Heart development, also known as cardiogenesis, refers to the

prenatal development Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal deve ...

of the

heart The heart is a muscular Organ (biology), organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as ca ...

. 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 the first functional organ in

vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with ...

embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

s. The tubular heart quickly differentiates into the truncus arteriosus, bulbus cordis, primitive ventricle, primitive atrium, and the

sinus venosus The sinus venosus is a large quadrangular cavity which precedes the atrium on the venous side of the chordate heart. In mammals, it exists distinctly only in the embryonic heart, where it is found between the two venae cavae. However, the sinus v ...

. The truncus arteriosus splits into the

ascending aorta The ascending aorta (AAo) is a portion of the aorta commencing at the upper part of the base of the left ventricle, on a level with the lower border of the third costal cartilage behind the left half of the sternum. Structure It passes obliqu ...

and 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 ...

. The bulbus cordis forms part of the ventricles. The sinus venosus connects to the fetal circulation. The heart tube elongates on the right side, looping and becoming the first visual sign of

left-right asymmetry Left-right asymmetry, (LR asymmetry) is the process in early embryonic development that breaks the normal symmetry in the bilateral embryo. In vertebrates, left-right asymmetry is established early in development at a structure called the left-ri ...

of the body.

Septa The Southeastern Pennsylvania Transportation Authority (SEPTA) is a regional public transportation authority that operates bus, rapid transit, commuter rail, light rail, and electric trolleybus services for nearly 4 million people in five c ...

form within the atria and ventricles to separate the

left Left may refer to: Music * ''Left'' (Hope of the States album), 2006 * ''Left'' (Monkey House album), 2016 * "Left", a song by Nickelback from the album '' Curb'', 1996 Direction * Left (direction), the relative direction opposite of right * ...

and right sides of the heart.

Early development

The heart derives from embryonic

mesodermal The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical Embry ...

germ layer A germ layer is a primary layer of cells that forms during embryonic development. The three germ layers in vertebrates are particularly pronounced; however, all eumetazoans (animals that are sister taxa to the sponges) produce two or three p ...

cells that differentiate after

gastrulation Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals the blastocyst is reorganized into a multilayered structure known as the gastrula. ...

into

mesothelium The mesothelium is a membrane composed of simple squamous epithelial cells of mesodermal origin, which forms the lining of several body cavities: the pleura ( pleural cavity around the lungs), peritoneum ( abdominopelvic cavity including the mes ...

endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...

, and

myocardium Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...

. Mesothelial

pericardium The pericardium, also called pericardial sac, is a double-walled sac containing the heart and the roots of the great vessels. It has two layers, an outer layer made of strong connective tissue (fibrous pericardium), and an inner layer made ...

forms the outer lining of the heart. The inner lining of the heart – the

endocardium The endocardium 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 protection to the va ...

, lymphatic and blood vessels, develop from endothelium.

Endocardial tubes

In the splanchnopleuric mesenchyme on either side of the

neural plate The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region ant ...

, a horseshoe-shaped area develops as the cardiogenic region. This has formed from cardiac

myoblast Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development. Muscle fibers generally form through the fusion of precursor myoblasts into multinucleated fibers called ''myotubes''. In the early development o ...

s and blood islands as forerunners of blood cells and vessels. By day 19, an endocardial tube begins to develop in each side of this region. These two tubes grow and by the third week have converged towards each other to merge, using

programmed cell death Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell (biology), cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers ...

to form a single tube, the tubular heart. From splanchnopleuric mesenchyme, the cardiogenic region develops cranially and laterally to the

. In this area, two separate

angiogenic Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splittin ...

cell clusters form on either side and coalesce to form the endocardial tubes. As embryonic folding starts, the two endocardial tubes are pushed into the thoracic cavity, where they begin to fuse together, and this is completed at about 22 days. At around 18 to 19 days after fertilisation, the heart begins to form. The heart begins to develop near the head of the embryo in the cardiogenic area. Following

cell signalling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellular ...

