right ventricle has been working against the systemic
uterine life. Prostaglandins appear to have a role in maintaining this pressure in the fetus, the pulmonary circulation not yet being active,
patency. Fetal and neonatal ductal tissue can produce prostaglandins and there is a preponderance of right ventricular function in the first 2
E, I and Fa, which inhibit the ability of the ductus to contract in or 3 months after birth. With the establishment of the pulmonary cir-
2 2 2
response to oxygen. culation, the work of the right side of the heart decreases, and the left
side of the heart, particularly the ventricle, grows rapidly to meet the
Closure of the ductus arteriosus
demands of the active neonate. By the end of the second year, the left
The ductus arteriosus starts to close immediately after birth, although side weighs twice as much as the right, a ratio that continues to middle
blood probably continues to flow intermittently through it for a week age. At birth, the average thicknesses of the lateral walls of the ventricles


or so. The flow is reversed relative to that occurring in the fetal circula- are approximately equal (5 mm). By the end of the third postnatal
tion, reflecting the increased systemic vascular resistance that follows month, the left ventricle has already become thicker than the right; it
exclusion of the placental circulation, and the decreased pulmonary becomes twice as thick by the second year, and three times as thick by
resistance that follows expansion of the lungs. Animal studies have puberty.
shown that reversal of flow occurs rapidly after ventilation begins.
Blood flow from the left ventricle travelling via the aorta and ductus
arteriosus contributes almost 50% of total pulmonary blood flow. CONGENITAL HEART DEFECTS
Initial constriction at birth has been attributed to increased oxygen
tension. A neural factor may also be involved; the muscular wall has Defects of cardiac development may not come to light until after birth,
afferent and efferent nerve endings and responds to adrenaline (epine- although many, if not most, can now be observed on fetal ultrasonic
phrine) and noradrenaline (norepinephrine) within 10 minutes of ven- examination. They may affect any part of the developing heart, and
tilation onset; this reduces to about 25% by 2 hours. It is suggested that include more complex forms with inappropriate connections of cardiac
the turbulence and increased shear-stress of this blood flow releases components. They include anomalies such as double inlet ventricle;
vasoconstrictive factors from the endothelium (Crossley et al 2009). absence of one atrioventricular connection, commonly described as
The first stage of ductal closure is completed within 10–15 hours and tricuspid or mitral atresia; and discordant atrioventricular and
the second stage takes 2–3 weeks. The first stage consists of contraction ventriculo–arterial connections, also known as congenitally corrected
of the smooth muscle cells and development of subendothelial oedema. transposition.


heart and great vessels
923
25
retpahC
A C
Doubly committed
juxta-arterial defects
• beneath aortic and
pulmonary valves
Superior Atrioventricular
‘sinus venosus’ septal defect • can extend to become
defect (‘ostium primum’) perimembranous
Perimembranous defects
Fossa ovalis
defect • abut on central
fibrous body
Muscular defects
• entirely enclosed
• can extend to open
Inferior between inlet, in muscular septum
‘sinus venosus’ apical trabecular
defect or outlet trabecular • can occur between
inlet, apical
components, or can
trabecular or
Coronary be confluent
outlet ventricular
sinus defect
components
B
Fig. 52.22 A, Location of the defects that produce an interatrial communication. Only
defects within the fossa ovalis are true atrial septal defects. B, Shunting across an
atrioventricular septal defect. This can be atrial (left), ventricular (right) or at both
levels (middle), depending on the attachment of the bridging cusps. C, Ventricular
septal defects. Depending on the structure of the anatomical borders seen from the
right ventricle, these defects can be placed into perimembranous, muscular or doubly
committed groups. (B and C, Courtesy of Professor RH Anderson, Institute of Child
Health, University College, London.)
Congenital cardiac anomalies are often multiple, and probably occur leaflets. Two major subgroups are identified. The more frequent pattern
more frequently in siblings and in children of consanguineous mar- has a common atrioventricular orifice, and the potential for shunting
riages; there is a low correlation among monozygotic twins. Ventricular through the septal defect at both atrial and ventricular levels (see Fig.
septal defects are the most common lesions, making up around one- 52.22B). The less common form has separate right and left atrioven-
fifth of all cases, followed by persistent patency of the ductus arteriosus, tricular orifices, and shunting occurs only at atrial level. Occasionally,


