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==THE DEVELOPMENT OF THE CARDIAC LOOP IN THE RABBIT, WITH ESPECIAL REFERENCE TO THE BULBOVENTRICULAR GROOVE AND ORIGIN OF THE INTERVENTRICULAR SEPTUM==

HENRY A. MURRAY, JR.

College of Physicians and Surgeons, Columbia University, N. Y.

SEVEN FIGURES

The process of union of the two lateral cardiac vessels to form the heart has recently been described in detail by Doctor Schulte as exemplified in the series of young cat embryos of the Columbia Collection. It was at Doctor Schulte's suggestion and under his supervision that I undertook to ascertain whether fundamentally the same processes took place in the embryo rabbit.

Earlier investigators had described how the lateral plexuses of blood-vessels, forming into two longitudinal endothelial tubes in the splanchnopleure, unite in the midline to create a cylindrical median structure — the heart; and they considered that during subsequent growth the heart became coiled to accommodate itself within the pericardium. Doctor Schulte's investigation, previously mentioned, showed that it was not such a simple process, but that a number of very interesting factors were responsible for the changes that took place. Through the kindness of Dr. F. T. Lewis in putting at my disposal the beautiful Harvard series of rabbit embryos and by his guidance and suggestions, I was able to study the fusion and subsequent history of the heart in another species. Approximately forty embryos from the Harvard rabbit and Columbia cat series were examined under the microscope and a dozen and a half models were constructed in wax, according to the Born method. The cat embryos were cut in 13.3/x sections, whereas the rabbits were cut in 6/x or 10/z sections, mostly transverse. The thicker sections are less apt to be damaged, pile into better models, and under some conditions are to be recommended. For the finer details, however, thin sections are naturally the more desirable. The embryos were variously stained. My observations lead me to believe that the development of the rabbit heart tallies in every important respect with that of the cat.

In the accompanying diagram (fig. 1), the schema usually presented to portray the formation of the cardiac loop may be contrasted with a parallel series of figures representing Doctor Schulte's findings. Note that the initial and final stages in each



Fig. 1 A. Schema of cardiac loop formation; as presented in most modern text-books, based on the His models. B. Schema representing the same period of development, as observed by Doctor Schulte in the Columbia Laboratory. (Note that the bulboventricular clefts are formed in both hearts before fusion takes place, that the left groove together with the left shoulder of the ventricle becomes accentuated, that there is a corresponding obliteration of the right groove and shoulder, and that the venous end of the heart migrates to the left. These are the principal factors in the formation of the loop.)

case are the same, but that the intervening processes are dissimilar. Instead of reiterating Doctor Hchulte's conclusions, I will ask the reader to examine carefully figure 2 before reading the following explanation. It is a model of the endocardial cavity in a nine-day rabbit. The myocardial mantles, not represented in the model, have completely fused, but the endothelial tubes have not as yet entirely coalesced. The picture presents a condition previous to the complete amalgamation of the vessels to form a common cavity. Those points where the endocardia are still separate mark out the line of fusion of the two primitive tubes, and it is thus quite evident what portions of the cavityare derived from the right cardiac vessel and what portions from the left. 1

The elements represented are: a) the sinus venosus at the confluence of the vitelline veins; b) the canal between the sinus venosus and the ventricle, which, as the atrium develops at this point, we may call the atrial canal; c) the common ventricle,




Fig. 2 Model representing a cast of the cavities within the heart and the connecting vessels in a rabbit embryo of nine days. Ventral view. Harvard Embryological Collection, Series 619. 1, aortic branches; 2, right and left bulbs; 3, apertures formed by the septum dividing the bulboventricular canal; 4, right shoulder; 5, left shoulder; 6, aperture formed by the septum dividing the common ventricle; 7, atrial canal; 8, right vitelline vein; 9, left vitelline vein. X 100.



