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Thorax VI
Embryological Development of the Heart
Cathleen C. Pettepher, Ph.D. September 3, 2004 (10:00 am)
Sadler: Langman's Medical Embryology: 8th ed: pp. 208-259
Moore & Persaud: The Developing Human, 6th ed: pp 349-403
Larsen: Human Embryology, 2nd ed: pp. 151-187
Netter’s Atlas of Human Embryology: pp. 83, Figs: 4.1, 4.6, 4.8, 4.10 – 4.27, pp. 111
Sulik & Bream: Embryo Images; Normal Development (CD-ROM): Cardiovascular Development
Plates 1-3, 9-15, 17
As a result of attendance at audiovisual presentations, and reading/viewing textbooks, CDs, and notes,
participation in dissection and integration of embryological facts, students should gain an appreciation
how the remnants of early heart development can still be identified in the adult heart and how the study of
embryology can contribute to an understanding of congenital heart defects.
1. Explain where and how the pericardial cavity forms.
2. Describe the cells/tissues, location and events of heart tube formation.
What are the 3 layers of the heart tube? What is the position of the heart tube
relative to the surrounding developing structures in the embryo?
3. Identify the major inflow and outflow vessels associated with the heart tube.
Relate these embryonic structures to the transverse and oblique pericardial
sinuses in adults.
4. Describe the process and time of formation of the cardiac loop. Name the
regions of the early heart tube and what their fates will be. Use this knowledge
to explain positional abnormalities of the heart such as dextrocardia.
5. Describe how the atrium is separated into right and left portions while still allowing blood to cross
uni-directionally from the right to the left side. Include the following in your description:
a) septum primum
b) septum secundum
c) ostium primum
d) ostium secundum
e) foramen ovale
g) sinus venosus
6. Which of the above in #5 could contribute to the formation of an ASD?
7. What 3 major tissue structures are required to completely separate the right and left ventricle?
8. Describe the mechanism by which the outflow tract is divided so that the aorta and pulmonary trunk
are connected to the appropriate ventricle. What are the origins of the cells contributing to the
formation of the aorticopulmonary septum?
9. Describe the formation of the semilunar valves. How does their embryological origin explain why the
pulmonary trunk has an anterior cusp but the aorta a posterior cusp while both vessels have a right
and left cusp?
10. Describe the formation of the atrioventricular valves.
11. Compare and contrast the fetal blood flow patterns with the changes that occur in the immediate
postnatal period and in the 1st week of life.
12. Familiarize yourself with the following congenital heart defects: Tetralogy of Fallot, persistent ductus
arteriosus, and transposition of the great vessels.
Development of the Heart
Cathleen Pettepher, Ph.D. September 3, 2004
I. Earliest Development of the Cardiovascular System (Figure 11.1, Langman’s Medical Embryology,
Eight Addition, p.209; Netter Embryology Figs. 4.10 & 4.11)
st
This is the 1 organ system to become functional (day 21)
A necessity since the rapid growth rate of the embryo exceeds the nutritional requirements
provided by diffusion alone.
Just lateral to the primitive streak lying in the epiblast layer are cardiac progenitor cells.
These cells are destined to form the heart and they begin to migrate through the streak until
they reach a position rostral to the buccopharyngeal membrane and neural folds.
Here the cells reside in the splanchnic layer of the lateral plate mesoderm where they are
induced to differentiate into cardiac myoblasts or muscle cells.
Endocardial cells or angioblasts, also appear in this mesoderm, and they begin to proliferate
and grow to form blood islands or clusters. This process is known as angiogenesis.
Within time, these clusters will unite to form a horseshoe-shaped endothelial-lined tube
surrounded by cardiac myoblasts.
Remember that this region is anterior to the prochordal plate or head region and is now
referred to as the cardiogenic area.
The intraembryonic cavity overlying this cardiogenic area later develops into the pericardial
cavity.
II. Blood Vessel Formation (Netter Embryology Figs. 4.10 & 4.11)
Other clusters of angiogenic cells will begin to appear bilaterally and close to the midline of
the embryo.