coarctation, pulmonary stenosis, Fallot’s tetralogy, transposition, aortic when the bridging leaflets are attached to the underside of the atrial
stenosis, and hypoplasia of the left heart. septum, shunting is confined at ventricular level and is typically small.
Atrial septal defects Ventricular septal defects
A persistent communication between the atrial chambers within the The most common defect of the ventricular septum occurs around the
fossa ovale is common, and results from the failure of the flap valve of expected site of the membranous septum in the right wall of the aortic
the primary atrial septum to fuse with the infolded muscular rims of vestibule, below the zone of apposition between the non-coronary and
the fossa. When the flap valve is still able to overlap the rims, the com- right coronary leaflets of the aortic valve (Fig. 52.22C). The defect is
munication is of no functional significance as long as left atrial pressure closely related to the septal leaflet of the tricuspid valve, but can extend
is greater than right, which is usually the case. However, when the flap to open into the ventricular outlet beneath the supraventricular crest.
valve is smaller than the fossa ovale, or when it is perforate, there is a It occurs because the ventricular septum is incompletely closed by its
true atrial septal defect (Fig. 52.22A). membranous component, and it is often associated with overriding of
In normal development, the free leading edge of the septum primum the crest of the muscular septum by the aortic orifice, together with
merges with the atrioventricular endocardial cushions, permitting sub- pulmonary stenosis or atresia and hypertrophy of the right ventricle
sequent formation of the atrioventricular septum. When this does not (this latter combination is known as Fallot’s tetralogy). Rarely, the pul-
happen, there is a common atrioventricular junction and an atrioven- monary trunk can be normal or even dilated with this combination of
tricular septal defect. This can occur when the leaflets of the atrioven- abnormalities (Eisenmenger complex). Perimembranous defects, which


tricular valves are fused to the crest of the ventricular septum (see Fig. retain the remnant of the membranous septum as part of their perim-
52.22A), producing an interatrial communication at the expected site eter, can also occur with abnormal ventriculo–arterial connections, e.g.
of the atrioventricular septum. This is the so-called ostium primum the pulmonary trunk may override the muscular septum (the Taussig–
defect; in reality, it is an atrioventricular septal defect permitting exclu- Bing anomaly). In perimembranous ventricular septal defects, the atrio-
sive atrial shunting. Other interatrial communications can be formed ventricular bundle and its right and left branches are always found
in the mouths of the vena cavae, most frequently the superior vena cava, along the posteroinferior margin of the defect.
and are usually associated with drainage of the right pulmonary veins Less commonly, a septal defect can be found in the ventricular
into the cavo-atrial junction. Known as sinus venosus defects (see Fig. outflow tracts roofed by the conjoined facing leaflets of the aortic and
52.22A), their essential feature is a bi-atrial connection of the involved pulmonary valves. Such juxta-arterial defects are doubly committed, in
caval vein. An interatrial communication can also occur through the that they open beneath the orifices of both aortic and pulmonary valves.
mouth of the coronary sinus when there is a deficiency or absence of They are the result of the failure of formation of the free-standing sub-
the walls that usually separate the sinus from the left atrium. pulmonary muscular infundibulum, but with appropriate septation of
Atrioventricular septal defects result from failure of fusion of the the ventriculo–arterial junctions. They usually have a muscular postero-
endocardial atrioventricular cushions, producing a common atrioven- inferior rim, which protects the atrioventricular bundle, but can extend
tricular orifice and deficiencies of the adjacent septal structures (Fig. to become perimembranous.
52.22B). The common orifice is guarded by a basically common valve, The third type of ventricular septal defect occurs within the muscu-


with superior and inferior leaflets bridging the scooped-out ventricular lature of the septum; defects may affect all parts of the septum and can
septum and tethered in both right and left ventricles. Although the left be multiple, producing a so-called ‘Swiss cheese’ septum.
component of the valve thus formed is often interpreted as a ‘cleft mitral Defects within the inlet part of the septum are important because
valve’, it bears no resemblance to the normally structured mitral valve, the atrioventricular bundle passes in their upper border. Perimembra-
in reality, because it has three leaflets; the ‘cleft’ forms the zone of nous defects open into the inlet of the right ventricle, where the atrio-
apposition between the left ventricular components of the bridging ventricular bundle is posteroinferiorly located.


