Embryology and Etiology

The First Week of Life

The salient events of the first week of life ( Fig. 2.1 ) are (1) ovulation, (2) fertilization, (3) segmentation, (4) blastocyst formation, and (5) the beginning of implantation.

A living human ovum surrounded by its corona radiata is shown in Fig. 2.2 . The single-celled ovum stage is Streeter’s horizon 1. This ovum is thought to be 1.25 days old or less. One cannot tell by inspection whether this ovum has been fertilized. Fertilization normally occurs in the distal fallopian tube (see Fig. 2.1 ).

When fertilization has occurred, the next stage is known as cleavage . The large single-celled ovum undergoes mitotic division forming two cells ( Fig. 2.3 ). A rapid succession of mitotic divisions produces a progressively larger number of smaller cells known as blastomeres ( blastos = offspring or germ, and meros = part, Greek). A morula is shown in Fig. 2.4 . A morula consists of 16 cells with no central cavity. Morula means “little mulberry” ( morus = mulberry, Latin). This solid mass of blastomeres, formed by the cleavage of a fertilized ovum, fills all the space occupied by the ovum before cleavage. The stage of cleavage ( Figs. 2.3 and 2.4 ) is Streeter’s horizon 2 . Cleavage occurs during the voyage of the zygote down the fallopian tube and into the uterine cavity. It is thought to take 3 to 4 days to reach the morula stage.

Then the morula develops a cavity, forming a blastocyst ( Fig. 2.5 ). Blastocyst literally means “offspring” or “germ” ( blastos , Greek) plus “bladder” ( kystis , Greek). The formation of a cavity (bladder) separates the thick inner cell mass (future individual) from the thin-walled trophoblast (future placenta). Trophoblast means “nourishment” ( trophe , Greek) plus “offspring” or “germ” ( blastos , Greek). The blastocyst stage is reached by 4½ to 6 days of age and constitutes Streeter’s horizon 3 .

Parenthetically, etymologies are included to help the reader to remember these terms. If one understands what a designation really means (its etymology), then it is much easier to remember.

The blastocyst begins to implant in the uterine mucosa at about 7 days of age, that is, 7 days after ovulation ( Figs. 2.1 and 2.6 ). Implantation is Streeter’s horizon 4 .

The Second Week of Life

The principal developments during the second week of life are summarized diagrammatically in Fig. 2.7 :

• 1.

  Implantation is completed.

• 2.

  A bilaminar disc of ectoderm and endoderm develops out of the inner cell mass.

• 3.

  The amniotic cavity appears.

• 4.

  The yolk sac develops.

• 5.

  Primitive villi of the developing placenta make their appearance.

At the beginning of the second week, that is, at about 7½ days of age, the zygote normally is implanted, but the trophoblast still has no villi. This stage is horizon 5 ( Fig. 2.8 ).

About 2 days later, that is, at 9 days of age, primitive villi are seen ( Fig. 2.9 ). The embryonic disc is now bilaminar, consisting of columnar ectodermal cells and cuboidal endodermal cells. The amniotic cavity and the yolk sac can now be seen. This is Streeter’s horizon 6 . The embryo shown in Fig. 2.9 closely resembles the diagram of Fig. 2.7 .

Although the cardiovascular system is the first organ system to reach functional maturity, during the first two weeks of life, humans have no heart and no vascular system; that is, the cardiovascular system does not yet exist.

What germ layer does the cardiovascular system come from? From the mesoderm. But where does the mesoderm come from? As will soon be seen, from the ectoderm.

Ectoderm means “outside skin” ( ektos = outside + derma = skin, Greek). Endoderm means “inside skin” ( endon = within or inside + derma = skin, Greek). Mesoderm means “middle skin” ( mesos = middle + derma = skin, Greek).

The Third Week of Life

The main events during the third week of embryonic life from the cardiovascular standpoint normally are:

• 1.

  the development of the mesoderm from the ectoderm on the 15th day of life,

• 2.

  the appearance of the cardiogenic crescent of precardiac mesoderm on the 18th day of life,

• 3.

  the development of the intra-embryonic celom on the 18th day of life,

• 4.

  the development of the straight heart tube at 20 days of age,

• 5.

  the beginning of D-loop formation in normal development, or the beginning of L-loop formation in abnormal development, at 21 days of age, and

• 6.

  the initiation of the heartbeat at the straight tube stage or at the early D-loop stage.

