Heart Tube Formation

The cardiovascular system is derived primarily from the splanchnic mesoderm, which develops on the 15th day after ovulation. Migrating cells form the cardiogenic crescent, which fuses in the midline as embryonic folding occurs, creating the heart tube by day 20 to 21 of development. The heart begins to beat on day 22 of development. At this time, the heart tube segments begin to differentiate, with constrictions demarcating specific segments of the tube (Figure 42-1). Most cranially, the bulbus cordis leads into the truncus arteriosus, which connects to the aortic sac, the aortic arches, and the dorsal aorta. Caudal to the bulbus cordis is the primitive ventricle followed by the primitive atrium, which is connected in turn to the sinus venosus. Between these segments, transitional zones exist that will become septa, valves, conduction tissue, and fibrous skeleton structures.

Figure 42-1 Formation of the heart tube and looping.

Cardiac Looping

The crucial process of cardiac looping evolves over day 23 to 28 of gestation, with the bulbus cordis of the heart tube bending ventrally, caudally, and toward the right of the embryo, forming a D-looped heart (see Figure 42-1). This positions the proximal bulbus cordis to become the future right-sided right ventricle and the primitive ventricle to become the future left-sided left ventricle while also positioning the atria dorsal to the future ventricles (Figure 42-2). The process and direction of looping appear to be under genetic control within the myocardium, with dysregulation of this process potentially resulting in abnormal positioning of the four chambers of the heart, such as occurs in an L-looped heart (i.e., ventricular inversion). Through looping, the transitional zones are brought together along the inner curvature, and the primitive chambers are more predominantly located along the outer curvatures. Shortly after the completion of looping, blood begins circulating within the embryo and cardiac septation begins, as does the formation of the aortic arches.

Figure 42-2 Fate map of looped heart tube.

Endocardial Cushion Development and Atrial Septation

After looping has completed, the division of the four chambers and ventricular outflow tract must begin through division of the atrial and ventricular structures via the endocardial cushions, and division of the right and left sided structures through a complex process of septation (Figure 42-3). The endocardial cushions develop early in this process, appearing at the level of the future atrioventricular (AV) valves. Inferior and superior endocardial cushions grow toward each other, dividing the common AV canal into left and right AV openings. In so doing, they establish the site of the future AV valves, which will develop between the fifth and eighth weeks of development through a process of invagination of the cardiac wall.

Figure 42-3 Development of cardiac septa.

Around day 26 to 28, atrial septation begins with formation of a crescent-shaped membrane from the posterior-superior wall of the atria, called the septum primum. On day 35, septum primum begins to extend toward the fusing endocardial cushions, gradually separating the left atrium from the right atrium. The endocardial cushions of the AV canal continue to develop and separate the atria, closing the ostium primum (see Figure 42-3). Failure of the aforementioned processes results in AV canal defects, frequently associated with trisomy 21. Classical embryologic teaching has been that before completing the division between the two atria, perforations develop in the septum primum, creating the foramen secundum, allowing continued flow between the two atria. However, virtually all hearts that have a septum primum display a crescentic superior edge with attachments on both ends of the crescent and no remnant of septum primum above the crescent indicating that there is no hole within septum primum but rather that the crescent shape was there originally.

Septum secundum is an infolding of the atrial wall, typically where the truncus arteriosus indents the roof of the embryonic atrium. This structure is thick and muscular unlike the septum primum, which is thin and membrane-like. The septum secundum grows posteriorly and inferiorly and forms the limbus of the fossa ovalis by day 42. The space between these two structures is the foramen ovale, which allows continued right-to-left blood flow between the atria during the fetal period.

During this time, the systemic (superior and inferior venae cavae) and the pulmonary venous connections are also incorporated into the right and left atria, respectively. Abnormal progression of atrial septation can result in ostium secundum atrial septal defects (defects in the septum primum) and ostium primum atrial septal defects (defects in formation or fusion of the endocardial cushions)

Ventricular Septation

Ventricular septation also involves coordination of multiple converging septal structures (see Figure 42-3). The muscular interventricular septum begins development by day 30 and continues into the seventh week of life. While the muscular ventricular septum is forming, myocardial trabecula develop in both ventricles. The posterior portion of the muscular septum is the inlet ventricular septum, smooth walled and close to the AV canal, and the anterior portion, called the primary ventricular fold or septum, is trabeculated. The muscular septum growth slows in the seventh week of life, but ventricular septation continues between 36 and 49 days of life with the closure of the infundibular septum (separating pulmonary outflow area from aortic) and closure of the membranous ventricular septum (closed by fusion of the left and right bulbar ridges along with the posterior endocardial cushion). Depending on the location, defects in ventricular septation can result in five major types of ventricular septal defects, which are further discussed in Chapter 43.