x The valuable study of the development of the pericardium in ferrets by Professor Robinson (Journ. of Anat. and Phys., 1902, vol. 37) has recently been extended by his pupil, Doctor Wang, with results which deserve more critical consideration than can be given here. Being concerned especially with early stages, Wang does not discuss the questions raised by Schulte, and his interpretation of the model shown in figure 2 would differ from ours, as may be seen by comparing it with his figure 31 representing the heart of a ferret of 13 to 14 segments. Wang's most interesting observation is of a 'primary heart rudiment,' a vessel crossing the median line and subsequently dividing into two endothelial tubes. The lateral vessels thus formed, or others somewhat posterior and leading to them, then reunite to make a 'secondary' heart. In the rabbits of the Harvard Collection, as Doctor Lewis informs me, there may be seen a strand of presumably angioblastic tissue in the region of the primary heart of Wang, but nothing which should be interpreted as a heart. At present, therefore, we are not inclined to recognize a heart previous to the union of the lateral cardiac vessels.

with a right and left shoulder; d) the restricted portion between ventricle and bulb, which may be called the bulbo ventricular canal; e) the bulb, and /) the arterial branches. The following points should be particularly noted: 1) the atrial canal has been forced to the left, and that portion of the canal contributed by the right heart has become relatively much reduced; 2) the left shoulder of the ventricle is elevated, the right depressed; 3) the left bulboventricular cleft is pronounced, the right is obscure, and 4) on account of the greater impression made by the left bulboventricular cleft that portion of the bulbar canal contributed by the left heart is diminished. Later, the right bulboventricular cleft disappears, the left becomes more pronounced and vertical, the atrium develops from the atrial canal growing cephalad behind the ventricles, and the cardiac loop is then complete. My observations commence at a stage when the original lateral tubes have become ventrally placed and are united through the intervention of a middle cardiac plate. The process by which this change is effected — a subject upon which Wang speculates at some length — will not be discussed. Attention will be focused on what may be considered the most fundamental aspects of the succeeding modifications, namely, 1) the middle cardiac plate with a consideration of its future history and possible connection with the interventricular septum, and 2) the bulboventricular groove.

MIDDLE CARDIAC PLATE AND INTERVENTRICULAR SEPTUM

In figure 3 observe the middle cardiac plate connecting the two hearts. It will be noticed that it is narrow cephalad, connecting the bulbs, and broad caudad between the ventricles. This mesothelial element gradually becomes incorporated into the myocardial walls of the enlarging ventricular cavity and is later represented in the rabbit by a ridge or series of ridges marking the original line of fusion. The ridges which are quite apparent on the inner aspect of the ventral wall are well shown in figure 4; they are placed opposite the septa which still remain between the two endothelial tubes (compare fig. 2). The early embryos of the cat in the Columbia series show similar ridges and also some intermediate stages. The rabbit differs from the cat in that this ental protrusion of the myocardia is a simple ridge and is not surmounted by a groove. Has this ridge any definite relation to the future interventricular septum? I think not. After modeling a number of rabbit and cat hearts between this stage an,d the stage when the interventricular septum is first apparent, I find no connection between the two. As shown in figure 4, when last observed the median ridge is directed towards the atrial canal. As the latter does not change its position until a later date, if the interventricular septum were a product of this ridge we should expect to find it at first obliquely placed




Fig. 3 Model of the myocardium (ventral view) from a rabbit embryo of nine days; H. E. C, Ser. 620. 1, right bulb; 2, left bulb; 3, right bulboventricular groove; 4, left bulboventricular groove; 5, right ventricle and shoulder; 6, left ventricle and shoulder; 7, middle cardiac plate. X 100.

and in line with the canal. This is not the case. On the contrary, we find a septum arising apparently as a thick muscular ridge from the most caudal portion of the ventricular loop, corresponding to a groove on the exterior. 2 Both septum and groove are sagittally placed and are not at this early stage directed towards the atrial canal (compare fig. 6). Furthermore, the septum appears at a considerably later date, after the common atrium is well formed and the ventricular wall has undergone great expansion and growth with considerable trabecular formation. In both the rabbit and cat embryos the increased



2 As Mall says, it is more correct to speak of the downward growth of the apices of the two ventricles than the upward growth of the septum.



