255 Internutronal Journal of Cardiology. 25 (1989) 255-264 Elsevier

CARD10 00971

Editorial

A suggested nomenclature for the developing heart

T. Pexieder ‘, A.C.G. Wenink ’ and R.H. Anderson 3 on behalf of the Working Group for Embryology and Teratology of the European Society

of Cardiology

’ Instrfure of Histology und Emh@ogy, Unwersity of Lmsunne, Switxrlond; ’ Department of Anatomy. Stare Uniuersit_v of Leiden.

The Netherlands; ’ Department 01 Paedratrics. Natronal Heart and Lung Institute. London. U.K.

(Received 27 June 1989; accepted 27 June 1989)

Key words: Embryology; Congenital malformation; Development of heart: Terminology

0167.5273/89/$03.50 ill 1989 Elsevier Science Publishers B.V. (Biomedical Division)

introduction

There is no question but that knowledge of the mechanisms of development of the human heart is important in the understanding of the structure of both the normal and congenitally malformed heart and, potentially. could be crucial in determining the reasons why the heart develops abnormally. It is also true, nonetheless, that our present state of understanding of cardiac development is less than perfect. Much of the early investigation was based upon examination of human embryos recon- structed by the classic technique established by Born [l]. While these studies provided vital infor- mation, standardization of fixation of such speci- mens was impossible. Furthermore, there could be no certainty that the embryos studied were, in fact, normal. There is also the difficulty of obtain- ing sufficient specimens to provide a stepwise sequence covering the crucial periods of cardiac development. The development of more sophisti- cated techniques, such as scanning electron mi- croscopy, has circumvented many of these heuris-

Corresppndence to. Prof. R.H. Anderson. Dept. of

Paediatrics, National Heart and Lung Institute. Dovehouse

Street. London SW3 6LY. UK.

R.H.A. is supported by the Joseph Levy Foundation to- gether with the British Heart Foundation.

tic problems and. additionally, obviates the need for reconstruction. These newer techniques have, to date, largely been conducted on animal species. It is well recognized that important differences exist between the anatomy of the heart, particu- larly in avian species, and the morphology of the human organ. It is now becoming possible to collect human hearts which can be prepared under conditions approaching perfect fixation [2]. and these hearts can then be processed either for scan- ning electron microscopy [3] or for study by the more classical techniques of serial sectioning and

reconstruction [4]. If the results of these later studies are to bear

their fullest fruit, one further caveat must be over- come, particularly if the findings are to prove of value in the description and understanding of the normal and abnormal heart in infants, children and adults. This caveat concerns the need to have a vocabulary for description of the developing heart which is unambiguous and non-controver- sial, and which is as meaningful to the clinical cardiologist as to the experimental embryologist. Many of the controversies which have bedevilled previous accounts of cardiac development and maldevelopment have stemmed purely from semantic differences. For example. how can there be agreement on what develops, in the formed and definitive heart, from the embryologic “ bulbus cordis” when there is no consensus amongst em-

256

bryologists on the precise boundaries of this re- gion within the developing heart? Mindful of the needs for a unified nomenclature, the working group of the European Society of Cardiology con- cerned with embryology and teratology of the heart has met several times in an attempt to formulate a mutually acceptable terminology. The first meeting took place at Macclesfield, U.K., in November 1982, generously sponsored by Im- perial Chemical Industries. A document emerging from this meeting was circulated amongst the par- ticipants and the underlying concepts, semantics and problems were dissected in a series of bi- lateral talks between the senior author (T.P.) and the leaders of individual teams of investigative embryologists. These talks occurred within the framework of the meeting of the working groups of the European Society of Cardiology held at Spa, Belgium, in September, 1983. Subsequent to this, further discussions and modifications were suggested at the meeting of the working group held at Gottingen, Federal Republic of Germany, in September 1986. From all these discussions has emerged a tentative proposal for a descriptive nomenclature covering the significant early stages of development of the heart. We outline this sug- gested terminology in this presentation. We recog- nize that any vocabulary will become of value only when used, and that consensus will dictate which terms are, eventually, to be employed. The system presented here, therefore, is advanced in the hope of stimulating further discussion and, more im- portantly, laying an unambiguous framework for subsequent descriptions of the developing heart.

A Nomenclature for Description of the Developing Heart

The philosophy underlying the construction of the suggested nomenclature centres upon three axioms. Firstly. prenatal development of the heart should be considered in three phases, namely those of early organogenesis, advanced organogenesis and fetal growth. Secondly, the nomenclature is conceived so as to avoid contentious terms used in the description of the definitive normal and abnormal heart, and also to avoid terms derived from comparative anatomy or embryology. Third-

ly, the system is constructed so as to allow for the future integration of new knowledge.

The phase of early organogenesis

This commences with formation of the cardiac crescent and ends at the stage of a fully-formed heart loop. The phase can be further divided into pretube, tube and loop stages.

