3D Anatomy of the Developing Heart:Understanding Ventricular Septation
Timothy J. Mohun1 and Robert H. Anderson2
1The Francis Crick Institute, London NW1 1AT, United Kingdom2Cardiovascular Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon TyneNE1 7RU, United Kingdom
Understanding how the four-chambered mammalian heart is formed from a simple, loopedtube remains challenging, notwithstanding the descriptive accounts left by generations ofcardiac anatomists. Much of the difficulty lies in attempting to visualize an intricate series ofmorphological transformations through the restrictive lens of two-dimensional imagesderived from histology. Modern imaging methods offer a way to overcome this limitationby providing comprehensive and high-resolution image sets of the developing heart.Wehaveused one such method, high-resolution episcopic microscopy (HREM), to obtain virtualthree-dimensional (3D) models of successive stages in mouse heart development. Takingadvantage of the ability afforded by 3D modeling to view each heart in any orientation orerosion plane, we provide an illustrated account of how the mouse heart divides into left andright ventricular chambers, and how each acquires its own distinct outflow vessel.
Of all the many extraordinary changes thatoccur during development of the mamma-
lian heart, perhaps the most challenging to un-derstand is the transformation that establishesseparate left and right ventricular chambers,eachwith its own distinct arterial root and vessel.Because the heart initially forms as a simple,looped contractile tube, its conversion to thema-ture chambered structure requires several dis-tinct and coordinated changes. One of these isthe apparently simple division of the ventricularloop into left and right chambers via the growthof an interventricular muscular septum. Expan-sion of the atrioventricular canal ensures thatboth of the forming ventricles have an inlet to
receive blood from the appropriate atrium. Thefinal change is the division of a single commonoutflow originating from the original loopedheart tube into the intrapericardial aorta andpulmonary trunk. This provides each chamberwith its own arterial outflow and enables separa-tion of the systemic and pulmonary circulations.
Understanding how these changes areachieved has proved enormously challenging,and not just because of their morphologicalcomplexity. The difficulty is also the conse-quence of a simple and obvious topologicalobservation. Subsequent to expansion of theatrioventricular canal, the common outflowlies asymmetrically in the early heart, sitting
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above, and sharing a largely common lineagewith, the future right ventricle (Fig. 1).
With such an arrangement, how then canthe left and right ventricles be separated fromeach other without confining both arterial rootsexclusively to the right chamber?Answering thisquestion not only reveals the exquisite choreog-raphy of morphological change that underpinsseparation of the chambers. It also sheds light onan apparently diverse range of congenital heartdefects, ranging from malformation or aberrantpositioning of the arterial roots to the multipledefects, which result in abnormal retention ofinterventricular communication even afterchamber formation.
Cardiac anatomists have long grappled withthe issue of how the left and right sides of theheart are separated. It is testament to their skilland prescience that they have given us suchdescriptive accounts, despite being restrictedalmost exclusively to analysis of histologicalstudies. Although their efforts have provided aremarkably accurate outline for many facets ofcardiac development, in our view the variousaccounts addressing ventricular septation andformation of the arterial roots remain the leastcompelling and most opaque of their legacies.
In recent decades, such anatomical issueshave often been eclipsed by the avalanche ofadvances in genetic and molecular studies ofcardiac development. But those same advances
have increasingly demanded a morphologicalframework with which to provide a context forunderstanding their significance, bringing a re-newed relevance to descriptive cardiac anatomy.Parallel advances in imaging technology havealso freed us from the constraints that hamperedprevious generations. We can now combine avariety of imaging modalities with computer-based three-dimensional (3D) reconstructionto interrogate the topology of the developingheart in remarkable detail.
Here we reexamine the manner in whichseparate ventricular chambers and their arterialroots are established during mouse cardiac de-velopment. Our studies use a library of novelimage data obtained from high-resolution epi-scopic microscopy (HREM) of mouse embryohearts. Our efforts, however, also rest heavilyupon foundations provided by previous genera-tions of cardiac anatomists. Their work is nowwidely accessible, either from primary literatureor summarized in secondary reviews and text-books. For this reason, we have eschewed refer-encing their individual contributions. Instead,we have revisited the events surrounding ven-tricular septation, using 3Dmodeling to providea fresh perspective on the transformations inheart structure. We hope that our approach il-lustrates and clarifies the sequence of morpho-logical changes that underpin this critical step incardiac development.