In somewhat greater detail, the main events in the development of the cardiovascular system during the third week of embryonic life are as follows:

• 1.

  The mesoderm develops from the ectoderm, appearing in the normal human embryo on the 15th day of life ( Fig. 2.10 ). Note that the villi are branching and that the primitive streak has appeared, these being the features that typify horizon 7.

  

The primitive streak is a depression that marks the long axis of the embryo when viewed from the dorsal aspect ( Fig. 2.11 ). As the mesoderm buds off from the ectoderm, the right-sided mesoderm migrates rightward and then cephalically, while the left-sided mesoderm migrates leftward and then cephalically. Since the mesoderm remains ipsilateral (right remains right sided and left remains left sided), rather than crossing the midline, the result is a depression between the right-sided and left-sided mesoderm—the primitive streak—that marks the long axis of the embryo when viewed from its dorsal or amniotic sac aspect ( Figs. 2.11 and 2.12 ). This lateral and then cephalic migration of the mesoderm bilaterally can be well documented in explanted chick embryos by cinephotomicrography. I have made many movies of this process.

• 2.

  The cardiogenic crescent of precardiac mesoderm appears on day 18 in the normal human embryo. The left-sided and right-sided precardiac mesoderm unite in front of the developing brain, forming a horseshoe-shaped crescent of precardiac mesoderm, as in Carnegie embryo 5080 of Davis ( Fig. 2.13 ). The reconstruction of this embryo is shown in Fig. 2.14 . This embryo was 1.5 mm in length. The first pair of somites was just forming. This stage corresponds to Streeter’s late horizon 8 (no somites) and early horizon 9 (one to three pairs of somites), that is, at the junction of horizons 8 and 9 (horizon 8/9). A late horizon 9 embryo with three pairs of somites is shown in Fig. 2.15 .

  
  
  

The notochord gives our phylum its name: Phylum Chordates . This phylum includes all animals with a notochord and is essentially synonymous with the craniates and the vertebrates.

The prochordal plate , as its name indicates, lies anterior to (in front of) the notochord. The prochordal plate consists of ectoderm and endoderm, is never normally invaded by mesoderm, and subsequently breaks down, contributing to the formation of the mouth.

The cloacal membrane caudally also is normally not invaded by mesoderm. This membrane subsequently breaks down to help create the cloacal opening.

• 3.

  The intraembryonic celom appears on the 18th day of life, in horizon 9, because the mesoderm cavitates (see Fig. 2.15 ). The mesoderm splits into dorsal and ventral layers, which are separated by the intraembryonic celom (or space). The dorsal layer of the mesoderm is called the somatopleure because this layer is adjacent to the body wall and forms, for example, the pericardial sac. ( Soma = body + pleura = side, Greek.) The ventral layer of the mesoderm is known as the splanchnopleure because this layer is on the inside, that is, on the visceral side. ( Splanchnos = viscus + pleura = side, Greek.) The splanchnopleure forms, for example, the myocardium.

The intraembryonic celom communicates with the extraembryonic celom ( Fig. 2.15 , arrows). The intraembryonic celom forms all of the body cavities, which at this stage are not divided from each other. The intraembryonic celom includes the future pericardial, pleural, and peritoneal cavities. Note that even the somites, which form the future skeletal muscles, contain small central cavities (see Fig. 2.15 ). The ability to form cavities is one of the more important characteristics of mesoderm.

In Fig. 2.15 , buccopharyngeal membrane is another name for the prochordal plate. The intermediate cell mass is early kidney (see Fig. 2.15 ). The brain is still a neural plate , not having formed a tubular structure as yet. The notochord indicates the long axis of the embryo. The somites ( soma = body, Greek) form from the paraxial mesoderm , the mesoderm that is beside ( para = beside, Greek) the long axis of the body, indicated by the notochord. By contrast, the heart forms from the lateral plate mesoderm , so called because it is lateral to the paraxial mesoderm (see Fig. 2.15 ). The precardiac mesoderm of the cardiogenic crescent then continues to migrate cephalically on the foregut endoderm to form a straight heart tube ( Fig. 2.16 ).

