The

heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...

is the first functional organ in a vertebrate embryo. There are 5 stages to

heart development Heart development, also known as cardiogenesis, refers to the prenatal development of the heart. This begins with the formation of two endocardial tubes which merge to form the tubular heart, also called the primitive heart tube. The heart is ...

Stages of heart development

Initiation

Specification of cardiac precursor cells: The

lateral plate mesoderm The lateral plate mesoderm is the mesoderm that is found at the periphery of the embryo. It is to the side of the paraxial mesoderm, and further to the axial mesoderm. The lateral plate mesoderm is separated from the paraxial mesoderm by a narrow r ...

delaminates to form two layers: the dorsal somatic (parietal) mesoderm and the ventral splanchnic (visceral) mesoderm. The heart precursor cells come from the two regions of the splanchnic mesoderm called the cardiogenic mesoderm. These cells can differentiate into

endocardium The endocardium (: endocardia) is the innermost layer of tissue that lines the chambers of the heart. Its cells are embryologically and biologically similar to the endothelial cells that line blood vessels. The endocardium also provides prot ...

which lines the heart chamber and valves and the

myocardium Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall o ...

which forms the musculature of the ventricles and the atria. The heart cells are specified in anterior mesoderm by proteins such as Dickkopf-related protein 1,

Nodal homolog Nodal homolog is a secretory protein that in humans is encoded by the ''NODAL'' gene which is located on chromosome 10q22.1. It belongs to the transforming growth factor beta superfamily (TGF-β superfamily). Like many other members of this supe ...

, and

Cerberus In Greek mythology, Cerberus ( or ; ''Kérberos'' ), often referred to as the hound of Hades, is a polycephaly, multi-headed dog that guards the gates of the Greek underworld, underworld to prevent the dead from leaving. He was the offspring o ...

secreted by the anterior

endoderm Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gastr ...

. Whether Dickkopf-1 and Nodal act directly on the cardiac mesoderm is the subject of research, but it seems that at least they act indirectly by stimulating the production of additional factors from the anterior endoderm. These early signals are essential for heart formation such that removal of the anterior endoderm blocks heart formation. Anterior endoderm is also sufficient to stimulate heart differientation since it can induce non-cardiogenic mesoderm from more posterior positions in the embryo to form heart. The secretion of Wnt inhibitors (such as Cerberus, Dickkopf and Crescent) by the anterior endoderm also prevents Wnt3a and Wnt8 secreted by the

neural tube In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural folds become elevated, ...

from inhibiting heart formation. The

notochord The notochord is an elastic, rod-like structure found in chordates. In vertebrates the notochord is an embryonic structure that disintegrates, as the vertebrae develop, to become the nucleus pulposus in the intervertebral discs of the verteb ...

secretes BMP antagonists (Chordin and Noggin) to prevent formation of cardiac mesoderm in inappropriate places. Other cardiogenic signals such as BMP and FGF activate the expression of cardiac specific transcription factors such as homeodomain protein Nkx2.5. Nkx2.5 activates a number of downstream transcription factors (such as MEF2 and GATA) which activate the expression of cardiac muscle specific proteins. Mutations in Nkx2.5 result in heart development defects and congenital heart malformations.

Step 1: Tube formation

Migration of cardiac precursor cells and fusion of the primordia: The cardiac precursor cells migrate anteriorly towards the midline and fuse into a single heart tube. Fibronectin in the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...

directs this migration. If this migration event is blocked, cardia bifida results where the two heart primordia remain separated. During fusion, the heart tube is patterned along the anterior/posterior axis for the various regions and chambers of the heart. The surrounding mesocardium degenerates to leave the primitive heart attached only by its arterial and venous ends, which are anatomically fixed to the pharyngeal arches and the septum transversum, respectively. The developing tubular heart then folds ventrally and bulges in five regions along its length: the first one and closest to the arterial end is the truncus arteriosus, then follow the bulbus cordis, the primitive ventricle, the primitive atrium and the sinus venosus. All five embryonic dilatations of the primitive heart develop into the adult structures of the heart.

Step 2: Looping

The heart tube undergoes right-ward looping to change from anterior/posterior polarity to left/right polarity. The detailed mechanism is unknown however the looping requires the asymmetrically localized transcription factor . The direction of asymmetry is established much earlier during embryonic development, possibly by the clockwise rotation of

cilia The cilium (: cilia; ; in Medieval Latin and in anatomy, ''cilium'') is a short hair-like membrane protrusion from many types of eukaryotic cell. (Cilia are absent in bacteria and archaea.) The cilium has the shape of a slender threadlike proj ...

, and leads to sided expression of Pitx2. Looping also depends on heart specific proteins activated by Nkx2.5 such as , , and Xin. Heart chamber formation: The cell fates of the heart chambers are characterized before heart looping but cannot be distinguished until after looping. Hand1 is localized to the left ventricle while Hand2 is localized to the right ventricle.

Step 3: Septal formation

Proper positioning and function of the valves is critical for chamber formation and proper blood flow. The

endocardial cushion Endocardial cushions, or atrioventricular cushions, refer to a subset of cells in the heart development, development of the heart that play a vital role in the proper formation of the heart septum, septa. They develop on the atrioventricular canal ...

serves as a makeshift valve until then.