These clusters of cells will form adhesions with each other resulting in vascular sacs with a
lumen.
These dilated sacs eventually coalesce into two primitive longitudinal blood vessels referred
to as the dorsal aortae.
These vessels ultimately gain connections to the horseshoe-shaped heart tube via the aortic
arches.
By day 26, the embryonic cardiovascular system has been established and the primitive heart
and circulatory system begin to move O2, nutrients and wastes around the embryo and to the
developing placenta.
III. Formation, Position and Subsequent Folding of the Primitive Heart Tube (Figures 11.2 & 11.32,
Langman’s Medical Embryology, Eight Addition, p.210; Heart development Images from the Vesalius
website; Figure 14.2, Moore’s The Developing Embryo, Sixth Addition, p.351, Netter Embryology Figs.
4.11, 4.12 & 4.13))
In the crescent-shaped cardiogenic area, the heart arises by the fusion of paired, longitudinal
endothelial channels.
These endothelial channels canalize to form two, thin-walled endothelial heart tubes.
As lateral embryonic folding occurs these tubes gradually approach each other and fuse to
form a single endothelial-lined heart tube.
Fusion of these tubes begins at the cranial end of the developing heart (future ventricle) and
extends caudally.
This forms an unpaired midline endocardial heart tube.
The primitive heart tube shows a series of regional dilations or primary cardiac chambers.
Listed from the caudal or venous end of the heart tube to the cranial or arterial end (ultimate
direction of blood flow), the chambers are:
sinus venosus
atrium
ventricle
bulbus cordis
The cranial (arterial) and caudal (venous) bifurcations remain at each end. Blood exits the
heart tube (outflow side = arterial) by way of the paired dorsal aortae that later form the five
aortic arches in the neck region and the caudal bifurcation becomes the sinus venosus, which
receives the six embryonic veins:
Right & Left Umbilical Veins
Right & Left Common Cardinal Veins
Right and Left Vitelline Veins
Cardiac myoblasts that had migrated into the region begin to contract spontaneously at day
22. The embryo now has a heartbeat and the beginnings of blood flow.
Timing - 1 week after the mother probably noticed a missed menstrual period.
The embryo begins cephalocaudal folding (embryonic flexion) to accommodate the rapidly
expanding brain vesicles on the dorsal aspect.
Thus the cardiogenic area becomes progressively tucked under the ventral surface of the
embryo.
Also undergoing ventral folding is the mesoderm (septum transversum) that will help
contribute to the future diaphragm.
Also undergoing ventral folding is the intraembryonic coelom (space) that will form the
pericardial cavity.
IV. Formation of the Pericardial Sac (Figures 11.3 & 11.5, Langman’s Medical Embryology, Eight
Addition, pp.211 & 213; Figure7.8, Larsen’s Human Embryology, Second Edition, p. 159; Figures 14.8
& 14.9, Moore’s The Developing Embryo, pp.357-359; Netter Embryology, Fig. 4.12)
As the heart elongates and bends, it gradually invaginates into the pericardial cavity.
The heart is initially suspended from the dorsal wall of this cavity by a dorsal mesocardium,
but the central part of this mesentery soon degenerates.
This forms a communication, the transverse pericardial sinus, between the right and left side
of the pericardial cavity.
The heart tube is now suspended in the cavity by blood vessels at its cranial and caudal ends.
V. Morphogenesis of the Heart Chambers and Valves (Figure 7.7, Larsen’s Human Embryology,
Second Edition, p. 158; Figure 14.7 & 14.8, Moore’s The Developing Human, p. 356-357)
Occurring simultaneously, the heart tube becomes surrounded by mesoderm that
differentiates into myoepicardial mantle cells, which are contractile cells.
These cells begin to beat with no directionality (an ebb & flow pattern) and give an all-or-
none contraction on day 21.
The contractile cells will ultimately become the myocardial layer (cardiac muscle).
Another group of mesothelial cells in the region of the sinus venosus migrates over to the
heart to form the epicardium (outside covering and mostly fat).
Thus, the trilaminar heart wall is completed.
