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The Embryology of Ventricular Flow Pathways in Man
By ROBERT P. GRANT, M.D.
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elemelnts, etc. Clinlical problerns in congenital
heart disease most commonly involve derangements of the former, and for that reason the
present discussion is principally concerned
with the way in which the flow pathways
develop.
Essentially, the flow paths in the heart pose
aii architectural problemn. Visual, graphic
methods of presentation are far superior to
verbal methods for elucidating it. To be sure,
with a visual method some of the dinmensional
and timing features may become lost. The
visual method, however has the great advantage of showing relationships that the verbal
method cannot, and it eliminates some of the
artificial nomenclature that has grown up
about cardiac development, the various sulei,
ridges. flanges, and crests, whieh have made
understanding cardiac development so complicated and difficult. In the present discussion great reliance will be placed ulpoln the
schenmata of figures 1 and 2 with as little
'naming"lof comnponients of the heart as
possible.
The Primary Heart Tube
In 1948 Streeter' introduced the coneept of
the "primary heart tube." This concept is
of great assistanee in understanding the development of flow paths in the heart because
it emphasizes the remarkable differenee in
growth potential in various regions of the
heart, and it focuses attention on the parts
of the heart miost responsible for partitioning.
The primary heart tube is, in its earliest fornm.
the nontrabeculated portion of the fetal heart
between the atrioventricular orifice anid the
trunceus arteriosus. It should not be confused
with the "primitive cardiac tube,'" a term
often used for the product of fusion of the
bilateral cardiac prinmordia at the earliest
stage of heart growth. Figures 1 and 2 illustrate seheinatically the ehanges in the primar.y heart tube with growth.
IT IS A CURIOUS FACT that, despite the
importance of congenital heart disease in
modern eardiology, researeh on the emibryology of the heart holds little interest for eardiologists and clinical investigators. The reasoni
for this cannot be that all cardiac developnment problems are solved, for there is seareely
a single form of congenital heart disease the
developmental neclhanism of whieh is coi1fidently known, and many aspects of normal
heart development are still obseure. Most
embryologic research in the past has been concerned with early stages of cardiac development, up to the time of closure of the initerventricular septum. But this happens durin:og
the first maolnth or so of fetal life, amid we are
in virtual ignorance of what liappeiis to the
heart during the succeeding 8 maonths of fetal
life. That cardiologists have not taken part
in embryologic research might be of only
passing interest were not classical emiibryologists turning away from organi differenitiatioti in their research toward mneh earlier
stages, toward cellular and mnolecular embrvology. If we are to make progress in our
understanding of the later developimental
mechanisms responisible for congenital heart
disease, clinical investigators will have to
provide it. It is in the hope of demonstrating
that cardiac embryologic research is an appropriate and rewarding field of research for
the clinically oriented investigator that the
following is written a elinieian's view of
humBan cardiac development.
Fronm the morphologic point of view, cardiac development has two aspects: one is the
development of the flow pathwavs of the heart,
and the other is the developmnent amid differenitiation of the substance of the heart, its mvoeardiunm, conduetion tissue, conneetive-tissue
\Vork doine dluring tihe teiiure of a Cominoimx ealth
Funi-d Fellowsship.
756
Circulation, Voltme XXV, May
1962
757
EMBRYOLOGY OF VENTRICULIAR FLOW PATH HYAYS
STAGE
Streeter Age - Xi
(23-24 days)
Embryo size -2 mm.
Heart size -.6 mm.
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STAGE 4
Streeter Age - XVIII
(37-38 days)
Embryo size - 1S mm.
Heart si ze
- 2.5 mm.
STAGE 2
Streeter Age - Xill
(28-29 days)
Erbryo size 3.5 mr.
Heart size - mm.
STAGE 3
Streeter Age - XVI
(32-34 doys)
Embryo size - lOamm.
Heart size - 2 mm.
STAGE 5
Streeter Age - XXII
(about 50 days)
Embryo size 25 mm.
Heart size - 3 mm.
-
Figure 1
Geometric schema of the evolution of flow surfaces in the primary heart tube. The substance of the heart is not shown. Flow surfaces are rectangular to make directional
changes easier to visualize. Measurements below each drawing indicate dimensional
changes. Atria are shown only in stage 1; for subsequent stages, the line of atrial
attachment is shown by dashed lines. Trabeculated regions join the primary heart tube
over dotted areas. The sixth schema shows leftward rotation of the heart a't stage 5,
with the frontal view of the adult cardiac silhouette drawn around it. The interrventricular canal can still be seen at this stage, but is much narrower than this drawing
would indicate.
When the heart is at the stage of a gently
coiled tube, the first important event to take
place is trabeculation. This fragmentation of
the cellular mantle (well shown in figure 3),
first appears in the third week of life, when
the fetus is barely 2 mm. in length. It takes
place in two well-defined zones of the heart
tube, separated by a nontrabeculated portion.
The two zones will become the two ventricles
(the dotted areas of figure 1) and the conduit
between thenm the interventricular canal.
Growth is vastly greater in trabeculated thani
Circulation, Volume XXV, May 1962
nontrabeculated regions, and in the adult
heart the trabeculated regions accotunt for
well over 90 per cent of the total ventricular
mass and give the heart its shape. The nontrabeculated regions shall be represented by
the "smooth" distal septal surfaces of each
ventricle and the connective-tissue structures
of the heart, such as the valve rings, leaflets,
and chordae tendineae. At this early fetal
stage the two ventricles function in series,
while in the adult heart they operate in
parallel.2
75S
GRAN'I'
/
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3
Figure 2
fl/o srfatesr in thtI)tprinJar.q heart tea0 ni from wiv thin. Stages 1I
It-olftion of tht
i, 4, and 5 of' figucrec 1 aire sho:wn. Tie surfaces rt madW sometwhat rectangular to assi4s
in visuali--ation. No effort has eun mat/de to fgilve coin Piete dimnitiniojonl atcuracy, aind
these drunin0es mtuSt be conslidrfed schematic. Fr etcah view, the trabec-eated rtgion of
th?e left vtntricle eiid thle centradl tldl of the inlterventrirular canal have beten removed.
rThedi is alnothev (liffei enetf e betwveenr the tea
beculated and(I the iioiitvrabheculated regyionis of
the primary heart tube. C(ardiae jelly thickly
lines the noitrabeenlated regioni, whIle in trabeculated regions it is mnuch sparser and sooIn
vanishes or- becomes incorporated into eellulai
substance.l
Onie wotnders if the cardiac
jelly may riot in some way proteet the cellular
manitle fromTn a digestant or other substanice
t-liat fragmen-its t-lhe cell nmfasses, leadiing to thle
t l)eeulat ioll. I'v vietfic, of this disruption,
thwe celluilar surfaice a,Irea exposed to eirculating bloodl is greatly increased in the trabeculatedl areas. Perhaps this in part accounts
for the vastly greater (cellular growthi of thlese
regionIs.
The architectural changes ini the p)rimary
heart tube which lead to divided flow atrC'
Circulation, Volume XXV, May 1962
EMBRYOLOGY OF VENTRICULAR FLOW PATHWAYS
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schematized in figures 1 and 2. It is to be
emphasized that the mnajor events leading to
partitioning of the tube take place during
only a 2-week period at the elnd of the first
month of life, when the heart is barely a
millimeter in its largest diameter. Indeed,
by the end of the fifth week of fetal life the
heart has an external shape and a position
in the chest identical with that of the adult,
when the fetus is barely a centimeter in
length and the heart no bigger than the capital letter that begins this sentence.
In general, two architectural changes convert the primary heart tube frolm its first to
its final form: rotation and partitioning. The
rotational event swings the right side of the
primary heart tube (the right ventricle, the
bulbus cordis and the truncus arteriosus)
leftward, like turninlg a page of a book, until
the right ventricle comes to have its adult
relationship, lying anteriorly to the left ventricle, its outflow tract at right angles to that
of the left ventricle and enmbracing the base
of the left ventricle. The fulcrum about which
this rotation takes place lies where the interventricular canal opens into the common
chamber distal to the right ventricle, the
bulbus cordis, as can be seen fronm figure 1.
Doerr7 has described other torsional coniponents of this rotation in greater detail.