Development of the thorax
924
7
noItCeS
Fig. 52.23 This heart oesophagus, giving so-called dysphagia lusoria. Persistent patency of
possesses a common the ductus arteriosus must be distinguished from delayed closure. The
arterial trunk, with a persistently patent ductus can be an obligatory part of the circulation
common truncal valve when associated with aortic or pulmonary atresia. Coarctation of the
overriding a juxta- aorta can be found as an isolated lesion when the ductus arteriosus is
arterial deficiency of the closed, or with an open duct, when it is more likely to be associated
ventricular septum, the with additional lesions within the heart.
result of failure of
In the adult, the right subclavian artery occasionally arises from the
septation of the arterial
arch of the aorta distal to the origin of the left subclavian artery, and
pole of the developing
then passes upwards and to the right, behind the trachea and oesopha-
heart. (Courtesy of
gus. This condition is possibly explained by the persistence of the
Professor RH
embryonic right dorsal aorta and the obliteration of the fourth aortic
Anderson, Institute of
arch of the right side.
Child Health, University
College, London.
Specimen prepared by Ultrasound antenatal imaging of the heart
Dr Leon M Gerlis.) and vessels
In a four-chamber view of the fetal heart, up to about 28 weeks’ gesta-
tion, the heart occupies about one-third of the thorax in the anterior
left quadrant of the chest. The two atria are of equal size, as are the two
ventricles, which have an intact interventricular septum between them;
the apex of the heart points to the left anterior thorax. In moving
images, the ventricles show equal contraction, the two atrioventricular
canals open equally, and the foramen ovale flap valve can be seen
flickering in the left atrium (see Video 14.1). The blood flow through
the heart can be demonstrated with colour flow (Fig. 52.24). After 28
weeks’ gestation, the right ventricle may look dilated compared with
the left.
Ultrasound evaluation of the fetal heart checks that the fetal heart


ANOMALIES OF THE GREAT ARTERIES AND VEINS and stomach are both on the left and that the liver is on the right.
Within the four-chamber view, the function and rhythm of the heart
and the origin of the great vessels from their respective ventricles can
A number of outflow anomalies may occur if the outflow cushions
be observed. The great vessels can be assessed in transverse section and
either fail to develop or fuse in inappropriate fashion. When the spiral
the aorta can also be assessed longitudinally (see Fig. 14.4); it normally
septum cushions fail to fuse, the result is a common arterial trunk,
arises in the centre of the thorax, and the vessels to the head and neck
represented by an undivided arterial channel, guarded by a common
can be seen arising from the curve of the aortic arch. For further details
arterial valve, positioned above and astride the free margin of the mus-
of ultrasound findings, consult Coady and Bower (2015).
cular ventricular septum (Fig. 52.23). There is, therefore, a coexisting
juxta-arterial deficiency of the ventricular septum. The right and left
pulmonary arteries usually arise via a confluent segment but can take
NEONATAL ARTERIAL AND VENOUS VESSELS
independent origin from the common arterial trunk, which continues
as the ascending aorta. The common valve usually has three leaflets but
In the neonate, the blood vessels of the trunk and their associated vis-
may have two, four or more. The lesion is almost certainly linked to
ceral branches are relatively larger than the vessels in the limbs, an
abnormal migration of cells into the heart from the neural crest.
arrangement that favours central pooling of blood. Neonatal peripheral
Transposition of the arterial trunks (also referred to as transposition
vessels are nearly microscopic; consequently, their cannulation poses
of the great vessels) is the condition in which the aorta arises from the
much more of a problem than is the case with their adult counterparts.
right ventricle and the pulmonary trunk from the left. Better described
Large vessels are in the same relative positions as in the adult but may
as having discordant ventriculo–arterial connections, such hearts can
correspond to different vertebral levels. Thus, although the bifurcation