34 HENRY A. MURRAY, JR.

growth in thickness of the ventricular wall is first manifest on the ventral wall and gradually spreads laterally and dorsally. In my series, the actual height 3 of the heart in the rabbit when the last sign of a middle cardiac plate can be determined is 0.32 mm., whereas the earliest sign of an interventricular septum is found in an embryo with an actual heart length of approximately 0.75 mm. Doctor Schulte, in the latest stage in which a middle cardiac plate was present in his material, found it continued caudad by a sulcus which he regarded as the beginning septum ventriculorum. Beyond this stage there was a gap in his material to the period of a well-developed septum with no remnant of the middle cardiac plate. My reason for dissenting from his conclusion that the median plate gives rise to the septum is that in the rabbit models and in embryos of the cat subsequently obtained the sulcus mentioned is found to disappear and the ventricle becomes evenly convex without a trace of indentation referable to the middle cardiac plate. Only later does the ventricular septum arise in the manner I have described. The interior of the model portrayed in figure 5 shows a smooth wall with no sign of a ridge, although at two points the endothelial tubes have not yet completely united. Considerably later, as the atrial canal is moved to the right while the interventricular septum remains fixed, the canal comes to be immediately dorsal to the septum ; the septum will then be seen to extend toward the centre of the canal and still later to become fused to the endocardial cushion. The subsequent development of these parts is beyond the scope of this paper.

THE BULBOVENTRICULAR GROOVES

These clefts first appear on each side before the lateral cardiac vessels have fused. They have been given this name because in their primary position they separate primitive bulb from primitive ventricle. Later, as we shall see, the bulb contributes to the right ventricle, and the left bulboventricular cleft may then be termed an 'interventricular groove.' In figure 3 the

3 As measured from the most cephalic to the most caudal points, regardless of what portions of the heart these may be.



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Fig. 4 Model of the myocardium (dorsal view of the ventral wall) from a rabbit embryo of nine days; H. E. C, Ser. 619. 1, bulboventricular canal; 2, left shoulder; 3, left bulboventricular groove; 4, right shoulder; 5, right bulboventricular groove; 6, inward protrusions of the myocardium in a line directed toward the center of the atrial canal; 7, sinus venosus. X 100.

Fig. 5 Model of the myocardium (ventral view) from a rabbit embryo of nine and one-half days; H. E. C, Ser. 565. 1, aortic branches; 2, bulb; 3, bulboventricular groove; 4, shoulder; 5, common ventricle; 6, right vitelline vein; 7, left vitelline. X 100.



36 HENRY A. MURRAY, JR.

grooves are horizontal. The left groove is already assuming a more significant r61e and the asymmetry forecasts future changes. In the cat this prominence of the left cleft is not accentuated until somewhat later. A subsequent stage in the rabbit is represented in the endothelial model, figure 2, and in figure 5 a fully developed cardiac loop is seen. The bulboventricular cleft (there is now only one, the right having become obliterated) is more oblique. From this stage onward there is a continual progressive extension of this furrow, and as it develops, its plane is modified so that in figure 6 we find it very nearly vertical. Notice in this drawing its relationship to the primitive septum. It is not in line with the latter structure. In the next period, however, the bulboventricular groove, formerly horizontal, is now vertical, protrudes into the ventricular chamber, becomes continuous with the septum, and together with it divides the cavity into right and left portions. This is well shown in figure 7. The division of the common ventricle then seems to be the result of four processes: 1) the interventricular septum growing cephalad from the floor of the loop; 2) the bulboventricular groove becoming vertical and forming the ventral portion of the septum; 3) the migration of the atrial canal to the right, allowing the endothelial cushions to play their part, and finally, as His has shown, 4) the downgrowth of the pulmonoaortic septum which fuses with the above-mentioned elements so as to form a continuous partition between the right and left hearts.