The phase of advanced organogenesis

This commences with the appearance of widen- ing of the atria1 segment of the loop and with the

first signs of septation within the ventricular com- ponent. It ends when the fully formed right and left ventricles are septated completely one from the other. This phase can be divided into stages of septation of the outflow tracts and closure of the embryonic interventricular communication.

The phase of fetal growth

This starts when the two ventricles are com- pletely septated one from the other and ends with birth. Very little is known. as yet, concerning this, by far the longest stage of development in terms of time. Essentially, it encompasses the third through the ninth months of intrauterine growth and can reasonably be described in temporal fash- ion.

Description of the Developing Heart

Note should always be taken of at least three specific features so as to describe fully cardiac development. These are the external aspect (such as grooves and expansions). the cavities (atriums versus ventricles and so on) and the internal aspects of the chambers (ridges, cushions, folds, valves, etc.). A summary of the proposed vocabul- ary is given in Table 1, along with a review of previously used terms which, in our belief, would best be discontinued.

The phase of early organogenesis

Since it is not possible to determine at this early stage which parts of the loop will form

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258

definitive structures, it seems preferable simply to distinguish descending and ascending limbs of the heart tube (or. if preferred, proximal and distal limbs named according to the direction of the flow of blood). The descending limb commences at the point of junction of the heart tube with the venous sinus (sinus venosus). The venous sinus will itself become incorporated eventually within the devel- oping heart. The descending limb of the initial heart tube finishes at the apex of the loop. The ascending limb then extends from the apex to the junction of the tube with the arterial segment in the branchial region. The absence of any specific

internal features at this stage makes further de- scription superfluous.

Phase of advanced organogenesis

The guiding principle for division of the em- bryonic heart is the finding of more-or-less dis- tinct areas in which septation occurs. Thus, during advanced organogenesis, the developing heart can be considered to have venous, atrial, atrioventricu- lar, ventricular, ventriculo-arterial and arterial components. The junctional structures during this phase of growth initially have their own identity and. indeed. are occupied by structures which are

$$-% - WVentricuJo-arterial cushions -F-r q-. *. -zy====y-. *

Fig. 1. These sections through human embryos show how the atrioventricular junction is initially (a) a structure with its own identity. Note that, at this stage. neither the atrioventricular nor the ventriculo-arterial cushions have fused. Subsequent to the completion of

septation (b; 40 mm stage), the extensive “AV canal” has been incorporated into the ventricle as part of the developing leaflet of the

tricuspid valve.

259

discrete from the primary septums which divide itself divided by the primary and secondary atria1 the developing atria1 and ventricular cavities. The septal structures (septum primum and secundum). venous sinus (sinus venosus) is enclosed and de- these forming the oval foramen (foramen ovale) marcated by the extensive valvar apparatus seen by the conclusion of the phase of advanced

between it and the atria1 segment and by the organogenesis. The atrioventricular junctional seg-

external sinuatrial groove. The atria1 segment is ment, or atrioventricular canal, has considerable

Fig. 2. This scanning electron micrograph is from a microdissected human embryo between stages XVIII and XIX of Streeter’s classification. It shows the stage of incorporation of part of the initial interventricular communication as the subaortic vestibule.

Conventionally, this is described as the secondary foramen (arrow 2). The hole which is closed to complete septation is then described

as the tertiary foramen (arrow 3). It is between the fused atrioventricular cushions (AVC) and the developing outlet septum (OS). Note that the right ventricular aspect of the primary septum shows smooth (S) and trabeculated (T) components. OF = oval foramen:

Ao = aorta: PT = pulmonary trunk.

260

length in its own right at the initial phase of advanced organogenesis. and corresponds exter- nally with the atrioventricular groove. Within the lumen of this junctional component are found the prominent endocardial atrioventricular cushions (Fig. la). By the completion of advanced organo- genesis, the atrioventricular junctional region has been incorporated into the adjacent ventricular component so that, by then, it is truly a junction between adjacent segments (Fig. lb).

The ventricular segment of the heart tube is septated by means of the primary ventricular sep- tum, which forms concomitant with the trabecular components of the developing morphologically right and left ventricles. The site of the septum is marked externally by the interventricular groove. continuous superiorly with the inner curvature of the heart loop. It seems probable that a further component of the ventricular septum is developed within the descending limb of the ventricular loop, and that the commitment of the right atrioventric- ular junction to the developing right ventricle is intimately related to the way in which this septal component achieves union with the atrioventricu- lar endocardial cushions and the primary ventricu- lar septum. The ventricular segment itself, at the beginning of advanced organogenesis, commences at the distal surface of the atrioventricular (inflow) endocardial cushions and extends to the proximal surface of the structures which septate the outflow (or ventriculo-arterial junctional) segment. This outflow segment differs from species to species in terms of the structures which are contained within it. It contains either four endocardial cushions or two endocardial outflow ridges. In those species with cushions (including man), these are arranged in proximal and distal pairs which can be des- ignated right and left and ventral and dorsal, respectively. The two ridges, when present, can be distinguished as right and left according to the position of their proximal ends. The outflow seg- ment, the distal part of the ascending limb of the cardiac loop, finishes at the arterial component. which extends into the branchial region. The arterial component is septated by the arterial sep- tum which is derived from peribranchial mesenchyme. It is known that the neural crest makes important contributions to this arterial sep-

tum [5,6]. which divides the arterial segment into aortic and pulmonary trunks.