All shape changes in the heart must be due
to cellular multiplication, as modified by such
factors as growth gradients, available space,
and perhaps hemodynamic forces. The type
and location of cellular multiplication, which
accounts for the rotation, are not known. In
part, the rapid increase in atrial volume is
responsible, crowding against the prinmary
heart tube.2 Another factor is probably related to the fact that the right ventricular
trabeculation lies on the posterior part of the
primary heart tube. Continued outward
growth of this region would swing the rightward portion of the primary heart tube toward the left. This can be seen by comparing
the upper and lower drawings of figure 4.
Goerttler3 has studied rotations due to differences in growth potential of various parts of
Circulation, Volume XXV, May 1962
759
the fetal heart by mitotic figure counts. Further work along this line should greatly
clarify the source of energy responsible for
the rotation and other embryologic events.
The leftward swinlg of the right side of the
primarv heart tube telnds to increase the angulation of the flow path where the interventricular canal empties into the outflow tract
beyond the right ventricle. Keith4 noted this,
and named the tissue forming the angle the
bulbo-ventricular flange or spur. He thought
it homologous to a similar spur in the heart
of the adult elasmnobranch, where apparently
it is nearly obstructive to flow. In elaborating
his theory of the phylogenetic basis of human
cardiac development, he concluded that in the
human this flange or spur must undergo resorption at later fetal ages, and this concept
gained wide currency for several years.
Kramer,5 however, and more recently deVries
and Saunders,2 have shown by careful reconstructions of human fetal hearts that in man
the angulation is never im-pedimental to flow
and that. rather than resorption taking plaee,
it is the markedly greater growth of tissue
surrounding the flange that accounts for its
seeming diminution in size.
Another major rotational event occurs after
stage 4 of figure 1. A counterclockwise swing
of the entire heart, as viewed from below,
takes place to give it the leftward lie seen in
the adult and shown in the last drawing of the
figure. This too occurs at the end of the first
fetal month, after partitioning is nearly complete. In part it appears to be brought about
by the axial growth of the left ventricle and
in part bv the restrictions of the humani
thoracic cage, for certaill other mamumals with
deeper thoracic cages do not show as much
leftward rotation as is seen in m-an.
The Partitioning of the Heart
The partitioning events that convert the
primary heart tube into a four-chambered
organ with separate venous and arterial pathways have been the most challenging and elu-
sive feature of cardiac morphogelnesis. They
are elusive because many steps are still not
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clearly known. After reading the confident
accounts of septation in cardiology textbooks,
it mnay surprise many that there have beeni
only two studies of ventricular septation at
the time of and after closure of the interventricular septum in which scale reproduction-s
of original human nmaterial were used.5 6 And
there are no published accounts using reconstruction methods with human material of
later events, such as the consolidation of tissue leading to the mnembranaceous septumn, the
joining of the aortic and pulmonary rings,
the development of right and left ventricular
inifundibula, etc. Much more work inust be
done before we will understand cardiac partitioning with accuracy.
A second reason why the problem is an elusive one is that it is difficult to visualize the
three-dimensional properties of the events. All
comnponents in partitioning are multi-relational. For example, the septuin membranaceunn not only fornms part of the interventricular
septum, but it also has important immediately
contiguous relationships with left ventricle
musele, with the aortic ring and two aortic
valves, with the tricuspid ring, with the right
atrium, with the aortico-pulmonary ligament,
with the anterior leaf of the imitral valve, with
chordae to the septal leaf of the tricuspid
valve even with the bundle of His. It is
difficult to reconstruct all these relations in
depicting the developnment of closure of the
inlterventricular canal, and it is impossible to
describe them in words. Clearly this problemn
will require the tools of geometry for final
elucidation.
Four partitional events take place in the
prim-ary heart tube: (1) division of the atrioventricular orifice imito the mitral and tricuspid orifices, (2) elaboration of the mnuseular interventricular septum, (3) division of
the truncus arteriosus into aorta and pulmonary artery, alid (4) elaboration of right and
left ventricular infulndibula. These four
events take place at different regions of the
heart tube, by different mechanismis and at
different times. Yet, with almnost incredible
proprioeeptive aecuraey both in timing ancd in
GRANT
distance they convert a rather simple I ube
into ain intricate four-chamber, two-channel
svstemn. Clearly, there are powerful integrating forces that bring about this precise
interplay of disparate growth mechanisms.
Locating and measuring them, the encoded
genetic imperatives in tissue growth, the mechanical resistive and modulatinig factors, the
metabolic feedback mlechanisms, the balanced
differences between nyoplastic anid fibroplastic
growth, all offer rich opportunities for imaginative research. Doerr' and Goerttler3 have
emiphasized the importance of differential
growth centers in the heart, and undoubtedly
this line of research will bring us closer to
understanding the nmechanisms of the abiiormnal partitioning in many types of congenital
heart disease.
Some of these modulating factors can be
identified. Certainly one of themi. is genetic,
and this is one of the most exciting and active
fields of modern embryologic research.8 Phylogenetic imperatives have received a great deal
of speculative attention in the past, but, since
they do not lend themselves to mneasurenment
or experimentation and by their nature are
remote forces, they are not likely to be more
than inferentially useful.
There are, however, two modulating factors
that appear to be unique for the heart and
lend themselves both to measurenment and experimentation. One is a rather remarkable
difference between trabeculated and nontrabeeulated regions of the primuary heart tube
in their outward-inward growth gradients.
In nontrabeculated regions, cell inultiplication appears to be greatest at the endocardial
surface, with the older cells epicardial in location.' As a result, growth of these tissues is
inwards resulting in invasion of flow pathways. On the other hand, in trabeculated tissues cell multiplication is muainlv at the epicardial level; the trabecular cells are older
and mnore mature than the cortical cells and
they tend to be the first to develop fibrillae
and show striations.' As a result, growth of
these tissues tends to be outward, increasing
chamber and channel size. This explains why
Circulation, Volume XXV, May 1962
776G.]
EMBRYOLOGY OY VENTRICULAR FLOW IATHWAYS
A
tnsBsnm.
iX
_
_
,
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T
D.
EE
ttmm,
F--
ifw
mm
Figure 3
Photonicrograph.s of betlions throulgh: thle atrio utribcualear cancil regf3ion of thle ha110
heart at fire stages of development. Bee)cath each section the degree oa magn?ifi:ttioan
is indiciatedl by th7e length of line repres Wtinig 1 nmn. The absolitte distantwe separatingff
the mitral antd tieiaspic? orifices is essentitilliq the, sonic nii C, DI, tine E. oVote also tfl
sparseness of' car7diatc, gelly over the trc)ibecnlateel re,gina inR B. CJ, cwreiae jell!y; C,
atrioventricilar cushion; M, mitral orifice; T1, tr iciuspd o ifice . A, (arm gie collec lion11
No. 59,23) (2?.5 mim. emIbryqo le-ngth, about 23 daeiyIs old); 1B, No. 83.6 (5)..3 woint., 28 days);
e1aljs);
C, No. 6520 (12 mmii., 31 da
80
Ao. ii? (S, nto., Sc) days); E, No. l72 ( o
into.y
d-ag?s).
is Inuln,nily (11de tvo go\vth of the
t1ontrabecutlated ti ssueS.
Another mnodulating- factor in partitioning,
oif the heart may be hemodynamie, for at
stage 1 of heart development, the lheart is
conltracting-t anid propelling blood. This fac.tor
has two aspecits. First, fL3ronlt the voIllilluetric
point of view, the Iltitnell Of the l)rimary hieart
tlbhe illtcreast'eS ninlch less rl)i-adl tlital th-1e
vohine of tissue enclosing- it; that is, eltannel
awl eliamttber capacities inerease ittore slowly
thlian thle channel and. chamber wall-thick-
p)artition1ng>
Ciroulation, Voliume XXV, May 1962
nesses. In. fact, thle+ ratio of wal1 thickness
to chamiiber volnint-e is nnauy timies greater in
the fetuis thani in the adult. Even at stage 5,
when the external appearance of the hiear t
and its location in the chest ar:e identical
wvith that of the adnlt heart. thle right and
left venitric lilar wval i arcp'ioportionately
illor-e thani twvie cas thick as iii thie adt1lt leart,
ult the chamber, capclities arcl mutclt smaller
fot titat wvall tlitiekness (figurs8 anid 10). At
all stages; of fetal growt It thlie eitt rieilcar insle' mass; is relativel-y greater than ini the adulllt.
