Heart Embryology

I. Development of the Heart

GLOSSARY
arrhythmia general term for an irregularity or rapidity of the heartbeat, an abnormal heart rhythm. caudal pertaining to toward the tail or distal end of the body. cephalic pertaining to the head or to the head end of the body. blastula usually spherical body produced by cleavage of a fertilized ovum, consisting of a single layer of cells (blastoderm) surrounding a fluid-filled cavity (blastocele). embryo developing human from conception until the end of the 8th week by which time all organ systems have been formed. ischemic heart disease atherosclerosis (atheromatous plaques) causes obstruction to coronary arteries depriving the myocardium of blood containing oxygen and necessary nutrients. karyotype chromosomal characteristics of an individual or cell line. myocardium the heart muscle.

IT IS NOT WIDELY KNOWN THAT IN THE HUMAN embryo, the unique little heart begins to beat as early as day 22. Further research in cardiovascular embryology is crucial to the understanding of different cardiac anomalies and the development of therapeutic and preventive strategies.

I. DEVELOPMENT OF THE HEART

Commitment to the cardiogenic cell lineage occurs early in development soon after gastrulation (the embryonic state following the blastula), approximately 48 h following fertilization. The molecular basis for the formation of cardiac myocytes from the presumptive mesoderm requires further elucidation. The mesoderm consists of three germ layers that are incorporated in the building of the tissues and organs of the embryo. Cells committed to the cardiac lineage are first seen to possess characteristics of cardiac myocytes prior to the formation of the tubular heart. Within 1014 days of gestation a pair of mainstem vessels are first differentiated; they are the primitive aortae. This pair of tubes comes to lie parallel and close to each other in the cephalic region of developing body cavity (see Fig. 1). These vessels appear in the splanchnic mesoderm of the pericardial region of the embryonic area and extend to the caudal end of the embryo. At the cephalic end the primitive aortae are continuous with another pair of stem vessels called the vitelline veins. Within a few days when the embryo is less than 2.5 mm long, the heart is formed in the septum transversum and the dorsal wall of the pericardium by fusion of the caudal parts of the ventral aortae. A section of main vascular tube specializes and possesses contractile elements within its walls. These walls of the heart tubes consist of a twocell layer of myocardial cells and an internal single layer of endothelial cells separated from each other by a third layer called cardiac jelly.

FIGURE 1 Primitive ventral aorta; formation of a tubular heart and

subsequent stages of development.

In the embryo between 14 to 18 days, precardiac cells are present in a pair of crescent-shaped regions of mesodermal tissue lateral to the primitive streak. Further development involves hyperplasia, proliferation of the myocyte cell pool, and growth in cell size (hypertrophy). Pacemaker activity begins at an early primitive stage before sinoatrial and atrial tissues have differentiated. By the 21st day, a small region in the left caudal part of the conoventricular tube acts as a pacemaker. Study of the biophysical differentiation of the heart in the embryo may reveal embryonic cardiac action currents that indicate how sodium and other channels work in the adult. Appreciation of the sodium channels and potassium flux is essential to our understanding of arrhythmias and the cardioactive agents that may show salutary effects without causing harm. Conditions and properties of the cardiac action potential in the embryo resemble those in patients with ischemic heart disease. In the second month the tubular heart doubles over onto itself to form two parallel pumping systems, each with two chambers and a great artery. The tubular heart now speeds up its development. Figure 1 shows further stages in heart development. The tubular heart is separated

FIGURE 2 Sections through heart of embryos of different ages. Diagrammatic. (A) 6 mm, (B) 9 mm, (C) 12 mm, (D) 17 mm, and (E) 40 mm.
(From Van Mierop LHS: Embryology of the atrioventricular canal region, in Feldt RH (ed.) Atrioventricular Canal Defects, W. B. Saunders, Philadelphia, 1976, p. 6.)

by constrictions into six parts named from the caudal to the cephalic end: (1) sinus venosus, (2) atrium, (3) atrioventricular canal, (4) ventricle, (5) bulbus cordis, and (6) truncus arteriosus. Two ventral aortae and two dorsal aortae fuse in parts of their extent to form a median descending aorta. As the heart tube elongates by additional precardiac mesoderm at the caudal end and starts to take on a curved shape, the pacemaker cells move progressively to the caudal-most extremity that remains part of the ventricle. After a few days pacemaker function shifts to the right side, as sinoatrial tissue begins to form. The pacemaker activity, thus, commences at a primitive stage in the development of the embryo before the atrial or sinoatrial tissues have differentiated. The two atria develop from the sinoatrium. Figure 2 shows sections through the heart of an embryo at different stages of development. The AV canal is divided by the endocardial cushions into tricuspid and mitral orifices, and the right and left ventricle are formed from the primitive ventricle and bulbus cordis. The atrioventricular canal leads into the primitive left ventricle, and blood reaches the primitive right ventricle only through the primary interventricular foramen. Table 1 shows developmental stages in human embryos. From day 33 to 36 upper limbs are paddle shaped, lens and nasal pits are visible, optic cups are present, lower

limb buds have appeared, and most important, the heart prominence is distinct (see Fig. 3). Several anomalies may result from defects in the basic cardiac developmental pattern. Table 2 gives teratogenic agents in humans. Lithium plays a role in Ebsteins anomaly and tricuspid atresia. Dilantin is known to cause pulmonary stenosis, aortic stenosis, coarctation, and patent ductus arteriosus. Rubella is a known cause of patent ductus arteriosus, atrial septal defects, and ventricular septal defects as well as other anomalies. During the past decade workers have identified several myogenic determination genes and factors involved in the regulation of muscle gene expression. Gene regulation in the heart is still poorly understood and fruitful research is on the horizon. A single gene mutation is causative in the familial forms of atrial septal defect, mitral valve prolapse, ventricular septal defect, situs inversus, Noonan syndrome, Holt-Oram syndrome, and Marfan syndrome as well as other anomalies.

BIBLIOGRAPHY
Friedman, W. F., and Silverman, N. Congenital heart disease in infancy and childhood. In Heart Disease, sixth edition. E. Braunwald, D. P. Zipes, and P. Libby, eds. W. B. Saunders, Philadelphia, 2001. Kalousek, D. K., and Hendson, G. Embryofetopathology. In Encyclopedia of Human Biology, second edition, Academic Press, San Diego, 1997, p. 605. Shepard, T. H. Teratology. In Encyclopedia of Human Biology, second edition, Academic Press, San Diego, p. 253, 1997.