AP
OT
Rightventricle
Leftventricle
Figure 1. E11.5 heart, with midseptal plane marked. The distalmost end of the outflow tract (OT) dividesinto distinct pulmonary (P) and aortic (A) vessels lying on either side of the midseptal plane. Scale bar,0.5 mm.
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HOW FAR DOES THE OUTFLOW TRACT,AND THE VESSELS TOWHICH IT GIVES RISE,CHANGE POSITION DURING CARDIACDEVELOPMENT?
In the mouse, division of the common outflowtract occurs during the 1-day window of E11.5–E12.5. Because the base of the outflow tract liesover the right ventricle at E11.5, the pulmonarytrunk, as it is separated from the aorta, is alreadypositioned appropriately to drain its ventricle.In contrast, without change in either locationor orientation, the newly formed aortic rootwould occupy a comparable but inappropriateposition, and the left ventricle would lackany direct outlet. To resolve this topological co-nundrum, it has been suggested that the outflowvessel shifts and rotates to a more midlineposition between the left and right sides of theheart, so-called “wedging.” It is then further sug-gested that, to establish a connection with theleft ventricle, the aortic root shifts its positionleftward.
Inspection of 3D models covering this peri-od provides little support for this view. Whennewly formed, the roots of both the pulmonarytrunk and aorta retain their position lying aboveand to the right of a plane bisecting themuscularventricular septum (Fig. 2).
Septation of the outflow tract itself proceedsin a distal to proximal direction, with the resultthat, although distinct pulmonary and aortictrunks first replace the distal portion of the out-flow, the medial region remains common, en-compassing the newly appearing primordia ofthe arterial roots. These latter components arereadily recognized by their characteristic trifoli-ate structure. Forming within a common vessel,and by a shared process, these primordia neces-sarily lie on the same plane (Fig. 3).
As outflow septation proceeds, the two nas-cent valves become separated by arterial wallsin the pulmonary and aortic roots, and imme-diately diverge in their individual planes. Thepulmonary root retains a similar axis to that ofthe original outflow tract. The aortic root, incontrast, shifts its axis such that the plane ofthe valve comes to provide a mirror image ofits pulmonary counterpart (Fig. 3).
Both valve primordia now lie slightly closerto the midseptal plane, presumably as a result ofgrowth and development of the supporting col-lar of ventricular tissue. The pulmonary valvarprimordium now variably straddles the mid-septal plane, whereas the aortic valve remainssomewhat further to the right, despite its changein plane. This arrangement of the roots is largelyunchanged during the next 2 days of develop-ment, during which septation of the left andright ventricles is completed and each chamberacquires its own outflow tract (Fig. 4).
In the remaining 4 days of development,from E14.5 to E18.5, both arterial valves do shiftleftward. At E16.5, the pulmonary valve lies forthe first time on the left, whereas the aortic valve
Pulmonary Aortic
E11.5
E12.5
Figure 2. Models of hearts at four successive stagesbetween E11.5 (top) and E12.5 (bottom), eroded toapproximate the midvalve level for pulmonary andaortic valves.
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straddles the midseptal plane. By full term, atE18.5, both valves lie immediately to the left ofthe midseptal plane and are positioned over theleft ventricle, although the pulmonary valve re-tains its origin from the right ventricle (Fig. 5).
In summary, for the entire period duringwhich the left and right ventricles becomefunctionally separated (E11.5–E14.5), their de-veloping outflow tracts remain asymmetricallypositioned on the right of a plane separating thetwo ventricles. No major leftward shift of theaortic root can be seen. Such a shift occursonly in the few days before full term. Instead,the most obvious change is a shift in the axis ofthe aortic root and the corresponding plane ofthe aortic valve. This occurs immediately afterthe valvar primordia become separated by in-growth of their own distinct walls. As a result,how the left ventricle acquires its connection tothe aortic root without ongoing interventricularcommunication remains a topological puzzle.
Its solution lies in other changes to heart mor-phology during this period, in particular the roleplayed by the cushions of the outflow tract.
ARCHITECTURE OF THE COMMONOUTFLOW TRACT
Between E10.5 and E11.5, the outflow tractdraining the ventricular loop acquires twomajorcushions, which run along much of its length.Their arrangement establishes the relative posi-tions of the pulmonary and aortic channels evenbefore their separation into the pulmonary andaortic trunks.