762
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in relation to the volume of blood beingo aecommodated. Can this mean that fetal mnvocardium is less adequate in its conitractile
properties and a larger nusele mass is needed,
or that the effective blood volume is relativelv
less in the fetus thain the adult, or that blood
is not a significant resistive factor to tissue
growth? Curiouslv enough the atria represent
a somewhat different circumstance. In the
fetus a mueh larger share of the total intracardiac blood volume is contained in the atria
than in the adult. Furthermore, the atrial
wall is nmuch thinner for the volumlie of blood
it contains (fig. 3 C and D) -anl opposite
circumstance to the ventricles. Mueh work
remuains to be done oni this aspect of human
cardiac development. There have been no
careful studies of the volumetric changes of
the heart during developmnent, and we know
lnothinig about the pressure-flow properties of
the fetal heart.
Henmodvnamic factors probablv also influence heart developmenit by the kineties of flow.
More than 100 years ago von Baer" suggested
that spirallin(g currents of blood flow in the
fetal heart mnay account for the spir alled partitioning of the truncus into an intertwined
aorta and pulmonary arterv. This theory has
gained considerable support in recent years
as a result of the ingenious experiments of
Goerttlermo and the morphologic observationis
of deVries and Saunders.2
The Division of the Atrioventricular Canal
The first partitioning event to take place
is the dividing of the atrioventricular orifice
into separated mitral and tricuspid orifices.
This is brought about by inward growth of two
loosely reticulated fibroblastic tissue masses
from the anterior and posterior walls of the
canal, the anterior (or ventral) atrioventrieular cushion, and the posterior (or dorsal)
atrioventricular cushion. Thev are first seen
in stage 3 of figures 1 anid 2. The two cushions
blend laterallv into the myoblastic tissue at
their bases, and here they elaborate certain
of the valve structures of the two orifices.
Fromn the anterior cushion, a small part of its
rightward margin appears to provide time
GRANT
chordae tendineae that connect the anterior
leaflet of the tricuspid valve to the small septal
papillary muscle, often called Lancisi's papillarv musele. But the greater part of it becomes the nmedial half of the aniterior leaflet
of the mnitral valve. It is important to note
that the chordae for this part of the anterior
muitral valve subtend froii the right side of
the cushion, as shown in the drawing for
stage a in figure 2.
The fate of the posterior cushioln is quite
different. From its left side it forms the
lateral half of the anterior leaflet of the mitral
valve, and fromii its right half it develops the
septal leaflet of the tricuspid valve, as Mall
noted.6 Mall also pointed out that in tlle
fetus the tricuspid valve has only- two leaflets,
one oni each side of the slit-like orifice. One
becomnes the anterior leaflet, and the other the
septal leaflet. Even in the adult heart it requires m-ore imagination than the present
author has to distinguish three leaflets to the
tricuspid vNalve. The line of fusion of the two
cushions to forum the anterior leaflet of the
mitral valve formus a cleft in the middle of
this valve (figs. 5 and 7).
II short, the two eonnective -tissue cushions
have different destinies, and this difference is
seen in certain types of congenital heart disease. For example, derangements of the anterior cushion are commonly seen inl the clinical
syndromes of persistent ostium primum and
atrioventricular communis, for the medial
half of the anterior mitral valve is frequently
abnormal in these cases. On the other hand.
Ebstein 's anomalv appears to inivolve a derangement of the posterior cushion, for the
septal leaflet of the tricuspid valve is alwavs
the displaced valve in this disorder.1'
A most remearkable feature of cushion tissue
is its limited growth capacity. Although it is
able to invade alnd divide the atrioventricular
canal, once this is accomplished further
growth of the tissue ceases, except where it is
ineorporated with myoblastie tissue in elaborating chordae tend ineae. This is demonstrated bv the fact that the width of the
c-ushion niass Awhleln first detectable in earlv
Circulation, Volume XXV, May 196."
EMBRYOLOGY OF VENTRICULIAR FLOW PATHWAYS
763
Table 1
Comparative Measurements in Humaw Embryo Hearts (Averages in Centimeters)
Streeter age group (approx.)
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Approx. Age (in days)
28
No. cases
4
C-R embryo size
.3
Embryo width
.12
Over-all heart width
.09
Length RV (apex to PV)
.03
RV infun-dibular length
.04
Length LV
.06
LV infundibulum
.02
LV diameter
.06
Max. RA diameter
.05
Max. LA diameter
.05
Total LV wall thickness
.02
% Trabeculated
3/4
Total RV wall thickness
.02
% Trabeculated
4/5
Width IV muscular septum
Dist. IVC to aortic valve (or anlage)
.03
Width ant. leaf MV (or A-V
.04
cushion or AVC-IVC distance)
Length IV canal (or dist. aortic
valve to nearest part RV
chamber)
.015
stage 3, remains the same at all subsequent
stages, as noted in table 1 and figure 6. Indeed, even in the adult heart it is apparent
that there can have been little lateral expansion of the cushions, for the mitral and tricuspid rings adjoin; they are no farther apart
in the adult heart than at earliest fetal stages.
As we shall see, the limited nature of cushion
growth potential is one of the most important
single factors in bringing about the curious
arrangement of flow paths that characterize
the adult heart. Evidently the cushions are
equipped with growth capacity only at their
most superficial endocardial surface, and when
these two surfaces of the cushions meet to
divide the atrioventricular canal further cell
multiplication ceases, perhaps because they
have obliterated their contact with circulating
blood.
Failure to recognize limited growth potential of the cushions has led to misinterpretation of embryologic events in the past. For
example, it has often been said that the anteCirculation, Volume XXV, May 1962
xvI
XvIII
33
3
38
2
.8
.3
1.6
.45
.24
.26
.12
.06
.11
.03
.08
.12
.08
.03
2/3
.02
4/5
.04
.05
1.5
.06
.12
.04
.10
.12
.10
.04
2/3
.04
2/3
.05
.05
.04
.04
xxI
50
4
.05
2.3
.6
.3
2.0
.07
.14
.03
.11
.14
.12
.05
1/2
.06
2/3
.06
80
2
5.0
1.2
.6
3.0
.12
.40
.06
.20
.18
.16
.07
1/5
.06
.05
2/3
.1
.05
.02
.01
.06
.05
rior cushion must undergo resorption lest it
obstruct left ventricular ejection, and that
failure to undergo resorption might be the
cause of aortic atresia and subaortic stenosis.
When the cushions are measured at successive
fetal stages, however, no enlargement or diminution proves to have taken place, and instead
it is the relatively greater growth of other
adjacent tissues that make the cushions appear to dwindle in size.
The Formation of the Interventricular Septum
The next partitioning event to be considered is the elaboration of the muscular septum. This has often been incorrectly described
as an "invagination" of myocardial tissue
from the caudal region of the primary heart
tube, and the present author has been guiltv
of using this term in the past." As Streeter'
and others have pointed out, however, it is
instead the marked downward growth of the
two ventricles that creates the septum. The
trabeculations where the two ventricles are
apposed become consolidated into a septum
GRANT
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B
//C
Figure 4
Drawings fromn two wax scale models of endocardial surface of human fetal hearts. A
is at stage 1 of development; B and C at stage 4. In B the model is viewed frontally;
C shows the sante model from the right side. The tricuspid channel leading into the
right ventricle can be seen in C. The rotation of the right limb of the primary heart
tube can be seen by comparing the tuwo models. The "knee" where the bulbus cordis and
the truncus meet is best seen in B and C. Tissue on the posterior region of this "knee"'
is in direct continuity with the tissue that sepairates the mitral and tricuspid orifice.
A. drawn directly from the wax nmodel of No. 836 in the Carnegie collection, prepared
by Mr. Heard. B and C, drawn from an illustration in the publication of de Vries and
Saunders.2 For this illustrationa both external and flow-path wax models tere made
from embryo S by Dr. de Vries.
but the crest of the septum is stationary,
forming the anterior, posterior, and caudal
margins of the interventricular canal.