, two strands or cords begin to form in the cardiogenic region As these form, a lumen develops within them, at which point, they are referred to as endocardial tubes. At the same time that the tubes are forming other major heart components are also being formed. The two tubes migrate together and fuse to form a single

primitive heart tube The tubular heart or primitive heart tube is the earliest stage of heart development. From the inflow to the outflow, it consists of sinus venosus, primitive atrium, the primitive ventricle, the bulbus cordis, and truncus arteriosus. It forms pri ...

which quickly forms five distinct regions. From head to tail, these are the truncus arteriosus, bulbus cordis, primitive ventricle, primitive atrium, and the

. Initially, all venous blood flows into the sinus venosus, and contractions propel the blood from tail to head, or from the sinus venosus to the truncus arteriosus. The truncus arteriosus will divide to form the aorta and pulmonary artery; the bulbus cordis will develop into the right ventricle; the primitive ventricle will form the left ventricle; the primitive atrium will become the front parts of the left and right atria and their appendages, and the sinus venosus will develop into the posterior part of the right atrium, the sinoatrial node and the coronary sinus.

Heart tube position

The central part of cardiogenic area is in front of the oropharyngeal membrane and the neural plate. The growth of the brain and the cephalic folds push the oropharyngeal membrane forward, while the heart and the pericardial cavity move first to the cervical region and then into the chest. The curved portion of the horseshoe-shaped area expands to form the future ventricular

infundibulum An infundibulum (Latin for ''funnel''; plural, ''infundibula'') is a funnel-shaped cavity or organ. Anatomy * Brain: the pituitary stalk, also known as the ''infundibulum'' and ''infundibular stalk'', is the connection between the hypothalamus an ...

and the ventricular regions, as the heart tube continues to expand. The tube starts receiving venous drainage in its caudal pole and will pump blood out of the first

aortic arch The aortic arch, arch of the aorta, or transverse aortic arch () is the part of the aorta between the ascending and descending aorta. The arch travels backward, so that it ultimately runs to the left of the trachea. Structure The aorta begins ...

and into the dorsal aorta through its polar head. Initially the tube remains attached to the dorsal part of the pericardial cavity by a mesodermal tissue fold called the dorsal mesoderm. This mesoderm disappears to form the two pericardial sinuses the ''transverse'' and the ''oblique'' pericardial sinuses, which connect both sides of the pericardial cavity. The

thickens and secretes a thick layer of rich

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

containing

hyaluronic acid Hyaluronic acid (; abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglyca ...

which separates the

. Then mesothelial cells form the pericardium and migrate to form most of the epicardium. Then the heart tube is formed by the

, which is the inner endothelial lining of the heart, and the myocardial muscle wall which is the epicardium that covers the outside of the tube.

Heart folding

The heart tube continues stretching and by day 23, in a process called

morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...

, cardiac looping begins. The cephalic portion curves in a frontal clockwise direction. The atrial portion starts moving in a cephalically and then moves to the left from its original position. This curved shape approaches the heart and finishes its growth on day 28. The conduit forms the atrial and ventricular junctions which connect the common atrium and the common ventricle in the early embryo. The arterial bulb forms the trabecular portion of the right ventricle. A cone will form the infundibula blood of both ventricles. The arterial trunk and the roots will form the proximal portion of the aorta and the pulmonary artery. The junction between the ventricle and the arterial bulb will be called the primary intra-ventricular hole. The tube is divided into cardiac regions along its craniocaudal axis: the primitive ventricle, called primitive left ventricle, and the trabecular proximal arterial bulb, called the primitive right ventricle. This time no septum is present in heart.

Heart chambers

Sinus venosus

In the middle of the fourth week, the sinus venosus receives venous blood from the poles of right and left sinus. Each pole receives blood from three major veins: the vitelline vein, the umbilical vein and the common cardinal vein. The sinus opening moves clockwise. This movement is caused mainly by the left to right shunt of blood, which occurs in the venous system during the fourth and fifth week of development. When the left common cardinal vein disappears in the tenth week only the oblique vein of the left atrium and the coronary sinus remain. The right pole joins the right atrium to form the wall portion of the right atrium. The right and left venous valves fuse and form a peak known as the

septum spurium During development of the heart, the orifice of the sinus venosus lies obliquely, and is guarded by two valves, the right and left venous valves Veins are blood vessels in humans and most other animals that carry blood towards the heart. Most v ...

. At the beginning, these valves are large, but over time the left venous valve and the septum spurium fuse with the developing atrial septum. The upper right venous valve disappears, while the bottom venous valve evolves into the inferior valve of the

vena cava In anatomy, the venae cavae (; singular: vena cava ; ) are two large veins (great vessels) that return deoxygenated blood from the body into the heart. In humans they are the superior vena cava and the inferior vena cava, and both empty into th ...

and the coronary sinus valve.