At E10.5, the two outflow cushions appear atfirst in an apparently rather uniform manner,arranged concentrically around the central andproximal portions of the outflow tract. As theirdistinct and abutting edges become clear, it isevident that the cushions are already in a spiralarrangement, rotating clockwise along the prox-
Early E12.5
Late E12.5
Figure 3. Early and late E12.5 hearts, with midseptal plane indicated. At the earlier stage, separation of aortic andpulmonary roots only extends through the distal outflow tract. Within the medial portion, the primordia of theaortic and pulmonary valves lie on a common transverse plane (pink) through the outflow. By late E12.5,separation of the aortic and pulmonary roots extends through this region. The two vessels adopt divergentorientations, as revealed by the symmetrical arrangement of their valve planes (yellow and mauve, respectively).
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imal to distal axis of the outflow tract. One cush-ion extends from a noticeably broad, but thin,base attached to the inner surface of the rightventricular wall. It twists to occupy a superiorposition in the central region of the outflow
tract. Finally, at its most distal end, it occupiesthe left side of the outflow tract. A second, ini-tially more bulbous, cushion begins from the leftside of the outflow tract as it emerges from theright ventricle, being attached to the right side of
Pulmonary
E16.5
E18.5
Aortic
Figure 5. By E16.5, the entrance to the pulmonary root lies clearly to the left of a midseptal plane, shifting furtherto the left by full term (E18.5). Over the same period, the aortic valve also shifts leftward, straddling the left face ofthe interventricular septum by E18.5. Scale bars, 0.5 mm.
E12.5 E14.5
Figure 4. Comparison of arterial valve planes between E12.5 and E14.5. Both the relative orientation of the valveplanes, and their location with respect to the midseptal plane (shown), remain unchanged between E12.5 andE14.5. Scale bars, 0.5 mm.
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the developing muscular ventricular septum.More distally, this cushion lies on the inferiorside of the central outflow, and then twists to theright side at its most distal end (Fig. 6).
As a result of this spiraling arrangement, thetwo cushions have been variously termed left/superior/parietal and right/inferior/septal, re-spectively. Over the course of the next day(E11.5–E12.5), two additional cushions appearin the central portion of the outflow tract. Lyingon either side between the main cushions, these“intercalated” cushions will contribute to form-ing the arterial valvar primordia. By trackingcushion arrangement in this region, it is clearthat at least the central portion of the outflowtract undergoes further progressive rotation asthe more distal outflow separates into distinctvessels. As a result, the intercalated cushionsshift from a largely left-to-right to a more ven-trodorsal orientation (Fig. 7).
Spiraling and rotation along the axis of theoutflow tract has a crucial consequence forsubsequent development. As a result of this ar-rangement of the cushions, the entrance to thefuture pulmonary channel will lie at the superioredge of the right ventricular chamber, whereasthat of the aortic channel will be much morecentral (Fig. 7).
SEPARATION OF THE PULMONARY ANDAORTIC CHANNELS
Fusion of the apposing surfaces of the parietaland septal outflow cushions along the length ofthe outflow tract separates the pulmonary andaortic channels, each of which becomes progres-sively enclosed within its own walls. This trans-formation begins in the distal outflow andprogresses ever more proximally. At their mostproximal ends, fusion of the parietal and septal
E10.5
E11.5
Right Left Left
Figure 6. At E10.5, progressive transverse erosion of the outflow tract from its distal portion toward the heartreveals the spiral arrangement and differing shapes of the septal (red) and parietal (green) outflow tract cushions.At E11.5, erosions reveal how the proximal portion of the two cushions face each other at the entrance to theoutflow tract. Note how the base of the more bulbous septal cushion attaches to the right face of the growinginterventricular septum.
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cushions is a critical step toward separation ofleft and right ventricles. As the faces of the cush-ions merge together in this region, they form athick “hanging wall,” or shelf, of cushion tissue.This forms a physical barrier separating the en-trances to the pulmonary and aortic channels(Fig. 8).
Furthermore, as a result of cushion spiraling,the entrances to the aortic and pulmonary chan-nels lie on significantly divergent axes. That ofthe pulmonary channel is approximatelyaligned with the overall axis of the outflow tract,passing leftward as it ascends. In contrast, theentrance to the aortic channel is relatively offset,passing rightward as it enters the base of theoutflow tract. This places it in a more appropri-ate orientation for draining from the left side ofthe heart, although it remains at this stage abovethe right ventricle (Fig. 9).