• 4.

  The straight heart tube or preloop stage normally occurs in the human embryo at 20 days of age ( Fig. 2.17 ). The straight heart tube stage can be achieved in the human embryo by horizon 9 , in Carnegie embryo 1878 of Davis and Ingalls that had two pairs of somites and was 1.38 mm in length ( Fig. 2.18 ). However, the straight tube stage often is not reached until horizon 10 , as in Carnegie embryo 3709 ( Fig. 2.19 ), with four pairs of somites, 2.5 mm in length, estimated age 20 to 22 days, and as in Carnegie embryo Klb ( Fig. 2.20 ), with six pairs of somites and a length of 1.8 mm.

  
  
  
  

At the straight tube stage, note that the endocardial lumina of the left and right “half hearts” may be largely unfused ( Fig. 2.20 ) or incompletely fused (see Fig. 2.19 ). The space between the myocardium and the endocardium is filled with cardiac jelly. As the precardiac mesoderm migrates cephalically and medially onto the foregut endoderm to form a straight heart tube, the foregut endoderm is growing caudally or posteriorly, as is well shown by my time-lapse movies in the chick embryo.

• 5.

  D-loop formation normally begins at the end of the third week of embryonic life in humans (see Figs. 2.16 and 2.17 ). By analogy with other vertebrates, it seems very likely that this is when the heart in human embryos starts to beat: Carnegie embryo 4216 ( Fig. 2.21 ), seven pairs of somites, 2.2 mm in length, horizon 10 (20–22 days of age); Carnegie embryo 391 ( Fig. 2.22 ), eight pairs of somites, 2 mm in length, horizon 10 (day 20–22); and Carnegie embryo 3707 ( Fig. 2.23 ), 12 pairs of somites, 2.08 mm in length, horizon 10 (20–22 days of age). When D-loop formation begins—the heart bending convexly to the right—the endocardial tubes have fused forming a single endocardial lumen. ( Dexter , dextra , dextrum are the masculine, feminine, and neuter adjectives, respectively, meaning “right sided,” Latin.)

  
  
  

At the horizon 10 stage (see Figs. 2.21–2.23 ), the future morphologically right ventricle (RV), which develops from the proximal bulbus cordis, is superior to the future morphologically left ventricle (LV), which develops from the ventricle of the bulboventricular loop. The future interventricular septum—between the bulbus cordis and the ventricle of the straight bulboventricular tube—lies in an approximately horizontal position. If an arrest in development were to occur at the horizon 10 stage (20–22 days of age), superoinferior ventricles would result, with the RV superior to the LV and the ventricular septum approximately horizontal. The atrioventricular canal, which is in common (not divided into mitral and tricuspid valves) at this stage, opens superiorly only into the ventricle—future LV. Hence, common-inlet LV is potentially present during horizon 10 (see Figs. 2.21–2.23 ). Both future great arteries originate only from the bulbus cordis (future RV). Thus, double-outlet RV would result from an arrest of development during horizon 10 (20–22 days of age).

To put it another way, common-inlet LV, superoinferior ventricles, and double-outlet RV are all normal findings at the horizon 10 (20–22 day) stage. This understanding illustrates why a knowledge of normal cardiovascular embryology appears to be so relevant to the understanding of the pathologic anatomy of complex congenital heart disease.

However, it must also be borne in mind that much remains to be learned concerning the etiology and morphogenesis of congenital heart disease. For example, if developmental arrest really is a pathogenetic mechanism leading to congenital heart disease, as is widely assumed, it remains to be proved when and why such developmental arrests occur in the human embryo. We think we know when —but this is only an extrapolation based on normal cardiovascular development—and we often have no idea why . Hence, in this chapter, I am not endeavoring to make implications concerning the causation of congenital heart disease. Instead, I am presenting factual data concerning normal cardiovascular development. The precise relevance of this understanding to the etiology and morphogenesis of human congenital heart disease remains to be proved. Nonetheless, when obvious correlations appear to exist, I will point them out, with the aforementioned mental reservations being understood.