Heart wall

The main walls of the heart are formed between day 27 and 37 of the development of the early embryo. The growth consists of two tissue masses actively growing that approach one another until they merge and split light into two separate conduits. Tissue masses called endocardial cushions develop into atrioventricular and conotruncal regions. In these places, the cushions will help in the formation of auricular septum, ventricular conduits, atrio-ventricular valves and aortic and pulmonary channels.

Atria

At the end of the fourth week, a crest grows that leaves the cephalic part. This crest is the first part of the septum primum. The two ends of the septum extend into the interior of the endocardial cushions in the

atrioventricular canal The proper development of the atrioventricular canal into its prospective components (The heart septum and associated valves) to create a clear division between the four compartments of the heart and ensure proper blood movement through the heart, ...

. The opening between the bottom edge of the septum primum and endocardial cushions is the ostium primum (first opening). The extensions of the upper and lower endocardial pads grow along the margin of the septum primum and close the ostium primum. Coalescence of these perforations will form the ostium secundum (second opening), which allows blood to flow freely from the right atrium to the left. When the right of the atrium expands due to the incorporation of the pole of the sinus, a new fold appears, called the septum secundum. At its right side it is fused with the left venous valve and the septum spurium. A free opening will then appear, called the foramen ovale. The remains of the upper septum primum, will become the valves of the foramen ovale. The passage between the two atrial chambers consists of a long oblique slit through which blood flows from the right atrium to the left.

Ventricles

Initially, a single

pulmonary vein The pulmonary veins are the veins that transfer oxygenated blood from the lungs to the heart. The largest pulmonary veins are the four ''main pulmonary veins'', two from each lung that drain into the left atrium of the heart. The pulmonary vei ...

develops in the form of a bulge in the back wall of the left atrium. This vein will connect with the veins of the developing

lung bud The lung bud sometimes referred to as the respiratory bud forms from the respiratory diverticulum, an embryological endodermal structure that develops into the respiratory tract organs such as the larynx, trachea, bronchi and lungs. It arises from ...

s. As development proceeds, the pulmonary vein and its branches are incorporated into the left atrium and they both form the smooth wall of the atrium. The embryonic left atrium remains as the trabecular left atrial appendage, and the embryonic right atrium remains as the right atrial appendage.

Septum formation of the atrioventricular canal

At the end of the fourth week, two atrioventricular endocardial cushions appear. Initially the atrioventricular canal gives access to the primitive left ventricle, and is separated from arterial bulb by the edge of the ventricular bulb. In the fifth week, the posterior end terminates in the center part of the upper endocardial cushion. Because of this, blood can access both the left primitive ventricle and the right primitive ventricle. As the anterior and posterior pads project inwardly, they merge to form a right and left atrioventricular orifice.

Atrioventricular valves

When forming intra-atrial septa, atrio-ventricular valves will begin to grow. A muscular

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

begins to grow from the common ventricle to the atrio-ventricular endocardial cushions. The division begins in the common ventricle where a furrow in the outer surface of the heart will appear the interventricular foramen eventually disappears. This closure is achieved by further growth of the muscular interventricular septum, a contribution of trunk crest-conal tissue and a membranous component.

Valves and outflow tracts

Truncus septum formation and arterial cone

The arterial cone is closed by the infundibular cushions. The trunk cones are closed by the forming of an infundibulotroncal septum, which is made from a straight proximal portion and distal spiral portion. Then, the narrowest portion of the aorta is in the left and dorsal portion. The distal portion of the aorta is pushed forward to the right. The proximal pulmonary artery is right and ventral, and the distal portion of the pulmonary artery is in the left dorsal portion.

Pacemaker and conduction system

The rhythmic electrical depolarization waves that trigger myocardial contraction is myogenic, which means that they begin in the heart muscle spontaneously and are then responsible for transmitting signals from cell to cell.

Myocytes A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...

that were obtained in the primitive heart tube, start beating as they connect together by their walls in a

syncytium A syncytium (; plural syncytia; from Greek: σύν ''syn'' "together" and κύτος ''kytos'' "box, i.e. cell") or symplasm is a multinucleate cell which can result from multiple cell fusions of uninuclear cells (i.e., cells with a single nucleu ...