That the canal is not " invaginated" by the
septum is demonstrated by measuring the
diameter of the canal at each stage of fetal
growth. There is no change during the first
five stages, a period of time during which
the ventricles have increased four- or five-fold
in length (table 1 and fig. 6). At the end of
stage 5 the canal appears as a thin, threadlike channel across the septunii although it
Circulation, Volume XXV, May
1962
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AV
Figure 5
(n/l(pI
frpi ior tn obllit erationi cit stage
7. The section Shiown i's Jron/ slide 'I Sf tibryoi No. 2-)0,2 ]/y1/
(I a't
ri/-eyie colleetioni
(21 nm. ii?J length, itbout 39 la/ys ol(). 7Ii small (drwiniig oni the leJt iiidui(/tes the plaIne
i/i /1/nhch the h(0a/t /u1/s sitiot1 d. Th/ i//t /C
rI)'//t/ric/lla (C//i/il Joi//s the right and left
treitricles. T'he ul)l1b)vs cordis (or right /e/nt/ic//l(/r i//'f/mitdib//lilfl) is (list//i to the c(/iinl
in th;is seCtio?. _p)V, pl/tno0/ir,/ arci/c; .,Ilo an/tie Inn/en; Pa, pitl/t/o/i/ar. artergl i/umen/
LV
leVft re/tricle; L,4 left atriv m; MV, 1//iterior
AYJ, aortic /calre; RV, right ,trie;
lec/flet of the mi/rtil til/e. Mcg/fiiifictitimi 5OX. (The Som/Ie heart is st'101c CagCi/ inl
t1iC lowcer drawiing of figure 10.)
765
7 G ;5
C(ircvhitiow, Volume XXV, Maqy 1962
the in ferc / r/cW11
tal
Photomicrograph d emo-strtatl Mg
766
GRANT
EMB
16
14
12
#1-
C
w
10
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w
Overall
Heart
08
z 6
4
RA
LA
INFUNDIB
2
-w
~~~~~.-
_- am
mm
__________________--IVIVC-MS
,
0
I
_
-S-
-
_
_
_
I
-I.
I
2
3
4
CUSH -AMV
Mom.,,
5
AGE GROUP
Figure 6
Rate of increase in certain linear measurements during growth of the fetal heart. Measurements
were
made
from
16
embryos from stage
2 to
O
in
the
Carnegie
collection
ancd
cited in table 1. For six of the embryos, wax scale models wvere available. Dash lines,
fibroblastic structures; solid lines, myoblastic structures. IVC-MS, diameter of the
interventricular canal; CUSH-MS, width of the anterior atrio ventricular cushion and
a corresponding measurement of the anterior mitral valve in later stages. It should be
emphasized that these are linear measurements, a.nd therefore do not fully reflect the
considerable growth of myoblastic tissues. The increase in ventricnlar mass would more
acccurately be represented by the cube of its linear measurement.
are
still has the same diameter as in stage 1. The
photon-iicrograph in figure 7 shows the canal
at about this stage, just before final attenuation and obliteration (the same heart is also
showni in the lower drawing of figure 10).
The conduction tissue of the bundle of His
lies on the dorsal surface of the canal, and
its superior surface is formed by the fused
atrioventricular eushions.
The canal is not "replaced" by the mnembranaceous septum, for the canal lies at the
edge of the cushion material that is to form
the mnembranaceous septum. In view of the
extrenmely tiny diameter of the interventricuCirculation, Volume XXV, May 1962
EMBRYOLOGY OF VENTRICULAR FLOW PATHWAYS
767
2
/
3
4
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(
I\
Figure 7
Schema of the primary heart tube showing the distribution of the fibroblastic continuum
respor sible for partitioning (dotted area). Schemata 1, 2, and 3 are at stages 2, 3,
and 4 of figure 1. Schema 4, the a,lignment of the four orifices and their fibrous connections in the adult heart, as viewed from the ventricular base with the atria removed.13
WVhere the fibroblastic process invades and divides the truncus, it has become called the
truncal ridge sy stem in classical embryology; where the process invades and divides
the atrioventricular canal it has become called the atrioventricular cushion system. Note
that the mitral and aortic orifices are aligned along the major axis of the fibroblastic
region. When division is complete and further expansile growth of the fibroblastic region
ceases, the tissue between the aortic and mitral orifices wvill become the anterior leaflet
of the mitral valve; the tissue between the aortal and the pulmonary artery at their
orifices will become the pulmonary-aortic tendon; and the tissue between the tricuspid
orifice and the mitral and aortic orifices will become the septum membranaceous and
certain parts of the tricuspid valve system. In the adult heart the four orifices hazve
essentially the same spatial and flow relationships with each other as in schema 3.
lar canal at all stages of fetal growth-never
more than 0.5 mm.-it is difficult to consider
" failure of the interventricular septum to
close " as an adequate explanation by itself
of any form of ventricular septal defect seen
clinically. The size of the interventricular
canal just prior to obliteration reminds one
of Galen's doctrine of the "invisible pores"
connecting right and left ventricular chainCirculation, Volume XXV, May 1962
bers, the pre-Harvey explanation of the circulation. Since normally the canal is never
more than half a millimeter in diameter, one
wonders if there may not be adult hearts in
which, by careful dissection, this tiny channel
can still be detected, vindicating Galen 's
doctrine.
The final obliteration of the interventricular canal involves only its more rightward
NAWI
(7 RAR
768
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Figure 8
of riqortic., t) skat the buibar aspelt of
tb1ijn1l
tim
fthetfetoill of the tightift rticile
f /u bet e au
a) frtilotiinft. In (littl th flair
Onhi
nitt.(n0 nontti)tlt niotid4tslei ritige can be seien (merging
7itis i)rt(7t r
ot
oe
nml; this is (tlled t/he et ft b)0)0r P
/ nii'
licut
ralI/ot u ep,ifp tiii sit iftt nit(;I/t eirtc)
cin tes.nlar
rO// (it c elasseitical Ce nib :ifedeol,yj. Ore th/ue ri/t, this tnge has tero7re ii teo teh
elt itetil tas I/tf ato crotor band ont Tantiler7's tritlt7 al?a septomorgintlits the mnost
proai''i l (in a flowc sensct) ilar/t otf the lf/itibtr n/lst alaulrt. On the right) th/ 1tin-o trtneol
tr
ritget s (fib rnbalt,u tissne) Iire fiiseti til1 the nag to the cshi/i nns, /tn it (i fit)ros 1act,
the pilt/io)ntlyi/ iortie bigonwt'itot,wiie1 e'tctids froan the pitlmittotarg antdc tioitit ri1/95 tt the
??elMiY
bro)iiiC etnt tptiit?t. I (tl be sitf7 ti/u both bitlbtii attd left t ttteit t' ittitiele;
it conot lie seen through
ieeist ies i't on this te tielOt. I/ire rnt-teiot leaiflet of thte mttitrtil rOe
so
2itcnfltor cntil oti t/it rig/it. Tihe rig/t atritinb is /ttiho toIt ift oaloietl sti
ti-e il/li rtlt
17/t1l Iti hc r littionls/lips tf I/it itiemitlwirtt oientis septtm call be better vistoli ed. J, tictlt/
ritdges ; 2, t interio t- iilfi tetil- eitiii t itsch int ; 3, /posterit/i irovtfen I uhieitoli.;e. t
eteIse bettetlviet "sitseit(l" tnd "pt/rietffl' com ponenits of the bitibor mitset.ltattitre'; this
It; iiprseu tit a litte of ftsion of tleo b1l)/ai 1rtitiges, ilthi/,ho
(TeSeo itts outie I/h nng/i t o5
r Iti tot corrr'te L pntttotiit i/
lftd/i itee/lttite itt/el ttit'iog1offic gfroi?itlds is tuetariq/ ierta
Rift1hI itti/to lalo
!Imifl
oor)tli 7J}b1y(mc
bot
{21/
I/etc of
s tIa ge s
o
c
*9
;
f9
}RP2
1
'1
?t1fc
. antI 1
Mid
1
cMI
wh
ea1g
if,
qiJRt,
At
'f
l
{1
l?Il?tf
(;,m-l),ncmssptn9 lo'igisrgh tidO.
lart. For the greater parft of its leng-th, the
iuitervenitrictzlar ('anal is ineorporated into the
left ventricular clhamhber to form tile infuiidibului-ni of the left ventricle, as ean be seen
iii figures 2 anid 9. MAall6 recognized that the
ii-ter-veitrieular en ua.l is converted into an
ii;fundihuli.in foir t1he left vt'ultriclec but subsequent winiters oni humiani c,urdiatc emn;brv ologv
lave overlooked il. Exiat]>tlv e same sequeuet'
of evenlts takes plate i tlhe chickhleart.1'2 I
is ofteni difficult to recognize a left venitricular- iiftuadibultliun iii the adul.t Ilniiani heart
etiu
uniiless thi- e-dimncinsional methods of dissee
tion are used. Inl the fetal hlutmaui heart, hoNwc c,l)
befor c the tracbeulated regions of the
left ventricle have grown7 greatly, the infundibulum is (uite striking: a snmooth-walled,
tubular region encomnpassing nearly hialf the
chanbetr.