Developing temporarily between the endocardial heart tube and the myoepicardial mantle is
the subendocardial layer, which makes cardiac jelly (mucopolysaccharides).
Primitive valves develop from thickenings of this cardiac jelly layer, helping with ebb and
flow until unidirectional (caudal to cranial) flow develops as contractions become peristaltic.
This jelly later contributes to the formation of the definitive heart valves.
Primitive heart chambers become evident in this heart tube during days 22-28.
Valves initially partition the cardiac tube into a sinus venosus, a primitive atrium, a primitive
ventricle and a bulbus cordis (direction of blood flow through the chambers).
Sinuatrial Valves - Separate the Sinus Venosus (of the inflow veins) and the primitive,
single and large atrium.
Atrioventicular Valve - divides the tube into a single atrium and a single ventricle. This
region will form the tricuspid and bicuspid valve in the adult.
Bulbar cushions separate the ventricles from the outflow tract (bulbus cordis).
They will form the semilunar valves of the pulmonary trunk and aorta in the adult.
VI. Vessels Returning Blood to the Heart (Figures 11.40, 11.41 & 11.42, Langman’s Medical
Embryology, Eight Addition, pp.247& 248; Figure 14.5, Moore’s The Developing Human, Sixth Edition,
p. 354; Netter Embryology Figs. 4.2, 4.9, 4.13 & 4.14)
Umbilical Veins - bring in oxygen and nutrients from the placental circulation
Vitelline Veins - drain the yolk sac (they develop in the gut region)
Common Cardinal Veins
Formed by the convergence of the anterior & posterior cardinal veins.
These drain the body wall regions.
The anterior set drain the head region, the posterior set drain the tail region.
Ultimately, these 3 sets of paired veins undergo extensive disruption and/or remodeling.
In general:
Vessels on the left side regress.
Vessels on the right side enlarge as blood is shunted toward the right side of the
body as it returns to the heart (as in the IVC or brachiocephalic vv).
The liver undergoes massive cell proliferation right in the midst of these vessels
This forces the blood vessels to undergo extensive remodeling.
All vessels enter the heart tube at the Sinus Venosus (Sinus of the Veins).
The sinus venosus is located at the caudal end of the heart tube.
VII. Establishment of the Heart Loop (23-28th days) (Figures 11.4, 11.6, 11.7, 11.8, Langman’s
Medical Embryology, Eight Edition, pp. 212, 214-215; Figure 7.9; Larsen’s Human Embryology, Second
Edition, p. 160; Netter Embryology Figs. 4.14 & 4.20)
Since the heart tube is fixed at both ends (branchial arches and the septum transversum), its
subsequent elongation causes it to bend or buckle ventrally into the pericardial cavity.
It bends in the form of an S and it also bends from side to side.
The dorsal wall of the pericardial cavity fails to keep pace with this elongation of the heart
tube so that the arterial and venous ends of the tube become approximated.
The cephalic (ventricle) portion moves ventrally and to the right.
The caudal (atrium) portion moves dorsally and to the left of the truncus arteriosus,
bulbus cordis and ventricle.
At the same time the sinus venosus is carried on to the dorsal and caudal wall of the
atrium and also projects more completely into the pericardial cavity.
While the cardiac loop is being formed, local expansions become visible along the length of
the tube.
The primitive atrium (initially a paired structure) becomes a common intra-pericardial
atrial chamber.
The atrioventricular junction remains narrow and forms the atrioventricular canal, which
connects the common atrium and the early embryonic ventricle.
The bulbus cordis is narrow except for its proximal third. This portion will become the
trabeculated part of the right ventricle.
The midportion or conus cordis, will form the outflow tracts of both ventricles.
The distal part of the bulbus, the truncus arteriosus, will form the roots and proximal
portion of the aorta and pulmonary artery.
The junction between the ventricle and the bulbus cordis, externally indicated by the
bulboventricular sulcus remains narrow and is called the primary interventricular
foramen.
Clinical Abnormalities of Cardiac Looping
Dextrocardia:
The heart loops to the left instead of to the right; therefore, the heart lies on the
right side of the thoracic cavity instead of the left.
