Early History

An organism of a cubic millimeter or so in volume (depending on the surface area and other factors related to the effectiveness of diffusion) may thrive without a vascular system. The human embryo enjoys the elaboration of a vascular system from its earliest stages, almost as if it can anticipate that its bulk will soon require a highly sophisticated transport system. As the embryonic disk becomes recognizable, blood islands rapidly accumulate around the periphery of the disk. These isolated “puddles” begin to coalesce and communicate with one another until the embryo resembles a bloody sponge. Most prominent is the precephalic region, where the seemingly random coalescence of blood islands forms a network in the region soon to be identified as the cardiogenic plate (Figure 2-1A).

FIGURE 2-1 A, Embryonic disk from above, with the head of the embryo facing upward. The dotted line indicates the plane of the longitudinal section below, with the cranial end to the left. In the section, the pericardial sac is above the heart tube, but as the head folds under the forebrain (direction of the large arrow), the positions of the heart and sac will be reversed, with the heart invaginating from above the pericardial sac. B, The two parallel primitive heart tubes (dorsal view) fuse in the midline to form a single heart tube and a single-chambered heart. C-E, Successive stages of the folding of the heart tube, viewed from the front. The venous end of the tube swings posteriorly to form the atria, whereas the arterial end (ventricles) remains anterior. This represents the loop stage.

(Adapted from Moore KL: The developing human, ed 3, Philadelphia, 1982, WB Saunders, 1982; and Rushmer RF: Cardiovascular dynamics, ed 2, Philadelphia, 1961, WB Saunders.)

In these earliest stages of development, the vascular system manifests some of its greatest mysteries: to what extent is the developmental pattern dictated by tissue needs and demands (possibly through the release of angiogenic factors or through stimuli provided by metabolic products), and to what extent is it dictated by factors such as extravascular pressures restricting flow in one set of possible blood channels and forcing the enlargement of adjacent alternative routes of blood flow? To what extent is the overall pattern dictated genetically? The similarity of the vascular tree from one individual to another favors the speculation that there is a detailed genetic code. The variability from one to another—each pattern seemingly equally efficient in supporting tissues and organs—argues for development according to need and use and based on mechanical and other adventitious factors.

In the case of the heart, a detailed genetic code is surely the guiding factor. Here, curiously, we begin with a parallel pair of cardiac tubes that fuse into one large tube; the latter then divides internally into the right and left hearts. At first glance, this seems inefficient. Why not simply have each original tube of the pair form a right or left heart? The reason is clear when examining the details of internal division of the heart, in which the single outflow tract is divided in such a way as to connect the right heart to the primitive vessels supplying the pulmonary circuit and to connect the remaining members of the branchial arch arteries to the left heart.

Heart

Our interest in the development of the heart in this chapter is restricted to its bearing on the origins of the great vessels. The heart is simply a highly modified artery from both histologic and embryologic viewpoints. Histologically, it resembles a muscular artery because it has three layers to its walls: adventitia (epicardium), tunica media (myocardium), and tunica intima (endocardium). At the beginning, the heart tubes are simply a parallel pair of vessels, seemingly little different from the other components of the random network of primitive blood vessels. Nonetheless, the fusion of these two tubes and the development of a feeble myocardial investment around the endothelium quickly lead to irregular contractions of the musculature, with feeble and inefficient ejection of blood. Subsequent events include the development of septa, dividing the single-chambered heart into right and left halves, and the appearance of valves that dictate unidirectional flow. The heart is beating with increasing regularity and with an efficiency-improving peristalsis and force as the myocardial element thickens and cytodifferentiates. Presumably from these first feeble, sporadic beats there is a stirring of the blood contents of the primitive vessels, perhaps providing some benefit to the growing tissues around them and perhaps beginning to stimulate the enlargement of those channels that will survive into later embryonic stages. Beginning to channel blood through preferred pathways leads to closure and disappearance of less satisfactory routes and enlargement of the more successful channels into definitive blood vessels that are soon worthy of names recognizable in terms of the adult circulatory pattern. Channel formation from blood islands might be influenced simply by the choice of the lowest resistance among the available pathways.