It is ilnpttrtiitm foar the cli.niciant to unde'rstand how tlle left cuiit rhiulao inufundibulum
is formed becamst'e it expklias sev-eral strueturna] features of the normrlal and abnornal
adult heart. For example, earlier it was
Circulation. Volume XXV, May 1962
p
A
T
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A~~~~~~~~~A
B
Figure 9
The molding of the bulbus cordis. Above, drawing made from the illustration in Mall6
of a wax scale reproduction of the heart of embryo No. 353 in the Carnegie collection,
magnified 5OX. The heart is visualized from the apex. The interventricular canal is
seen as relatively wide at this stage; the cleft of the mitral valve is evident. A, aorta;
P, pulmonary artery; M, mitra,l orifice; T, tricuspid orifice; B, bulbar ridge; S, muscular
interventricular septum. Below, tracings from photomicrographs of embryo No. 492
of the Carnegie collection, magnified 30X. Sections are coronal, with A more caudal,
and D more cephalad, just short of the two atrioventricular rings. This is an older
embryo than above, as the relatively smaller diameter of the interventricular canal wi'ould
indicate. Solid black areas indicate the frankly trabeculated regions, but myoblastic
tissue is not confined to these black regions, for it was thought useful to indicate the
distribution of nuclear densities. The bulbar ridge can be followed in A, B, and C.
The left ventricular infundibulum is shown in C and D; aortic valvular elements are not
encountered until several sections cephalad of D. In B it can be seen that the portionl
of the interventricular canal which is finally obliterated is only its most rightward portion.
769
Circulaiion, Volume XXV, May 1962
770
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:8W*,ijt;.
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Circulation, V7olumeu XXV, MVay 1962
EMBRYOLOGY OF VENTRICULAR FLOW PATHWAYS
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pointed out that the anterior leaflet of the
mitral valve is formed by fusion of a rightward portion of the ventral atrioventricular
cushion and a leftward portion of the dorsal
atrioventricular cushion. This in itself causes
a large portion of the interventricular canal
to become an infundibulum to the left ventricular chamber (fig. 2) and it explains why
the mitral leaflet has such a curious angle
with respect to the plane of the interventricular septum. Furthermore, the cushion
material is continuous with the aorta, and
this explains why there is no musculature
separating the mitral and aortic orifices. Indeed, from a muscular point of view, it could
be said that the left ventricle has but a single
orifice (the mitral-aortic orifice) which is
partitioned by the anterior leaflet of the mitral valve.
For another example, the interventricular
canal is almost at right angles to the long axis
of the developing left ventricle, as shown in
the figures. As the canal becomes converted
into an infundibulum this sharp angulation
is still evident, and it explains why in the
adult heart there is a nearly 90-degree bend
in the left ventricular outflow tract where it
leads into the root of the aorta. This sharp
angulation accounts for the muscular pseudo-
stenosis of the left ventricle in cases of left
ventricular hypertrophy.'3 Furthermore, the
angulated position of the aortic root explains
why, when a ventricular septal defect involves
musculature inserting on the aortico-pulmonary tendon, the aorta faces into the right
ventricle, accounting for so-called "over-riding" of the aorta in certain of these cases.'1
It also explains why in cases of atrioventricular communis the chordae tendineae of the
medial half of the mitral valve may insert
on the crest of the ventricular septum or
even on the right septal surface.
There is still much to be learned about the
manner of development of the left ventricular
infundibulum. Unquestionably it is closely
related to the development of the right ventricular infundibulum. For example, in certain cases of muscular subaortic stenosis, the
outflow tract of the right ventricle is also
abnormal, and perhaps certain instances of
"Bernheim's syndrome" are actually congenital anomalies on this basis. Also, in ventricular septal defect there must be an abnormality in the infundibulum of both right and
left ventricles for the defect to extend across
the septal wall. Understanding the way in
which right and left ventricular infundibular
musculatures become coupled will be crucial
Figure 10
Gross appearance of the fetal heart to show tissue mass, right ventricular views. (The
earlier schemata of figures 1, 2, and 8 show only flow surfaces of the heart and do not
attempt to show tissue mass. For example, in the upper drawing of the present figure
the pulmonary artery and aorta are completely divided (stage 3), but their tissue masses
are not separated als the earlier schemata of this stage would suggest.) Above, the tissue
continuity from aortic anlage to the atrioventricular cushions is shown. The projection
here is as if a right-angle section were removed from the right ventricular free wall.
Note the remarkable length of the tricuspid canal. 1, pulmonary valve anlage; 2, aortic
valve anlage; 3, left ventricular infundibulum; 4, left bulbar ridge; 5, interventricular
canal; 6 line of fusion of atrioventricular cushions. Drawn from slides and bromide
projections of embryo No. 6520 of the Carnegie collection. This embryo is also shotwn
in C of figure 3. A drawing of a wax scale reproduction of the flow surfaces of this same
heart is shown on page 176 of Streeter's publication.' Below, gross appearance of the
heart shown in figure 5 to demonstrate the size and lie of the interventricular canal.
The ventricular wall is much thicker for the chamber capacity than in the adult heart,
and the tricuspid valve is grosser, denser, and of rather tubular nature. Both drawings
were made by plotting from serial microscopic sections relecant landmarks on Cartesian
coordinates, the scales of which were adjusted to microscopic section thickness and fetal
size. Parallax lines had been established by personnel of the Embryology Laboratory
in earlier years. No effort is made to depict details of atrial internal structure, but the
outer dimensions of the atria are accurate. Magnification is indicated by the length
of the 1-mm. line for each drawing.
Circulation, Volume XXV, May 1962
771
7 72)
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for understanding the mechanism of forimation of these defects, and this is an aspect of
cardiac developmnent that has never been
studied.
Partitioning in the Truncus
and the Bulbus Cordis
The third partitioning event is the divisioin
of the truncus arteriosus into an aorta and
pulmonary artery. This is the nmost easily isolated of all the partitioning events and is
perhaps the best understood, from a muorphologic point of view. Two fibroblastic ridges
appear on opposite walls of the truneus, extending from the branehial arch system to
the region where the semilunar valves will
appear. The two ridges grow inward toward
each other along a slowly spiralled 180-degree
course and fuse to form the two great vessels.
Other aspects of this partitioning event will
be returned to later.
The most obscure and least studied of all
partitioning evenits is that which takes place
in the bulbus cordis, the region of the priimary heart tube, which extends from the right
ventricle and intervientricular canal to the
beginning of the truncus, where the semilunar
valves will be elaborated. In mnost discussions
of partitioning, the bulbar events are eonsidered to be simplv extensions into the bulbus of the same process that divides the trun(eus, with two bulbar ridges considered to be
continuous with the truneal ridges mnentioned
above. This is almnost certainly not correct.
In the first place, the bulbus cordis is mvoblastie tissue (but niotntrabeculated), while
the trumieus is fibroblastic, amid, as was pointed
out earlier, the growth of the two types of
tissue is quite different. In the second place,
bulbar evolution takes plaee after truncal
division is entirely completed. Third, the
proininences that are called bulbar ridges
never become fused. Fourth, Kramer and
others2' 5 have shown- there is no physical continuitv between the truleal ridges and the
bulbar promineniees; the break in con-tinuity
lies imimediately below the region where the
semilunar valves will appear. In fact, close
study of the bulbar events indicates that no
truie partitioning takes place here, if by par-
2GRANT
titiolillg we mean the invasive dividiiig of a
sinogle chainnel into two channels. This is important beeause it conforms with the generalization made earlier that only fibroblastic tissue growth can invade fluid pathways, and
that all truly partitioning processes in the
primary heart tube are attributable to fibroblastic tissue growth, none to myoblastic
growth.
The following description of embryologic
events in the bulbus in man is based upon
study of human embryos in the Carnegie collection. Because of time limiitations, it was
inot possible to make scale reproductions of
the hearts, which are indispensable for accurate understanding of morphologic events.
Therefore the conclusions drawni must be regarded as tentative alid at best only schemnatically correct.