Development of Major Aortic and Pulmonary Outflow Tracts

Development of the ventricular outflow tract and aorticopulmonary septa require division of the associated left and right-sided structures such that the right ventricle flows into the newly developed pulmonary artery and the left ventricle flows into the aorta. The specifics of this process are controversial, with multiple theories currently being explored, generally involving the formation of bulbar and truncal ridges through a process that appears dependent on neural crest cells (Figure 42-4). During this process, expansion of the bulbus cordis beneath the left-sided pulmonary artery with regression of muscle beneath the right-sided aorta while maintaining the fixed position of the superior aorta relative to the pulmonary artery at the level of the bronchus causes the outflow tract to twist around itself, bringing the pulmonary artery closer to the right-sided morphologic right ventricle and the aorta closer to the morphologic left ventricle. Abnormal migration of neural crest cells in certain conditions, such as DiGeorge syndrome, may account for their associated conotruncal anomalies, such as tetralogy of Fallot, truncus arteriosus communis, and interrupted aortic arch with ventricular septal defect.

Figure 42-4 Outflow tract septation.

Development of the Great Arteries

The great arteries are formed through the division of the truncus arteriosus, with more distal portions of the aorta and pulmonary arteries developing from the paired embryonic aortic arches. The aortic arches develop sequentially during early gestation, with the final pair appearing by the sixth week of development (Figure 42-5). The first aortic arches develop into the maxillary arteries and portions of the external carotid arteries. The second pair of aortic arches provides circulation to the stapes in the inner ear as well as the hyoid artery. The third pair of aortic arch arteries develops into the common carotids and the proximal portion of the internal carotid arteries. The fourth pair of aortic arch arteries has asymmetric development, with the left side developing into the aortic arch and the right side connecting the right seventh intersegmental artery (precursor of the right subclavian artery) to the right carotid to form an innominate artery. The fifth pair regresses without any known remnant structures in normal humans, although a persistent fifth aortic arch has been noted rarely. The sixth pair of aortic arches develops into the ductus arteriosus on the left with involution on the right. Through sequential development and regression, great artery arrangement is evident by the eighth week of development. Abnormal development during this process can result in coarctation of the aorta, double aortic arch, right-sided aortic arch, and anomalous right subclavian artery.

Figure 42-5 Aortic arch system.

Development of Major Systemic and Pulmonary Veins

The venous inflow tract, the sinus venosus, is originally connected to the common atrium but with asymmetric development such that the right horn is larger. During the fifth week of gestation, the sinus venosus becomes incorporated into the right-sided atrium and develops into recognizable systemic venous structures, including the superior and inferior venae cavae (right horn of sinus venosus) and the coronary sinus (left horn of sinus venosus). The pulmonary veins, in contrast, grow out of the left atrium toward the budding lung, with development beginning as a single vein during week 5 of gestation. Peripheral pulmonary veins develop within the lung and connect to the common pulmonary vein growing out of the heart. The common pulmonary vein and the proximal individual pulmonary veins are then incorporated into the left atrial wall, accounting for the smooth posterior wall of the left atrium. Failure of some or all of the pulmonary veins to incorporate with the left atrium can result in partial or total anomalous pulmonary venous connection. Incomplete incorporation of the common pulmonary vein may be the cause of cor triatriatum. Venous structures develop into significant portions of each atrium (including the sinus venosus on the right and the pulmonary veins on the left), resulting in smooth-walled compartments, with the original embryonic atria becoming the atrial appendages containing the pectinate muscles.

Development of Cardiac Conduction System and Coronary Vessels

The heart tube formed early in gestation has been observed to have peristaltic contraction by the third week of development. As development progresses, however, an organized conduction system must develop as well; this occurs through differentiation of primary myocardial cells into conducting myocardium. Additionally, the developing heart requires more active perfusion as its structure becomes larger and more complex, thus necessitating the development of the coronary vascular system, with cells from the epicardium working into the myocardium to develop the needed vessels.