The now-fused heart tube (see Figure 2-1B) begins to invaginate the presumptive pericardial cavity, acquiring its visceral and parietal layers of pericardium while still a single-chambered heart configured as a simple, relatively straight tube. As the somites begin to appear in the neck and trunk region, the heart tube begins to fold on itself, first bulging ventrally, further invaginating the pericardial sac. The heart that is now swinging ventrocaudally comes to lie in front of the head and will continue its descent down the front of the neck and into the anterior chest. The ventrally directed bulge created by the U-shaped fold of the heart characterizes the loop stage.¹ The ventral limb of the U is the arterial outflow path, and the dorsal limb of the U will become the venous inflow tract (see Figure 2-1C to E). By the 10-somite stage, approximately 3 weeks’ ovulation age, the heart has begun to fold in a coronal plane as well, directing the ventricular region to the left and forming a recognizable outflow tract, now termed the bulbus cordis, whose distal part is called the truncus arteriosus (see Figure 2-1C). At this stage, the heart is still a single-chambered structure innocent of valves but completely enclosed in a pericardial sac and demonstrably beating, albeit irregularly. There is no single primordium, no segment of the primitive heart tube, that can be identified as leading to a specific cardiac cavity in the early postloop stage. Instead, there are microscopically and experimentally identifiable zones, each of which gives rise to a specific anatomic region of a definitive cardiac cavity. These primordia are most accurately termed primitive cardiac regions; therefore referring to segments of the heart tube as forerunners of the chambers of the fully formed heart is misleading.¹ The folds in the heart tube and the peristaltic nature of myocardial contraction lead to a predetermined direction of flow out through the bulbus cordis, the folds acting as inefficient valves to direct the flow. Such early vitality is not surprising, because the cardiovascular system is the earliest to attain form and function among the organ systems of the body. The heart is disproportionately large for the size of the embryo at this stage, and this disproportion remains until birth, with only a modest decline in heart-to-body ratio toward birth. Obviously, this occurs because the heart must support not only the growing tissue of the organism but also the embryo’s share of the enormous placental circulation.

It is worth digressing here to emphasize the functional problems faced by the developing heart. It is required to form and to function in such a way as to maintain and support the growth of the developing organism in an intrauterine (aquatic) environment; that is, it must support an organism incapable of independent gas exchange and dependent on the placenta for oxygen and nutriments and for other metabolic exchange. The lungs are developed rather late and require only to be supplied with enough blood to support their growth. To perfuse the embryonic lungs with a rate of blood flow commensurate with an air-breathing existence would be energetically inefficient and perhaps an impediment to their growth and development, but during the early stages of development of the cardiovascular system, the lungs are simply not sufficiently developed to be called anything other than buds, volumetrically incapable of containing any significant quantity of blood. As a result, the heart must develop a mechanism whereby it can support the organism in an aquatic environment with extensive exchange across the placenta and provide adequate distribution of blood throughout the growing body of the embryo; however, it must simultaneously develop a configuration that will enable it to shift its mode of function instantly at birth to support the organism by way of pulmonary gas exchange. Simply put, in fetal and embryonic life, the two sides of the heart function as two pumps operating in parallel, with the output of both ventricles distributed to the placenta and to the growing tissues of the body, and with no interdependence of the output. However, the two hearts must have the means to shift from functioning in parallel to functioning in tandem at birth, wherein the outflow of one heart becomes the inflow of the other, and blood is obligated to perfuse the pulmonary circuit, return to the heart, and then perfuse the systemic circuit, and so on. One emphasis of this chapter is to focus on the development of features that render the heart capable of these sequential and different modes of function.