By E12.5 then, the arrangement and subse-quent fusion of the outflow tract cushions hasnot only enabled separation of the aortic andpulmonary vessels, it has also placed their en-trances in orientations that presage their ulti-
mate chamber-specific function. Cushion fu-sion has also created a physical partition thatrestricts the drainage offered by each channelto distinct regions of the right ventricle.
CLOSURE OF THE INTERVENTRICULARCOMMUNICATION
Throughout this period, access to the aortic rootfrom the left ventricular cavity is only possiblebecause of persistence of an interventricularcommunication across the crest of the muscularventricular septum (Fig. 10A).
Complete separation of the left and rightventricles therefore requires a mechanism forclosing the interventricular communication,while simultaneously establishing unfetteredpassage from the left ventricle to the aorticroot. Once again, a key role is played by outflowcushion tissue. As we have seen (Fig. 6) from itsfirst appearance, the septal cushion of the out-flow tract extends deep into the future right ven-tricle, attaching to the right side of the develop-ing ventricular septum. By early E12.5, the base
E11.5
E12.5
AA
P
PA
P
A
P
Figure 7.At E11.5, the spiral arrangement of the aortic (A) and pulmonary (P) arterial channels within the singleoutflow tract is revealed by progressive transverse erosion planes. Further rotation occurs during E12.5. This canbe seen by eroding successive developmental stages at a fixed transverse plane at approximately midlevel throughthe outflow tract. This region contains the intercalated cushions. The erosion plane reveals the trifoliate appear-ance of the valve primordia in the oldest sample. Models are oriented with respect to the plane of apposition(marked) between the superior and inferior cushions of the atrioventricular (AV) junction.
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of this cushion is a bulbous structure coveringthe cranial half of the septum. Because of this,communication between the left and right ven-tricles is restricted to the caudal half of the ven-tricular septal crest, a region that lies directlybeneath the aortic root (Fig. 10B).
Closure of this remaining interventricularcommunication is now achieved by a sequenceof tissue fusions involving the bulbous end of theseptal cushion. As fusion between this and theadjacent proximal portion of the parietal cush-ion establishes a growing barrier of tissue sepa-rating the pulmonary and aortic root entrances,the septal cushion also begins to fuse along anorthogonal axis. Merging of its convex face withthe adjacent superior atrioventricular cushioncloses most of the gap that allows communica-tion across the caudal region of the ventricularseptal crest (Fig. 11).
In doing so, this effectively walls in the baseof the aortic root, enabling it to traverse the
ventricular septum to the left ventricle. From atopological point of view, the original interven-tricular space directly above the crest of the sep-
Early Middle Late
P
A
Figure 8. Fusion of the proximal outflow cushions during E12.5. Apposing faces of the septal (red) and parietal(green) cushions fuse during E12.5, creating a shelf of tissue that separates the entrances to the pulmonary (P) andaortic (A) roots. Cushion fusion is visualized through erosion of three-dimensional (3D) models in either four-chamber (top row) or axial (bottom row) planes.
Figure 9. Midventricular erosion plane at E11.5viewed from the apical side. The spiral arrangementof outflow tract cushions results in divergent orienta-tions for the entrances to the pulmonary (yellow) andaortic (red) channels.
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Figure 10.E12.5 heart. (A) Four-chamber erosion plane. After separation of the aortic and pulmonary vessels, theaortic root continues to lie above the right ventricle. The interventricular communication across the crest of theinterventricular septum (IVS) permits access to the aortic root from the left ventricle. (B) Erosion through theright ventricle. The bulbous, septal cushion (SC) occludes much of the interventricular communication, restrict-ing it to the most caudal region. Fusion with the adjacent cushion tissue completes sealed access of the aortic rootto the left ventricle (arrows).
Av
SC
Right
Pv
Figure 11. E12.5 heart, eroded from the right. The erosion plane reveals the extent of fusion between the proximalseptal (SC) and parietal cushions (red dotted line) and the resulting separation of openings to the aortic (Av) andpulmonary (Pv) valves. Further axial erosion (yellow) shows that unique access of the aortic root to the leftventricle is achieved by fusion between the SC (red) and the superior atrioventricular cushion (blue). Note theadjacent residual interventricular communication.
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tum is not itself closed by this process. Rather itscaudal half is converted into the entrance to theoutflow tract serving the left ventricle.
By E13.5, the only remnant of interventric-ular communication lies at the most caudal endof the interventricular septal crest. Final closureis completed by the so-called “tubercles.” Theseare protuberances from the right side of theatrioventricular cushions that fuse with therightmost edge of the caudal interventricularseptum (IVS). Fusion seals the remaining pas-sage between left and right ventricles, whichnow each possess separate arterial drainage(Fig. 12).