It may coincide with “situs inversus”, in which all major organs are completely
reversed from their normal positions.
VIII. Septation of the Heart (Figures 11.15, Langman’s Medical Embryology, Eight Edition, pp. 225;
Figure 14.11, Moore’s The Developing Human, Sixth Edition, p.362; Netter Embryology Figs. 4.15)
th th
The major septa of the heart are formed between the 27 and 37 days of development.
Two actively growing masses of tissue or endocardial cushions located on opposite sides of
the atrioventricular canal begin to grow toward each other to form the septum
intermedium.
They continue to grow toward each other until they fuse, thereby dividing the lumen into two
separate canals.
This septum now divides the common atrioventricular canal into left and right
atrioventricular canals.
IX. Septum Formation in the Common Atrium (26th- 28th days) (Figure 11.13, Langman’s
Medical Embryology, Eight Edition, p. 22; Figure 7.14, 7.15, & 7.16, Larsen’s Human Embryology,
Second Edition, p. 165-167; Figure 14.12, Moore’s The Developing Human, p. 362; Netter Embryology
Figs. 4.15, 4.16 & 4.25)
th
At the end of the 4 week, a sickle-shape curtain descends toward the endocardial cushions
from the roof of the common atrium near the midline.
This crest represents the first portion of the septum primum.
The two limbs of this septum extend in the direction of the endocardial cushions in
the atrioventricular canal.
The opening between the lower rim of the septum primum and the endocardial
cushions is the ostium primum.
With further development, extensions of the superior and inferior endocardial cushions grow
along the edge of the septum primum, thereby closing the ostium primum.
Before closure is completed, cell death produces perforations in the upper portion of the
septum primum.
When these perforations coalesce, the ostium secundum is formed, thus ensuring a
free blood flow from the right to the left primitive atrium.
A second, thicker, cresentric flap of tissue descends toward but never reaches the endocardial
tissues. This is the septum secundum.
It bounds the remaining oval opening – the foramen ovale.
The passage between the atrial cavities now consists of an obliquely elongated cleft and
blood from the right atrium flows to the left side through this cleft.
After birth, when lung circulation begins and pressure in the left atrium increases, the valve
of the oval foramen is pressed against the septum secundum, thus obliterating the oval
foramen and separating the right and left atria.
Clinical Abnormalities Associated with Atrial Septal Formation:
Probe patency of the Foramen Ovale:
In about 20% of cases, fusion of the septum primum and septum secundum is
incomplete and a narrow oblique cleft remains between the two atria.
The fossa ovalis (postnatal depression) is floored by a remnant of the septum
primum and is an indication of the site of the fetal foramen ovale.
The postnatal remnant of the septum secundum is the limbus of the fossa
ovalis.
Atrial Septal Defect (ASD):
Incidence of 6.4 in 10,000 births
2.1 prevalence in females
Characterized by a large opening between the left and right atria – ostium
secundum defect – caused by inadequate development of the septum secundum,
excessive cell death or resorption of the septum primum.
X. Septum Formation in the Truncus Arteriosus and Conus Cordis and Between the
Ventricles (Figures 11.21, 11.22 & 11.23, Langman’s Medical Embryology, Eight Edition, pp. 231-233;
Figures 7.14, 7.15, 7.16, 7.17 & 7.18, Larsen’s Human Embryology, Second Edition, pp. 165-169, Figure
14.8, Moore’s The Developing Human, p. 370; Netter Embryology Figs.4.17, 4.18, 4.19, 4.13, 4.24 & 4.
26)
th
The two primitive ventricles begin to expand by the end of the 4 week at the same time that
the septum intermedium is forming.
The medial walls become apposed and fuse to form a partial interventricular septum so the
space between the free rim of the muscular ventricular septum and the fused endocardial
cushions permits communication between the two ventricles.
During the 5 week, pairs of opposing ridges – conotruncal ridges -- appear in the truncus
th
and conus.
These ridges or cushions spiral toward each other and distally.
They unite to form the conotruncal septum, which divides the right ventricular
outflow or pulmonary channel from the left ventricular outflow or aortic channel.