To understand the bulbar sequenees, we
must first return to the division of the truneus. At the time of truncal partitioning there
is no sharp histologic separation (by ordinary
light microscopy) between the myoblastic
tissue of the bulbus amid the fibroblastic tissue
il the region of the truncus where the semilunar valves will develop. Nevertheless, subsequent events make it quite clear that
fibroblastic processes are responsible for the
formation of the aorta and pulmonary artery
and for the semilunar valves, valve rings, and
the aortic-pulmoniary ligament. In the adult
heart, this ligament is continuous with the
ineibranaceous septum and, as the aortic annulus fibrosus, it provides an insertion for
both bulbar and left ventricular mLusculature
(fig. 1).
Here is one of the most perplexing steps
in human cardiac development. The aortic
ring amid its coniiective-tissue structures develop from a region of the primary heart tube
that is far out along its terminal limb, the
region forming a "knee" in the outflow limb
of the tube, as shown in the lower figure of
figure 4. Yet, in the adult heart, the aortic
ring and its structures are attached to the
irnfundibulum of the left ventricle. How can
a tissue originating so distally in the primary
heart tube end up attached to the left yenCirculation, Volume XXV, May
1962
EMBRYOLOGY OF VENTRICULAR FLOW PATHWAYS
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triele? The most widely held explanation has
suggested a shortening or resorption of the
bulbus cordis. But such a theory leaves unexplained that there is fibrous tissue continuity in the adult between the aorta and the
anterior leaflet of the mitral valve.
The explanation for this event becomes
clearer when at each stage of heart development the distance from the aortic anlage to
the interventricular canal is measured. There
is found to be no shortening of this distance;
in fact, it remains nearly exactly the same
from stage 2 through stage 5, 0.4 to 0.5 mm.
This finding indicates that there is a tract of
tissue of exceedingly limited growth potential
extending from the region of the truncus
where the aortic valve will develop to the
interventricular canal. This tract is continuous with or a part of the ventral (anterior)
atrioventricular cushion, which has already
been shown to have a limited growth capacity.
The tract can be visualized from the lower
drawings of figure 4. The anlage for aortic
ring structures lies on the posterior region
of the "kneee" of the truneus, and it can
be seen that this region is in direct tissue continuity with the ventral atrioventricular
cushion, the tissue that separates the mitral
and tricuspid orifices. The continuity between aortic valvular tissue and atrioventricular cushion tissue is also well seen in upper
figure 10.
The limited growth capacity of this tract
of tissue is evident when the same region is
studied in the adult heart. For example, in
the adult heart the aortic valves do not insert
directly into left ventricular musculature.
Instead they are separated from the musculature of the infundibulum by one or two mm.
of fibrous tissue, called by anatomists the
v 'aortic vestibule" or "aortic unprotected
area." This short span of connective tissue
can be traced to the fibroblastic tract mentioned above, and it has nearly the same dimensions in the adult heart as in the fetal
heart of stage 4. For another example, in
the adult heart two aortic valve leaflets obliquely cross the mnembranaeeous septunm.
Circulation, Volume XXV, May 1962
773
Their line of insertion on the septum is only
two to three mm. from the apex of the membranaceous septum, the site where the interventricular canal is last seen before obliteration in stage 5. On measurement, the distance
from the aortic leaflets to the site of obliteration of the interventricular canal is roughly
the same in the adult heart as the distance
from the aortic anlage to the interventricular
canal in stage 3. These measurements are
listed in table 1, and certain of them are
plotted in figure 6.
The pulmonary ring arises from tissues on
the anterior surface of the "knee" of figure
4. It has no direct tissue continuity with the
atrioventricular cushion except in that it is
attached to the aortic ring. The remainder of
the circumference of the pulmoonary ring adjoins t-he myoblastic tissue of the bulbus
cordis. The myoblastic tissue continues to
grow during the fetal period, swinging the
pulmonary ring on a fulcrum (its point of
attachment to the aortic ring) as far as possible. This brings the pulmonary ring into
essentially the same plane as the aortic, mitral,
and tricuspid rings.
Here, then, is the explanation for the remarkable circumstance that all four orifices
of the adult heart are in direct fibrous continuity with each other, unseparated by muscle.
The two atriovenitrieular orifices are created
by the invasive growth of the two fibroblastic
atrioventricular cushions; the two semilunar
orifices are created by invasive growth of the
two fibroblastic truncal ridges; and these two
invasive processes are in direct tissue continuitv with each other. When the two cushions and the two ridges each fuse (in the
fourth fetal week), their expansive and invasive growth history comes to an end, and
there is no further growth at their points of
continuity. The muscular part of the heart
continues to increase greatly in size, but the
distances between the four orifices at their
points of contact are relatively the samie in
the adult heart as they were in the fourth
fetal week (fig. 7).
W\\e must now turn to the evolution of the
7174
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nontrabeculated musculature that makes up
the bulbus cordis. With the downward growth
of the two trabeculated areas forming the ventrieles, there emerges from the septal surface
of the right ventricle a nontrabeculated myoblastic prominence that extends from the trabeculated zone of the right ventricle to the
base of the ventricle, where the membranaceous septum is appearing, and superiorly toward the pulinunary ring. It can be seen in
the drawinigs of stage 4 anid stage 5 in figure 8
and from the projections in figure 9. It has
beenl called the left (or sinistro-ventral)
bulbar ridge. Most accounits also describe a
second bulbar ridge-the right or dextro-dorsal ridge. Such terminology, however, is muisleading, for it suggests that the two ridges are
paired in the same sense that the two truncal
ridges are paired in developmental events. This
is not at all the case, for the two regions of the
bulbus have altogether different origins and
destiiiies. While the so-called left ridge is
myoblastic, giving rise to bulbar miusculature,
it plays no part in partitioniiig of the aorta
from the pulmonarv artery. On the other
hand, the so-called right bulbar ridge is fibroblastic, occupying the tract of continuitv described earlier, which exteiids from the aortic
ring to the ventral atriovelntricular cushion.
It becomes the aortic-pulmonary ligament, a,
fibrous structure that is the lowermost site of
separation of pulmoniary ai tery fronm aorta
and a tenidon for insertion of both left ventricular and bulbar nmiuseulature. In addition, the right ridge plays an important role
in the elaboratioll of other right v!entricular
connective-tissue structures, such as certain
of the leaflets of the tricuspid valve.
It is not surprising that the bulbar ridges
have often been a source of confusion in interpreting embryologic eveents. There have
been few studies of these structures in the
human embryo, and only one that utilized
seale reproductions. This is Mall's account of
nlearly 40 years ago.6 While Mall 's text is
often difficult to follow, the conelusions he
drew are essentially the same as those of the
present study. In fact, the upper illustra-
GRANT
tion of figure 8 is drawn from ani illustration
in his publication.
An important topographic structure to
emerge from the left, myoblastic bulbar ridge
is the nmoderator band and its attached anterior papillary muscle. The ridge continues
to the base of the heart and here it terminates,
inserting on the membranaceous septum and
the aortic-pulmonary ligament (fig. 8B). The
ridge with its moderator band becomes the
trabecula septomarginalis of the adult heart.
The trabecula is a useful topographic landniark, for it divides the right ventricle into
an inflow and an outflow portion, and it
separates the part of the right ventricular
musculature that is bulbar in origin from that
which is trabecular in origin. The right bundle branch of the interventricular conduction
system runs along the inferior edge of the
trabecula to the imoderator band. Where it
imeets the membranaceous septum is the point
of final obliteration of the iiitervenitricular
canal. But by the time the bulbar ridge is
well differentiated into its component parts,
the growth of the ventricular heart has beeni
considerable and the canal is now a relatively
thin, thread-like conduit. Whether final obliteration of the canial at this stage is acconmplished by the trabecula, which bridges over
it, or by fibrous tissue from the adjacent membranaceous septum, or by umusculature from
the inifundibulum of the left ventricle is difficult to determine, amid perhaps not very
meaningful.
By stage 5 of figure 1, the connective tissue
is becoming more sharply differentiated from
nmuscular tissue. The trabecular systems of
both right and left ventricles are well advaneed with chordae tendineae, trabeculae
carneae, and papillarv mnuseles well defined
(lower fig. 10). The cortices of the two ventricles show clear-cut nuclear orieimtation presaging the lie of muscle bundles, but no such
fiber orientation can yet be made out in the
bulbar musculature by ordinary light microscopy. Differentiation of bulbar musculature into its characteristic architecture does
not appear until later.