Division of the ventriculo-arterial junction (or outflow segment) is intricately tied up with the process of connexion of the aortic component of the arterial segment to the developing left ventricle. This, in turn, is related to closure of the em- bryonic inter-ventricular communication. The in- terventricular communication, initially, is located between the components of the heart tube from which develop the trabeculated portions of the right and left ventricles. This initial communica- tion can be designated as the primary interventric- ular foramen. The boundaries of the hole undergo marked distortion and moulding as the heart de- velops so that the right atrioventricular junction becomes connected to the developing morphologi- cally right ventricle, and the subaortic outflow tract becomes incorporated within the morpho- logically left ventricle. It is conventional to recog- nize secondary and tertiary stages in the modifica- tion of the interventricular communication, such that the hole which is eventually closed to com- plete ventricular septation is described as the ter- tiary foramen (Fig. 2). The precise mechanisms of this process remain to be established, but it is closure of the interventricular foramen which is taken to represent the end of the phase of ad- vanced organogenesis.

The phase of fetal growth

The embryonic inter-ventricular communication is closed in humans by the end of the second month of development, at which stage the entire embryo is no more than 2 centimetres long from crown to rump. Fetal growth then continues for a further seven months, by which time, at birth, the embryo has increased amazingly in size. Remarka- bly little is known concerning this phase of devel- opment. Crucial events occur after the completion of organogenesis, such as formation of the leaflets of the atrioventricular and arterial valves and sep- aration of the atria1 and ventricular muscle masses at the atrioventricular junction (Fig. 3). It is in those areas that most work is needed, particularly to resolve problems such as the way that the leaflets of the arterial valves are formed across the

__

Atriov.entricular groove

xoss

Fig. 3. These sections. from an embryo of about 7; weeks gestation. shortly after the completion of septation, show how the atria1

and ventricular walls are in muscular continuity across both the right (a) and left (b) atrioventricular junctions.

anatomic ventriculo-arterial junction, the base of each leaflet being attached to ventricular struc-

as morphologically right and left structures and,

tures while the apex of the commissures are at- similarly, the point at which the pattern of ventric-

tached to the arterial wall (Fig. 4). Further matters ular trabeculations serve to distinguish the right

are deserving of attention, such as the stage at and left ventricles. While there is much to be done

which the atria1 appendages become recognizable concerning organogenesis there is, perhaps, even more to be accomplished concerning mechanics of

Fig. 4. These dissections show that the leaflets of the pulmonary

valve do not have an “annulus” in the sense of a circular

fibrous ring. The leaflets are attached in semilunar fashion.

ascending to the commissures (asterisks) and descending to the

bases of the leaflets (arrows). These attachments cross the

circular junction of the wall of the pulmonary trunk and the

muscular infundibulum.

cardiac development within the phase of fetal growth.

Discussion

The vocabulary proposed is the outcome of many hours of discussion between the various interested parties of the Working Group on Em- bryology and Teratology of the European Society of Cardiology. Even amongst the members of the working group, it is unlikely that there will be universal approbation of all the suggested terms.

The table, as far as we can judge, represents the overall consensus of those working within Europe on the development of the heart. The scheme was deliberately formulated so as to avoid previous arguments which surrounded nominative terms such as “primitive ventricle” or “bulbus”. There was a constituency of thought which suggested that it might be preferable to avoid terms such as “ ventricle” or “atrium”. This notion was dis- carded when it was realised that one of the main purposes of studying development is to elucidate the steps leading to formation of the definitive organ. It would have been self-defeating, there- fore, to expunge from our vocabulary the names of the very structures the development of which is being examined. We have, nonetheless, only used names such as “atrium” and “ ventricle” when the developing structures are recognizable with rea- sonable certainty as the precursors of the defini- tive structures. It is our belief that adoption of the terminology as suggested would remove from the field those non-productive arguments which relate to semantics rather than scientific observations. None of the suggested terms seem contentious to us. But then, we have been intimately involved with their formulation and we recognise our own bias in this respect, If a vocabulary is to be of value, it has to be used. We hope that the pro- posed terminology will, indeed, be used. We in- tend to use it ourselves. But we are open to further suggestions concerning modifications and im- provement. Hopefully, this will be one step which will lead cardiac embryology from the armchair and to the workbench. Any progress will help to elucidate those important mechanisms which still remain to be unravelled concerning the normal and abnormal development of the human heart.

1

2

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