When the spiral septum fuses with the muscular septum, the heart is then completely
partitioned into a right and left ventricle
This septum is therefore called the aorticopulmonary septum.
Sometimes the septum spirals downward inside the arterial outflow vessel in an
uneven fashion making one side large (an overriding aorta) and one side small
creating a pulmonary stenosis. This eventually produces hypertrophy of the right
ventricle.
Development of the aorticopulmonary septum has decreased the size of the interventricular
foramen, which is found above the muscular portion of the interventricular septum.
During further development, closure of the foramen is accomplished by outgrowth of the
inferior endocardial cushion along the top of the intermuscular septum.
This tissue joins the aorticopulmonary septum.
After complete closure, the interventricular foramen becomes the membranous part
of the interventricular septum.
Clinical Abnormalities in Ventricular Septal Formation:
Ventricular Septal Defect (VSD)
Most common congenital cardiac malformation
Incidence of 12 in 10,000 births.
Sometimes the membranous portion of the septum doesn't grow enough and fails
to merge with structures in the middle of the heart. Blood then leaks from the left
ventricle back into the right ventricle.
May be found as an isolated lesion, but is usually associated with problems
involving partitioning of the conotruncal region.
Tetralogy of Fallot (Figure 11.28, Langman’s Medical Embryology, Eight Edition, p.
236)
Most frequently occurring abnormality in the conotruncal region
Due to an unequal division of the conus resulting from anterior displacement of
the conotruncal septum.
This displacements causes four cardiovascular alterations:
Pulmonary stenosis or a narrow right ventricular outflow
Interventricular septal defect
Overriding Aorta directly above septal defect
Hypertrophy of the Right ventricle
Persistent Truncus Arteriosus (Figure 11.29, Langman’s Medical Embryology,
Eight Edition, p. 237)
Incidence of 0.8 in 10,000 births.
Failure of the conotruncal ridges to fuse and spiral downward toward the
ventricles, which causes the pulmonary artery to arise some distance from the
undivided truncus.
Always accompanied by a VSD.
Transposition of the Great Vessels (Figure 11.30, Langman’s Medical Embryology,
Eight Edition, p. 238)
Incidence of 4.8 in 10,000 births.
Failure of the conotruncal ridges to spiral normally and the septum runs straight
vertically.
Therefore, the aorta originates from the right ventricle and the pulmonary artery
from the left ventricle.
XI. Valve Formation (Figures 11.17, 11.25 & 11.26, Langman’s Medical Embryology, Eight
Edition, pp. 227, 234-235; Figure 7.18, 7.19; Larsen’s Human Embryology, Second Edition, p. 169-170,
Figure 14.21, Moore’s The Developing Human, p.373; Netter Embryology Figs. 4.17 & 4.18,)
Semilunar Valve Formation:
When partitioning of the truncus has almost been completed:
right and left tubercles appear on the conotruncal ridges
an anterior tubercle in the developing pulmonary channel
a posterior tubercle in the aortic channel
The right and left tubercles are split into pulmonary and aortic portions by the
aorticopulmonary septum.
The tubercles remodel, developing concavities on the upper surfaces.
These are the cusps of the semilunar valves.
Atrioventricular Valve Formation:
After the atrioventricular endocardial cushions fuse, each AV orifice is surrounded
by localized proliferations of mesodermal tissue.
When tissue located on the ventricular surface of these proliferations becomes
hollowed out and thinned by the bloodstream, valves are formed that remain attached
to the papillary muscles of the ventricular wall by muscular cords (chordae
tendineae).
Finally, muscular tissue in the cords degenerates and is replaced by dense connective
tissue.
two valve leaflets are formed in the left AV canal -- mitral (bicuspid) valve.
three valve leaflets are formed in the right AV canal – tricuspid valve.
Clinical Abnormalities:
Valvular Stenosis:
Fusion of valves for a variable distance.
If occurs in the trunk of the pulmonary artery, it is usually very narrow or
atretic.
Patent foramen ovale becomes the only outlet for blood from the right
side of the heart. Always accompanied by a Patent Ductus Arteriosus (Netter
Embryology Fig. 4.27).