CONCLUSIONS
Generations of cardiac anatomists have high-lighted both the beauty of the mammalian heartand the intricacy of the steps that transform itfrom pulsatile tube into a mature, four-cham-bered organ. With modern imaging methods,we can now all share an appreciation of theseevents, using digital 3D models to retrace theirsteps and clarify the most stubborn and intrac-
table problems of embryonic heart morphology.Here we have reexamined how, subsequent toexpansion of the atrioventricular canal, partitionof the ventricular loop into left and right ventri-cles results in separate chambers, each with theirown arterial root. With the advantage of 3Dmodels, it is clear that both arterial roots retaintheir location over the right ventricular chamberthroughout growth of the muscular ventricularseptum. The onlymajor shift is the reorientationof the axis of the aortic root. This change onlybecomes possible when division of aortic andpulmonary roots extends through the centralpart of the outflow tract, separating their respec-tive valves.
Subsequent closure of the communicationbetween the two ventricles, and the establish-ment of left ventricular drainage through theaortic root, requires a sequence of events inwhich the outflow tract cushions play a centralrole. The spiral arrangement of parietal and sep-tal cushions places the entrances of the pulmo-nary and aortic channels over distinct regions ofthe right ventricle. This separation is then con-solidated by fusion of the proximal cushion re-
Right
Right Left
Figure 12. E13.5 heart, eroded from the right (red) and in the four-chamber plane (yellow). The remaininginterventricular communication (circled) is closed by fusion (red arrows) between the “tubercles” (protuberancesof the right margins of the atrioventricular cushions) and the adjacent right face at the caudalmost crest of theinterventricular septum.
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gions, creating a shelf of tissue between the en-trances to the two roots. Fusion of the bulbousbase of the septal cushion with the adjacentatrioventricular cushion closes much of the re-maining left-to-right ventricular communica-tion. At the same time, it creates a tunnel fromthe aortic root that crosses the caudal crest of themuscular ventricular septum. Final closure isthen achieved by fusion of the tubercles ofboth atrioventricular cushions with the rightside of the septum. (This results in the asymmet-ric and rightward tilt in the septum that is soevident in more caudal four-chamber views ofthe mature embryonic heart.)
This morphological account of course onlyprovides a skeleton for our understanding ofthese events and is derived only from studiesof themouse heart. Far fewer equivalent datasetsare available for human heart development, butour account is, to our knowledge, largely consis-tent with these and with earlier interpretationsof histological studies. Changes in cellular com-position, muscularization, and the distributionof different cell lineages all contribute to func-tional differentiation of the heart. The challenge,therefore, is to integrate them into a comprehen-sive account. Even the partial view we have pre-sented, nevertheless, suggests some importantconclusions. The right-sided location of bothentrances to the arterial roots, and the shift inorientation of the aortic root, are surely of sig-nificance for understanding the etiologies of ab-normalities involving the positioning of the
great vessels. Similarly, the central role playedby the major cushions in both outflow and ven-tricular septation accounts for the frequent as-sociation of abnormalities in both chamberdrainage and separation. Finally, it is clear thatclosure of interventricular communication isnot simply the result of growth of a septum toocclude the space above its crest. Rather it isachieved via changes involving several com-ponent tissues and steps. As a consequence,ventricular septal defects could have multipledistinct etiologies. These could include abnor-malities in the positioning or growth of eitherthe outflow cushions or the interventricular sep-tal wall. They could also result from lesions inany of the fusions that our 3D models have il-lustrated normally occur between these tissues.
ACKNOWLEDGMENTS
We thank our colleagues first at the MRC Na-tional Institute for Medical Research and morerecently at the Francis Crick Institute for sup-porting development of HREM imaging andprovision of the many mouse embryos that pro-vided the basis for our studies. T.J.M. was sup-ported by the Francis Crick Institute, which re-ceives its core funding from Cancer ResearchUK (FC001157, FC001117), the UK MedicalResearch Council (FC001157, FC001117), andthe Wellcome Trust (FC001157, FC001117).T.J.M. was also supported by the Medical Re-search Council (U117562103).
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published online January 27, 2020Cold Spring Harb Perspect Biol Timothy J. Mohun and Robert H. Anderson Septation3D Anatomy of the Developing Heart: Understanding Ventricular
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