Circulation, Volume XXV, May 1962
EMBRYOLOGY OF VENTRICULIAR FLOW PATHWAYS
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Discussion
The most unexpected aspect of human cardiac development to the clinician is probably the remarkably early age at which the
heart develops a shape virtually identical
with that of the adult. By the end of the
sixth week of fetal life, when the embryo is
barely a centimeter in length and the heart
no bigger than a match head, it has all the
external and most of the internal gross appearances of the adult heart (fig. 10). At
this age, the external ear is just beginning
to appear as a fold of skin, the bronchus has
not developed beyond its secondary branchings, and, in the kidney, Malpighian corpuscles have yet to appear.
Why does the heart develop a mature architecture so much earlier than other organs.
Indeed, it might seem to be in advance of
fetal needs, for the right ventricle and pulmonary artery are completely differentiated
8 months before a pulmonary eirculationi is
required. From the course of subsequent
events, it is almost as if some resolute designer
of hearts, proud of his achievement in developing a four-chambered heart in only 6
weeks of fetal life, suddenly realized, " I've
made a dreadful mistake! I've made a heart
capable of circulating blood through the
lungs, but the lungs are not ready. I must
devise some way to unload the right heart."
And to this end he punched a hole in the
already virtually closed atrial septum (the
foramen ovale) and delayed closure of the
ductus arteriosus far beyond the time when
other cardiac and major arterial structures
have matured. As a result, large portions of
venous return bypass the right ventricle and
lungs until that time, nearly 8 months later,
when the fetus is ready for air breathing.
But organ differentiation is not random.
There are two considerations that explain the
remarkably early shaping of the heart into
its adult form. One is a simple statistical
consideration of "shape'" as a property of
growth. The other relates to the circulatory
physiology of the fetus.
First, we must understalnd what we nmean
by the word "shape." In the development of
Circulation, Volume XXV, May 1962
775
any organ, three properties change: its age,
its size, and its shape. The first two are easily
measured and expressed in numbers; the
third is not. For, while we can say one fish
is twice as old, or twice as big as another,
we cannot say it has twice the shape of another fish.'4 In general, most changes in size
and shape in a developing organ are related
to cell multiplication. WVhen in a given orgain
the cells from all parts of the organ multiply
at the same rate and in the same direction
with respect to the axes of the organ, its size
will increase but its shape may not change.
But when there is a variation in rate, or direction, or polarity of cell multiplication at
different regions of the organ, both its size
and its shape will change with growth. It
has been shown that shape "increases" under
these circumstances.14 Now suppose that a
given organ consists of 10 growth zones, each
with a different rate and direction of growth,
growth rate than the others. At early stages
of growth, all 10 zones will participate in the
but one of these zones has a vastly greater
increase in shape and size. With 10 axes
along which this is taking place, shape will
increase very rapidly, perhaps faster than
size. But cellular multiplication is an algebraic function, and the zone with the faster
growth rate will soon dominate further
changes in size and shape. With growth now
taking place along a single axis, size will
continue to increase, but the rate of increase
of shape will rapidly decrease, approaching
a stable form.
From considerations such as these, various
methods have been devised for measuring
shape as a property of growth independent
of size.16 It has been found that " shape "
follows certain laws during growth just as
size does. For example shape tends to be a
continuous function of age. While shape increases with age, the rate of change of shape
falls off progressively in time as a stable
shape is approached. Thus shape tends to
have an S-shaped curve, just as size does, and
sueh a curve has been calculated for the chiek
heart.15 Finally, those shape changes that
i76
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take place along a single axis tend to be
simply graded; that is to say, it is as if the
shape were drawin oni an elastie sheet of
tapered thiekness, thicker in the direction of
growth. The shape changes that oceur under
these circumstances are as if the elastic sheet
were stretched. Such shape change MIedawar14
has termiied "m-nonotonic.
The shape changes of the hunaii heart appear to obey these laws. By the third week
of fetal life the heart has beconie a simple.
gently coiled tube. During the iiext 10 days.
through stage 3 of figure 1, the heart rapidlv
increases in shape. Thereafter, shape increases
more slowly, and after stage 5 further
changes in shape becomie mnore and more difficult to deteet. On the other hand, size coiitinues to increase rapidly throughout fetal
life, decelerating during childhood, and not
becoining stable until adulthood is approached.
What can be said analvtieally about an
organ in whieh shape becomes stable very
early, but size does not beconie stable uniitil
nueh, mnueh later? One possibilitv was imlenltioiied earlier. Perhaps at the timne of rapid
increase in shape, the primary heart tube
conisisted of many zones with different growth
rates and directions, but one zone had a vastly
greater growth rate than the others. (In the
cases of the heart, it could be two zones, side
by side, with similar growth rates and direetions-the two trabeculated regions.) But the
growth rate of this faster zone would have
to be tremendously faster than other zones
for it to dominate cardiac shape so earlv.
Linzbach'7 has measured total heart weight
ancd total body weight in man at each age
from earliest fetal weeks to adulthood. He
has found that the inerease in heart weight
bears a relatively simple relationship with the
incerease of total body weight, and it appears
that this relationship is not greatly different
from that of other humiani orgaiis. It is difficult to see how the heart could have a zonie
with a growth rate so munch faster than other
zones that it dominates size and shape within
the fir-st month of fetal life, and yet not eause
the heart to inerease in size at a rate imueh
greater than other body organs.
GRANT
There is one other possibilitv. It is ('OInceivable that certain zones which play an
importamit part in growth during the fourth
fetal week have a mnuch shorter growth history thani other zones; that is, they reach
their growth plateaus mluch earlier, perhaps
during the fifth week of fetal life. Under
these circumstances, the zone that doininates
further changes in size anid shape need iiot
have a growth rate muelh different from other
parenelhymn-al tissues.
The seconid possibilitv fits closely with the
morphologic measuremnents described earlier.
It was shown that the fibroblastic regions of
the primary heart tube, especially the atrioventricular cushions anid the truncal ridges.
play a v-ery important part in the shaping
and growth of the heart during the fourth
week of fetal life, up to the completion of
stage 4 in figure 1. Once their endocardial
surfaces meet, however, these tissues discontinue further radial growth, and this occurs
with the completion of stage 4. Froni this
date oni, by actual imeasurement, there appears
to be little further expansile growth of fibroblastie tissue. Subsequeent changes in size
and shape of the heart are nearly entirely due
to myoblastie growth originating in the maini
from the trabeeulated regions of the primarv
heart tube. This tissue has a grossly uniform
growth rate and growth direction, growth becomes -ioinoton-ic, and there is little further
shape chanige after the fourth or fifth week
of fetal life. Size alone continues to increase.
But there are also in-iportant phvsiologie
implications of this earlv shaping of the heart,
seemingly four-eharmbered before it is needed.
Whether "needed" or not, having paired yventrieles offers certain physiologic advantages
even at the earliest stages of the circulation.
As deVries and Saunders2 have pointed out.
when the two ventricular chambers are joined
by the interventrieular eanal, they fiunctionj
as two pumps in series, (lelivecilig blood inlto
the truncus. Later. wheni the initerventricuhlar
(eanal is closed but the ductus, arteriosus is
open, they pum-p ill parallel ini drivinlg bloo(d
into the deseeniding aorta.
There is aniother inore iniportaiit phvsioCirculation, Volu-me XXV. May 1,962
EMBRYOLOGY OF VENTRICULIAR FLOW PATHWAYS
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logic role of the four-chambered heart in fetal
life. This is related to the fact that every
mammal has two double circulations during
its lifetime, one duriiig fetal life, and a different one during extrauterine life.18 (By
double circulation it is meant that blood must
pass through the heart twice to complete a
single circuit.) The double circulation of
extrauterine life is well known: the right
heart drives blood through the pulmonary
circuit, and the left ventricle drives the blood
through the systemic circuit. The fetal double
eirculation is quite different. Radiologic
studies in the mammalian fetus, first performed by Barclay, Franklin, and Pritchard
in 1944 and since then extended by many
others,19 show that blood returning from the
placenta and the inferior vena eava passes
through the foramen ovale into the left
atrium, from here to the left ventricle, to be
delivered via the carotid arteries to the head
and the anterior body. The venous blood returning from this region enters the right
atrium, passes into the right ventricle and
out the pulmonary artery and ductus arteriosus into the descending aorta to be returned
to the placenta for further oxygenation. Following birth, physical closure of the ductus
arteriosus and functional (if not physical)
closure of the foramen ovale converts the
heart into the double circulation pattern required for extrauterine life.