Step 3(a): Atrial septation

The

primitive atrium The primitive atrium is a stage in the embryonic development of the human heart. It grows rapidly and partially encircles the bulbus cordis; the groove against which the bulbus cordis lies is the first indication of a division into right and left ...

is divided in two by joining of several structures. From the roof of the primitive atrium descends the septum primum, which grows towards the

endocardial cushions Endocardial cushions, or atrioventricular cushions, refer to a subset of cells in the development of the heart that play a vital role in the proper formation of the heart septa. They develop on the atrioventricular canal and conotruncal region of ...

within the

atrial canal The atrium (; : atria) is one of the two upper chambers in the heart that receives blood from the circulatory system. The blood in the atria is pumped into the heart ventricles through the atrioventricular mitral and tricuspid heart valves. ...

. Right before the septum primum fuses with the endocardial cushions there's a temporary space called the foramen primum. Once they fuse a new opening forms in the middle of the septum primum called the ostium secundum or ''foramen secundum''. To the right of the septum primum and also coming down from the roof of the

, descends a semilunar-shaped partition called the septum secundum. The free edges of the septum secundum produce an orifice called '' foramen ovale'', which closes after birth when the septum primum and secundum fuse to each other completing the formation of the atrial septum. The atrial canal is in turn divided into a right and left side by the atrioventricular septum, which originates from the union of the dorsal and ventral

. The right side of the atrial canal will become the

tricuspid valve The tricuspid valve, or right atrioventricular valve, is on the right dorsal side of the mammalian heart, at the superior portion of the right ventricle. The function of the valve is to allow blood to flow from the right atrium to the right vent ...

and the left will become the bicuspid valve. Defects in producing the AV septum produces

atrioventricular septal defect Atrioventricular septal defect (AVSD) or atrioventricular canal defect (AVCD), also known as "common atrioventricular canal" or "endocardial cushion defect" (ECD), is characterized by a deficiency of the atrioventricular septum of the heart that c ...

s, including a persistent AV canal and tricuspid atresia.

Step 3(b): Ventricular septation

The floor at the midline of the

primitive ventricle The primitive ventricle or embryonic ventricle of the developing heart, together with the bulbus cordis that lies in front of it, gives rise to the left and right ventricles. The primitive ventricle provides the trabeculated parts of the walls, a ...

produces the

interventricular septum The interventricular septum (IVS, or ventricular septum, or during development septum inferius) is the stout wall separating the ventricle (heart), ventricles, the lower chambers of the heart, from one another. The interventricular septum is di ...

, separating the chamber in two. The IV septum grows upward towards the endocardial cushion. As it grows, a foramen appears, the interventricular foramen, which later is closed by the non-muscular IV septum. Defects in producing the IV septum causes

ventricular septal defect A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart. It's a common heart problem present at birth ( congenital heart defect). The extent of the opening may vary ...

s, which communicate both ventricles.

Step 4: Outflow tract septation

The truncus arteriosus and the adjacent bulbus cordis partition by means of cells from the

neural crest The neural crest is a ridge-like structure that is formed transiently between the epidermal ectoderm and neural plate during vertebrate development. Neural crest cells originate from this structure through the epithelial-mesenchymal transition, ...

. Once the cells from the truncal ridge meet with the cells from the bulbar ridge they twist around each other in a spiral orientation as they fuse and form the aorticopulmonary septum. This will end dividing the

aorta The aorta ( ; : aortas or aortae) is the main and largest artery in the human body, originating from the Ventricle (heart), left ventricle of the heart, branching upwards immediately after, and extending down to the abdomen, where it splits at ...

from the

pulmonary trunk A pulmonary artery is an artery in the pulmonary circulation that carries deoxygenated blood from the right side of the heart to the lungs. The largest pulmonary artery is the ''main pulmonary artery'' or ''pulmonary trunk'' from the heart, and t ...

. Defects in this process is known as aortopulmonary septal defect, and causes

persistent truncus arteriosus Persistent truncus arteriosus (PTA), often referred to simply as truncus arteriosus, is a rare form of congenital heart disease that presents at birth. In this condition, the embryological structure known as the truncus arteriosus (embryology), t ...

, unequal division of the truncus arteriosus, transposition of the great arteries, aortic and

pulmonary valve stenosis Pulmonary valve stenosis (PVS) is a heart valve disorder. Blood going from the heart to the lungs goes through the pulmonary valve, whose purpose is to prevent blood from flowing back to the heart. In pulmonary valve stenosis this opening is too ...

tetralogy of fallot Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. Classically, the four defects are: * Pulmonary stenosis, which is narrowing of the exit from the r ...

Step 5: Heart valve formation

The

heart valves A heart valve is a biological one-way valve that allows blood to flow in one direction through the chambers of the heart. A mammalian heart usually has four valves. Together, the valves determine the direction of blood flow through the heart. Hea ...

are formed. Defects in this process are known as

valvular heart disease Valvular heart disease is any cardiovascular disease process involving one or more of the four valves of the heart (the aortic and mitral valves on the left side of heart and the pulmonic and tricuspid valves on the right side of heart). The ...

References

{{Development of circulatory system

External links

Cardiac Embryology Interactive 3D Module (Flash Player 10 required)
* ]http://php.med.unsw.edu.au/embryology/index.php/Cardiac_Embryology Cardiac embryology] at

UNSW The University of New South Wales (UNSW) is a public university, public research university based in Sydney, New South Wales, Australia. It was established in 1949. The university comprises seven faculties, through which it offers bachelor's, ...

Embryology of cardiovascular system