Arteries

During the early folding of the heart, and with identification of a bulbus cordis and truncus arteriosus as an outflow tract, the aortic arches are beginning to form. The truncus arteriosus is continuous with a ventral aorta. This large, single-channeled artery is connected to a pair of dorsal aortas through a series of branchial (pharyngeal) arch arteries. The developing pharynx passes through a period in its development when it is said to mimic the development of the gill apparatus of fish. Outpouchings of the pharyngeal wall grow as pockets toward the surface, where they are met or at least approached by corresponding infoldings of the ectodermal surface. Normally these outpouchings and infoldings neither meet nor coalesce to form gill slits or fistulas. The supporting tissue on both sides of the pouches is endowed with a cartilaginous supporting bar, a nerve, and a blood vessel, respectively known as the branchial arch (pharyngeal) cartilage, branchial arch nerve, and branchial arch artery. The first such cartilaginous bar is Meckel’s cartilage, in front of the first pharyngeal pouch; the second, Reichert’s cartilage, lies between the first and second pouches. The pharynx is supported by six arch complexes, surrounding and intervening between the pharyngeal pouches. The arteries of these arches are the connectives from the ventral aorta to the dorsal aortas, and they appear in sequence from cranial to caudal. Rarely are more than three such arch arteries identifiable at one time; in this case, as elsewhere in the embryo, the cranial development leads or precedes that occurring more caudally. As the fourth arch artery appears, the first is being transformed into its successor structures and ceases to be identifiable as an arch artery. In humans, there are five such arch arteries, numbered 1, 2, 3, 4, and 6, in recognition of the dropping out in phylogeny of the fifth arch artery, which has no significant role in human development (the fifth pharyngeal pouch fuses with the fourth at its opening into the pharynx; its rudimentary arch between the fourth and fifth pouches contributes to the formation of the larynx). In contrast to the constancy of innervation of the derivatives of the pharyngeal arches, the vascular supply to the arches is subject to later, often extensive modification. The motor nerve to an arch persists throughout phylogeny and throughout ontogenetic development in supplying the derivatives of that arch (first arch, mandibular nerve; second arch, facial nerve; third arch, glossopharyngeal nerve; fourth through sixth arches, recurrent and superior laryngeal nerves and vagal pharyngeal nerve). The geometric representation of the arch artery pattern and the fate of those arteries are summarized in Figure 2-2. The paired dorsal aortas sweep posteriorly and fuse in the midline to form a single dorsal aorta (see Figure 2-2, inset) posterior to entry points of the arch arteries.

FIGURE 2-2 Fate of the branchial arch arteries. A, Primitive arrangement of six arch arteries. Arches 1 and 2 have formed and have been accommodated into the vessels of the head (dotted lines indicate arteries that are no longer arches—that is, 1, 2, and 5). Arches 3, 4, and 6 connect the ventral aorta (aortic sac and truncus arteriosus) with the paired dorsal aortas. The latter fuse posteriorly to form a single dorsal aorta. B, Subsequent disposition of these vessels. The dotted lines indicate vessels that normally disappear, including the right sixth arch beyond the right pulmonary artery. The glossopharyngeal nerve (motor to the third arch) and the recurrent laryngeal nerve (motor to the sixth arch derivatives) are shown. The recurrent laryngeal nerve is a branch of the vagus “recurring” around the sixth arch in A; in B, these nerves recur around the ductus arteriosus and around the right subclavian. Inset, The first three aortic arch arteries from the front (ventral) view during the branchial period. At no time are all arch arteries evident at the same time. The paired dorsal aortas unite into a single dorsal aorta posterior to the entry of the arch arteries. The postbranchial period, when the heart descends from the branchial region into the chest, is characterized by modification of the arch system into the adult disposition of the derived arteries.