The early differentiation of the heart into
a four-chambered organ has important implications for the clinician. In practically all
types of clinically important congenital heart
disease, the structural abnormality of the
heart was acquired in its entirety within the
first month of fetal life, 8 long months before
birth. This means that the clinician sees only
those cases of congenital heart disease in
which the structural abnormality did not
seriously compromise the fetal type of double
circulation during the succeeding 8 months
of intrauterine life. But if the fetus requires
a four-chambered heart for its double circulation why are not the abnormalities as dangerous for the fetus as for the newborn? The
reason is that in the fetal heart the two eireuCirculation, Volume XXV, May 1962
777
latioiis are separated functionally but not
physically as they are in the newborn. In the
fetus, blood can reach the deseelnding aorta to
return to the placenta either from the left
ventricle or from the right ventriele via the
duetus arteriosus. Similarly, the presence of
a wide foramen ovale permits returning venous blood to eniter either the right or the
left ventricle. In short, within certain limits
there are alternative flow pathways in the
fetus by which an adequate circulation can
be maintained. This is no longer the case
after birth, for the two flow pathways are
now physically separated. Certain of the
surgical procedures used in the treatment of
congenital heart disease attempt to help the
circulation by restoring or constructing alternative flow pathways.
The cases of congenital heart disease that
survive the 8 months of intrauterine life to
become the population of clinical congenital
heart disease are necessarily but a small per
cent of all cases of congenital heart disease.
By and large they are instances of deranged
right heart flow. What happened to the
others? They died in the first month of life,
when barely a centimeter in size-a slight]y
delayed menstrual period, slightly excessive
flow scarcely noticed by the mother.
No one knows the iiicidence of congenital
heart disease among all successful conceptions. Certainly it must be considerably
higher than the incidence of congenital heart
disease in the newborn population. It has
been estimated that the highest mortality
among human beings occurs in the first day
after successful conception, when the mortality may be as high as 90 per cent.8 It is
difficult to ascribe these fatalities to heart
disease. Nevertheless, it is altogether possible
that heart disease is responsible for more
deaths during the first 6 weeks of fetal life
than in any subsequent age period. And
when fetal death is included in the mortality
figures, heart disease, already labeled the
"big killer, " may actually exact a vastly
greater toll in human lives than is often
appreciated. Demographers concerned about
"population explosions" need not be appre-
GRANT
778
hensive that preventing this
tality would compound their
all, it will still be difficult for
being to have more than one
nancy per year.
high fetal morproblems. After
a female human
successful preg-
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Conclusions
1. The morphogenesis of the ventricular region of the heart is outlined, based upon the
study of microscopic slides and scale reproductions of human embryos in the collection
of the Carnegie Institution of Washington in
Baltimore. The method of presentation derives from Streeter's concept of the "primarv
heart tube, the region of the heart from the
atrioventricular canal to the truncus arteriosus.
2. Four general changes in the primary
heart tube accounted for the partitioning that
converts the tube into a four-chambered organ. Two of these are due to invasive fibroblastic growth: (1) the division of the atrioventricular canal into a mitral and tricuspid
orifice, and (2) the division of the truncus
arteriosus into the pulmonary artery and
aorta. The other two are myoblastic processes;
while they are important in determining the
shape and size of the heart, careful measurement indicates that they play only a passive
role in partitioning. They are (3) the elaboration of the muscular interventricular septum, and (4) the molding of the bulbus cordis
into a right ventricle infundibulum separate
from the aorta.
3. From measurements in fetal hearts from
the fourth fetal week to the time the heart
first attains adult shape (sixth fetal week),
it has been shown that, when fibroblastic tissue has completed the partitioning of the
atrioventrieular canal and the truneus, it
ceases further to grow expansively. At this
stage the heart is only 3 mm. in size. Subsequent growth and shaping of the heart is
nearly entirely due to myoblastic growth,
originating from the trabeculated regions of
the primary heart tube.
4. The marked difference in growth of different parts of the fetal heart explains several
aspects of cardiac development that have beeln
perplexing in the past. For exaniple, it explains how the aortic valves, originating far
distally in the heart tube, come to be closely
related to the left ventricle in the adult heart.
for the distance from the left ventricle to the
aortic anlage is never more than 0.5 mm. at
any stage in the growth of the heart. It is
not necessary to postulate resorption of the
ventral atrioventricular cushion, or migration
of the aorta, or resorption of the bulbus to
explain this event. Similarlv, the interventricular canal measures about 0.4 mm. in diameter from the first to the fifth stage of
fetal development. The muscular interventricular septum does not narrow it, nor does
the membranaceous septum " replace" it, for
the canal can be seen to have exactly the same
diameter when the membranaceous septum is
well defined bordering it, and the interventricular septum has iiereased many fold in
size. When finally the canal is obliterated,
the heart has attained such a size that the
canal (still in its original diameter) is an unimportant thread-like conduit across the septum. It is difficult, and may be meaningless,
to attempt to ascribe to any particular tissue
a primary role in the final obliteration of the
canal.
5. The leftward part of the interventricular
canal early becomes ineorporated into the
chaiuber of the left ventricle to form a left
ventricular infundibulum. In early fetal
stages it is an important and large part of
the left ventricular chamber. Mall described
this many years ago, and it has long been
known to occur in the chick heart. But in
nore recent writings on human cardiac embryology this event has beconie lost. Some
anatomie and clinical implications of the wav
in which the infundibuluni develops are
pointed out.
6. The question is raised: why does the
human heart develop a shape identical with
that of the adult so early in fetal life, when
the fetus is barely a month old and has 8
nore months of intrauterine life before it. In
part it is answered by certain statistical and
geometric aspects of what is m-eant by
"shape " as a part of organ differentiation.
Circulation, Volume XXV, May 1962
EMBRYOLOGY OF VENTRICULIAR FLOW PATHWAYS
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Such consideration indicates that certain
parts of the primary heart tube must have
an exceedingly brief growth history, which
confirms the morphologic measurements cited
above. From the physiologic point of view,
the early development of a four-chambered
heart is related to the fact that every mammal
has two different "double-circulations" during its lifetime, one during fetal life and
another one during extrauterine life. The
principal morphologic difference between them
is that in the fetal double-circulation the two
paths in the heart are functionally separated,
while in the extrauterine double-circulation
the two paths are physically separated. This
has important clinical implications.
7. Since nearly all forms of congenital
heart disease represent structural abnormalities that were completely developed during
the first month of fetal life, the cases of congenital heart disease that are seen clinicallv
must represent a very small per cent of all
cases. The others died in the first month of
fetal life, scarcely noticed by the mother.
Indeed, it is likely that the intrauterine mortality from heart disease is greater than the
extrauterine mortality. When this is taken
into consideration, heart disease proves to be
a vastly greater cause of human mortality
than is often realized.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Acknowledgment
The author wishes to thank Dr. Ebert and his
staff of the Carnegie Institution of Washington in
Baltimore for permitting his access to the remarkable
collection of beautifully prepared and maintained
human embryos in the Carnegie collection, and for
their continued help and interest throughout the
study. He wishes also to thank Dr. Pieter de Vries
of San Francisco for permitting him to read the
manuscript of his work2 prior to publication. Finally,
he wishes to express thanks to Professor A. J. Linzbach for so generously opening the resources of the
Pathology Institute of the University of Gbttingen,
Germany, to him and for invaluable counsel and
interest during the course of these studies.
References
L. STREETER, G. L.: Developuiental horizons in
humani embryos. Carnegie Inistitution of Washington Bulletin 575, Contributions to Embryology 32: 133, 1958.
2. DEVRIES, P. A., AND SAUNDERS, J. D. M.:
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Development of the ventricles and the spiral
outflow tract in the human heart. Contributions
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GOERTTLER, K.: Stoffwechsel Topographie des
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KEITH, SIR A.: The bulbus cordis aind the human
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The Embryology of Ventricular Flow Pathways in Man
ROBERT P. GRANT
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Circulation. 1962;25:756-779
doi: 10.1161/01.CIR.25.5.756
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