Fig. 6 Model of the myocardium (dorsal view of the ventral wall) from a rabbit embryo of ten and one-half days; H. E. C, Ser. 559. 1, bulb; 2, ridge extending into the common ventricular cavity and corresponding to the bulboventricular cleft; 3, shoulder; 4, interventricular septum (this is the first indication of the ridge found at the apex of the ventricular loop). X 100.

Fig. 7 Model of the endocardial cavity (ventral view) from a cat embryo of 7 mm. ; Columbia Collection, Series 266. By kind permission of Dr. A. J. Brown. In the Harvard Laboratory there is a very similar model of the cavities in the heart of a 4.4-mm. pig embryo, made in 1909, under Dr. Minot's direction, by Mr. A. E. Meyers. 1, cleft made by the ridge growing upward from the caudal extremity of the loop, which is continuous with 2, the impression made by the bulboventricular groove. Together they partially subdivide the ventricular cavity; 3, atrial canal; 4, left atrium. X 50.



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38 HENRY A. MURRAY, JR.

SUMMARY

The processes in the early development of the rabbit's heart are fundamentally the same as in the cat. 1) The primary loop is due to the deepening of the left bulboventricular cleft and a disappearance of the right, accompanied by a reduction on the part of the right shoulder of the ventricle and a very marked growth of the left. 2) The middle cardiac plate, marked temporarily after myocardial fusion by a distinct ridge which corresponds precisely to the line of fusion of the endothelial tubes, eventually becomes entirely obliterated. 3) The primitive interventricular septum arises de novo from the floor of the loop in a sagittal plane. 4) The left bulboventricular cleft, at first horizontal, becomes oblique and then vertical; protruding into the common ventricular cavity as a well-marked ridge, it meets the septum developing in the apical portion of the heart and contributes to the formation of the interventricular septum of the adult.



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CARDIAC LOOP IN RABBIT 39

BIBLIOGRAPHY

Bremer, J. L. 1912 Development of the aorta and aortic arches in rabbits.

Am. Journ. Anat., vol. 13, no. 2. Lewis, F. T. Intraembryonic blood vessels of rabbits from 8| to 13 days. Am.

Journ. Anat., vol. 3. Mall, F. P. 1912 On the development of the human heart. Am. Jour. Anat.,

vol. 13.

1912 Bifid apex of human heart. Anat. Rec, vol. 6.

1912 Aneurysm of membranous septum. Anat. Rec, vol. 6. Parker, K. M. The early development of the heart and anterior vessels in

marsupials with special reference to Berameles. Proc. Zool. Soc,

London, 1915, Pt. 3. Robinson 1902 Early stages of development of the pericardium. Journ. of

Anat. and Physiol., vol. 37. Rouviere, H. 1904 Etudes sur le developpement du pericarde chez le lapin.

Jour, de l'anat et de la physiol., vol. 11. Schtjlte, H. W. 1916 The fusion of the cardiac anlages and the formation of

the cardiac loop in the cat. Am. Journ. Anat., vol. 20, no. 1. . 1914 Early stages of vasculogenesis in the cat with especial reference

to the mesenchymal origin of endothelium. Memoirs of Wistar Institute of Anat. and Biol., no. 3. Strahl and Caritjs 1899 Beitrage zur Entwickelungsgeschichte des Herzens

und der Korperhohlen. Arch. f. Anat. und Physiol., Bd. 15. Tandler, J. Keibel and Mall. Manual of human embryology, vol. 2. Wang, Chtjng-Ching 1917 Earliest stages of development of the blood-vessels

and of the heart in ferret embryos. Journ. of Anat., vol. 52, part 1,