The lungs begin their development as a ventrally directed outgrowth from the pharynx, and the single tube that will become the trachea descends into the presumptive chest cavity, where it branches into a pair of lung buds. These buds receive a small blood supply from branches of the sixth aortic arch arteries (see Figure 2-2A). Clearly the sixth arch arteries will have a role in the development of the pulmonary arterial tree. The developmental problem posed here is that the sixth arch arteries are initially part of the systemic circulation, simply representing the most caudal of the branchial arch arteries springing from the truncus arteriosus and uniting with the dorsal aortas. In the division of the heart tube into right and left hearts, some provision must be made for joining the right ventricular outflow tract to the sixth arch arteries and joining the remainder of the great branchial arch system and aortas with the left ventricle. The rationale for fusion of the primitive heart tubes into a single channel and subsequent division is now clarified by this need to divide the bulbus cordis and truncus arteriosus into a pulmonary artery and an aortic artery. The manner of that division solves the problem of connecting the right ventricle and the developing pulmonary artery to the lungs and connecting the remainder of the arch arteries to the systemic circulation and the left ventricle. The interested reader is encouraged to examine the article by Congdon² for further clarification of this point.

The heart is divided into four chambers that compose two separate hearts, with provision for a parallel mode of function before birth and a tandem mode after birth. The umbilical veins (after the sixth week, a single left umbilical vein) return blood to the fetal heart by their union with the inferior vena cava. This return route sees the umbilical vein enter the liver, where a shunt, the ductus venosus, bypasses the complex hepatic circulation and shunts the blood directly into the inferior vena cava. Thus, the right atrium receives a supply of freshly oxygenated blood, in contrast to the adult condition. Before separation of the right and left atria, that placental return is into the single atrial chamber, which is diagrammatically depicted in Figure 2-3A. The single chamber undergoes a constriction in the plane of the atrioventricular orifices and the atrioventricular sulcus on the exterior of the heart. From the margins of this constriction, endocardial cushions grow inward to begin the formation of the tricuspid and mitral valves. The single atrium begins its separation into halves by downgrowth from the dorsocranial wall of a filmy crescentic curtain—the septum primum (see Figure 2-3B). The leading invaginated edge of the crescent grows down toward the floor of the single atrium; that floor forms by virtue of the growth of the atrioventricular valve primordia. Figure 2-3B shows the septum primum from the right side as it progresses toward complete closure of the single atrial chamber in its midline. In addition, just before the foramen primum closes, a group of perforations forms in the dorsocranial part of the partition (see Figure 2-3B) and then coalesces into a foramen secundum (see Figure 2-3C). This process is necessary because throughout this developmental sequence, the heart is pumping blood to and returning it from the placenta, and the returning blood must be shunted from the right side of the heart into the left atrium in large volume to sustain the systemic circulation. Therefore at no point in fetal life may the right and left atria be functionally separate. During the time that the placental circulation is intact, the pressure in the right atrium exceeds that in the left atrium, and a right-to-left shunt will be operative. As a result, the foramen secundum opens just in time to continue that shunt as the foramen primum closes. Next, on the right side of the septum primum, a much more robust and rigid septum secundum begins its downgrowth, following the same pattern as that of the septum primum (see Figure 2-3C); a crescent-shaped leading edge grows down from above toward the endocardial cushions that will finally separate the atria from the ventricles. This downgrowth of the septum secundum comes to overlie the orifice of the foramen secundum. Fortunately, the septum secundum is sturdy and relatively unyielding, whereas the septum primum is thin and curtainlike. As long as the free lower edge of the septum secundum fails to reach the floor of the atrium, thus forming the foramen ovale, the elevated pressure in the right atrium pushes blood through the ovale, deflecting the septum primum and allowing blood to pass through the foramen secundum into the left atrium and permitting continuation of the obligatory right-to-left shunt. Inasmuch as the downgrowth of the septum secundum is arrested, leaving a fixed foramen ovale, such a shunt operates throughout the intrauterine life of the organism. The orifice of the foramen ovale is just above and medial to the orifice of the inferior vena cava (see Figure 2-3D), so that inferior caval (i.e., placental) blood is preferentially directed into that foramen, and then into the left atrium, with remarkably little mixing of this oxygenated blood with the oxygen-poor blood returning via the superior vena cava.