. Myocytes initiate rhythmic electrical activity, before the fusion of the endocardial tubes. The heartbeat begins in the region of the

pacemaker An artificial cardiac pacemaker (or artificial pacemaker, so as not to be confused with the natural cardiac pacemaker) or pacemaker is a medical device that generates electrical impulses delivered by electrodes to the chambers of the heart ei ...

which has a spontaneous depolarization time faster than the rest of myocardium. The primitive ventricle acts as initial pacemaker. But this pacemaker activity is actually made by a group of cells that derive from the sinoatrial right venous sinus. These cells form an ovoid

sinoatrial node The sinoatrial node (also known as the sinuatrial node, SA node or sinus node) is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approxima ...

(SAN), on the left venous valve. After the development of the SAN, the superior endocardial cushions begin to form a pacemaker also known as the

atrioventricular node The atrioventricular node or AV node electrically connects the heart's atria and ventricles to coordinate beating in the top of the heart; it is part of the electrical conduction system of the heart. The AV node lies at the lower back section of t ...

. With the development of the SAN, a band of specialized conducting cells start to form creating the

bundle of His The bundle of His (BH) or His bundle (HB) ( "hiss"Medical Terminology for Health Professions, Spiral bound Version'. Cengage Learning; 2016. . pp. 129–.) is a collection of heart muscle cells specialized for electrical conduction. As part of t ...

that sends a branch to the right ventricle and one to the left ventricle. Most conduction pathways originate from the cardiogenic mesoderm but the sinus node may be derived from the neural crest. The human

nic heart displays cardiac activity approximately 21 days after fertilization, or five weeks after the last normal

menstrual period The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs ...

(LMP), which is the date normally used to date pregnancy in the medical community. The electrical depolarizations that trigger cardiac

myocyte A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a mus ...

s to contract arise spontaneously within the

itself. The heartbeat is initiated in the pacemaker regions and spreads to the rest of the heart through a conduction pathway. Pacemaker cells develop in the primitive atrium and the sinus venosus to form the

and the

respectively. Conductive cells develop the

and carry the

depolarization In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is ess ...

into the lower heart. Cardiac activity is visible beginning at approximately 5 weeks of pregnancy. The human heart begins beating at a rate near the mother's, about 75-80 beats per minute (BPM). The embryonic heart rate (EHR) then accelerates linearly for the first month of beating, peaking at 165-185 BPM during the early 7th week, (early 9th week after the LMP). This acceleration is approximately 3.3 BPM per day, or about 10 BPM every three days, an increase of 100 BPM in the first month. After peaking at about 9.2 weeks after the LMP, it decelerates to about 150 BPM (+/-25 BPM) during the 15th week after the LMP. After the 15th week the deceleration slows reaching an average rate of about 145 (+/-25 BPM) BPM at term.

Imaging

Embryo at 5 weeks 5 days with heartbeat - annotated

In the

first trimester Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

, cardiac activity can be visualized and the fetal heart motion quantified by

obstetric ultrasonography Obstetric ultrasonography, or prenatal ultrasound, is the use of medical ultrasonography in pregnancy, in which sound waves are used to create real-time visual images of the developing embryo or fetus in the uterus (womb). The procedure is a stan ...

. A study of 32 normal pregnancies showed that fetal heart motion was visible at a mean

human chorionic gonadotropin Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantatio ...

(hCG) level of 10,000 UI/L (range 8650–12,200). Obstetric ultrasonography can also use Doppler technique on key vessels such as the umbilical artery to detect abnormal flow. In later stages of pregnancy, a simple Doppler fetal monitor can be used to quantify the fetal heart rate. A fetal heartbeat can be detected at around 17 to 20 weeks of gestation when the chambers of the heart have become sufficiently developed. During

childbirth Childbirth, also known as labour and delivery, is the ending of pregnancy where one or more babies exits the internal environment of the mother via vaginal delivery or caesarean section. In 2019, there were about 140.11 million births glob ...

, the parameter is part of cardiotocography, which is where the fetal heartbeat and uterine contractions are continuously recorded.

Additional images

EHR-BBII.jpg, M-mode sonography measuring embryonic heart rate. File:Blausen 0668 NeonatalHeartCirculation.png, Blood flow in a

neonate An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...

File:Slide1MINI.JPG, Human embryo, 38 mm, 8–9 weeks–anterior view, heart is visible.

References

{{Development of mammalian circulatory system Embryology of cardiovascular system