Cardiac Embryology

Michiko Watanabe and Jamie Wikenheiser

The care of children with heart disease has increasingly become a neonatal specialty. Fetal diagnosis of congenital heart defects (CHDs) is now routine. Reparative cardiovascular surgery is commonplace in the first month of life in select cases and is now undertaken in utero. Defects once considered inoperable, most notably hypoplastic left heart syndrome, can be treated, with greatly improved long-term results. In parallel with these clinical advances, there has been exciting progress in understanding the cellular and molecular basis of normal and abnormal cardiogenesis and the relationship of heart defects to other congenital defects. Nonetheless, the incidence of CHDs has not decreased,⁴⁹ indicating much more work is required to find ways to prevent CHDs. The expansion in our understanding from combining clinical and basic science findings may lead us to better predict the severity and consequences of congenital heart defects and also lead to strategies for alleviating the consequences to children and adults.

The development of the heart has been a topic of study for hundreds of years. Nonetheless, many surprisingly basic questions have yet to be answered. For example, how does the cardiac pacemaking and conduction system develop, what factors allow the heart tube to bend and loop in one direction and not the other, and how does the coronary vasculature develop in a stereotyped pattern? With the deployment of new technologies and fields of study, these and other questions are being revisited, and answers are beginning to emerge. In combination with the traditional techniques, these new approaches have significantly advanced our understanding of normal and abnormal development.

Much of the current knowledge about cardiovascular development is based on studies of species other than humans, notably the chicken, quail, mouse, rabbit, fruit fly, and zebrafish. Remarkable similarities have been detected in molecular and cellular developmental mechanisms among these diverse species. Research on the developmental genetics of the fruit fly, for example, has made an impact on our basic understanding of genes important for vertebrate systems, including humans. In the other direction, information from clinics has been analyzed in detail in more easily accessible and manipulatable systems such as the fruit fly, zebrafish, chicken, or mouse. The distance between the bedside and the bench is getting shorter.

The mature heart is the product of gene expression driven by endogenous and exogenous influences. The developing heart manifests its morphologic and physiologic plasticity under stress. A detailed understanding of the effects of the factors that drive normal cardiogenesis is necessary for understanding the causes and consequences of abnormal development. Errors in cardiac morphogenesis involved with septation, valve formation, and proper patterning of the great vessels are responsible for most forms of congenital heart disease. Normal heart development requires precise timing for coordination of the complex three-dimensional contortions of tissues, but paradoxically, these tissues also have a remarkable capacity for regulation that allows compensation for mistakes. These adjustments can allow abnormal heart structures and functions to be compatible with life up to and even after birth, but complicates identification of the primary causes of cardiac anomalies.

It is possible to investigate cardiovascular development at various levels using a variety of disciplines: molecular biology, biochemistry, biomedical engineering, cell and tissue biology, genetics, physiology, and epidemiology. Significant results have emerged when information was shared across disciplines. For example, the hemizygous deletion in the elastin gene has been shown to be responsible for Williams syndrome (or Williams-Beuren syndrome), the autosomal dominant form of supravalvular aortic stenosis.³⁹ Predictions about the clinical manifestations of this disease were elucidated after mutant elastin proteins were found in humans; existence of these mutant proteins was proposed based on knowledge about the protein structure provided by studies at the bench. In the reverse direction, analysis of the mutant human proteins in animal models, tissue culture, and other in vitro studies advanced understanding of the disease and the biochemistry and role of elastin in vascular cell signaling. These signaling pathways may become targets for therapy. The passage of information across these investigative levels has resulted in a remarkably productive synergy.

Overview of Normal Heart Development

The following description of human heart development, especially the earlier events, is synthesized from information provided by studies of animal models and human embryonic and fetal tissues. A timetable of selected events in human heart development is presented in Table 79-1.^33,36,44 Figure 79-1 is a diagram depicting the major transitions in early mammalian heart development.⁴⁷

TABLE 79-1

Developmental Landmarks in Cardiac Morphogenesis

Week	Days	Somites	Length (mm)*	Stage^†	Developmental Events
3	15			VIII	(Primitive streak)
	16
	17
	18	1-3	1.5		Blood islands in chorion, stalk, yolk sac
	19
	20	1	1.5		Cardiogenic plate
	21	4			Tubes (2) connect with blood vessels
4	22	4-7	2	X	Tubes fuse
	23			X	Single median tube (first contractions), looping begins
	24	13-20	2.5-3	XI
	25
	26	21-29	3.5	XII	Cardiac loop
	27				Single atrium
	28	25	4-5	XIII	Bilobed atrium, primary AS begins growth
5	29		6-7	XIV	IVS appears
	30	28			Primary AS continues growth (placental circulation begins)
	31		7-8	XV	Ridges form inside outflow tract
	32				Primary AS begins perforation formation
	33		9-10	XVI
	34			XVII	Secondary AS begins to grow; primary AS has foramen secundum
	35		11-14		AV cushions begin fusion (three-chambered heart)
6	36				Arterial (aortic arch) and venous morphogenesis begins
	37		14-16	XVIII	IVS growing
	38
	39		17-20	XIX
	40				Septation of bulbus and ventricle, valve formation
	41		21-23	XX	IVS maturation continues, AV canal splits into two
	42
7	43		22-24	XXI	Beginning of separation of AV myocardial connection
	44		25-27	XXIII	(Fetal stages begin)
	45
	46
	47
	48
	49				Membranous and muscular IVS is complete, resulting in four-chambered heart
24-40			210-360		Birth and beginning of neonatal circulation

AS, Atrial septum; AV, atrioventricular; IVS, interventricular septum.

^*Crown-to-rump measurements.

^†Roman numerals refer to Streeter horizons.

Data from Moore KL. The developing human: clinically oriented embryology. Philadelphia: Saunders; 1982; Pansky B. Review of medical embryology. New York: Macmillan; 1982; Sissman NJ. Developmental landmarks in cardiac morphogenesis: comparative chronology. Am J Cardiol. 1970;25:141.