Development of the Heart — Heart Tube, Looping, Septation and the Defects That Follow

The heart is the first functional organ to develop, because the growing embryo's metabolic needs soon exceed what diffusion can supply. Cardiac progenitor cells in the splanchnic (visceral) layer of lateral plate mesoderm coalesce into the cardiogenic field (a horseshoe-shaped region), and blood islands form vessels. Two endocardial tubes form on either side; with lateral folding of the embryo they fuse in the midline around day 22 into a single primitive heart tube, which begins to pump around day 23 and beats by the 4th week.

The tube has three layers: the endocardium (endothelial lining), a layer of cardiac jelly, and the myocardium with the visceral epicardium outside. Blood enters through the cardinal, umbilical and vitelline veins at the caudal end and leaves through the aortic arches to the dorsal aortae.

Around day 22–23 the heart tube elongates and bends into a cardiac loop: the cranial (bulboventricular) part bends ventrocaudally and to the right, and the caudal (atrial) part moves dorsocranially and to the left. Looping takes about five days and is complete by about day 28. After looping the bulbus cordis lies on the right and the primitive ventricle on the left, and the atria and sinus venosus lie dorsal to the ventricles — the pattern of the adult heart.

• Left–right axis: motile cilia in the primitive node beat clockwise to create a leftward flow; NODAL then induces LEFTY and PITX2, the key gene for left–right orientation.
• Dextrocardia: failure of this process (for example dynein defects) puts the heart on the right; it is seen in Kartagener syndrome.
• PITX2 mutations are also linked to ASD, VSD and tetralogy of Fallot.
• Other genes: TBX5 (Holt-Oram syndrome — ASD in about 58% and VSD in 28%, with upper-limb defects), NKX2-5 and GATA4 (atrial septation), NOTCH pathway.

The major septa form between days 27 and 37 by fusion of tissue masses called endocardial cushions. Atrial septation follows a fixed sequence; the exam favourites are the names of the two septa and the two openings.

1. By the end of week 4 a sickle-shaped septum primum grows down from the roof of the common atrium toward the endocardial cushions, leaving the ostium primum.
2. The septum primum fuses with the cushions, closing the ostium primum. Apoptosis creates perforations in the upper septum primum that coalesce into the ostium secundum, so right-to-left flow continues.
3. A second, thicker, crescent-shaped fold, the septum secundum, grows to the right of the septum primum but never completely partitions the atrium; its free edge leaves the foramen ovale.
4. The lower part of the septum primum persists as the valve of the foramen ovale.
5. At birth, the first breath increases pulmonary blood flow and left atrial pressure, pressing the valve against the septum secundum and functionally closing the foramen ovale.

By the end of week 4 the atrioventricular canal has superior and inferior (dorsal and ventral) endocardial cushions plus two lateral cushions. The superior and inferior cushions fuse and divide the canal into right and left AV orifices; mesenchyme around each orifice thins to form the AV valves (tricuspid and mitral), tethered to papillary muscles by chordae tendineae. The cross-like appearance of the fused cushions and septa on fetal ultrasound is used to confirm cardiac integrity.

• Muscular interventricular septum: the medial walls of the expanding ventricles come together and merge.
• Membranous interventricular septum: forms when the interventricular foramen is closed by tissue growing from the endocardial cushions.
• Complete AV septal defect (AVSD): cushions fail to fuse with the atrial and ventricular septa — an ASD, a VSD and a common AV valve. AVSDs are about 4–5% of congenital heart defects and are strongly associated with trisomy 21.

VSD is the commonest congenital cardiac anomaly in children. The perimembranous (membranous) VSD is the commonest type, about 80% of all VSDs; the rest are muscular, inlet and outlet types. Many close spontaneously.

In week 5 truncal swellings (ridges) appear in the truncus arteriosus and conus swellings in the conus cordis. The right superior truncal swelling grows leftward and the left inferior swelling rightward; they twist around each other and fuse into the aorticopulmonary (conotruncal) septum, which therefore spirals. It divides the truncus into an aortic channel and a pulmonary channel, and the conus into an anterolateral part (right ventricular outflow) and a posteromedial part (left ventricular outflow). The semilunar valves form from tubercles on the truncal swellings.

• Sinus venosus: its right horn is absorbed into the right atrium, forming the smooth sinus venarum. The horns also contribute to the venae cavae and coronary sinus.
• Pulmonary vein: a single embryonic pulmonary vein joins the left atrium and its branches are incorporated, forming the smooth-walled posterior left atrium. The trabeculated left auricle is the old primitive atrium.
• Pacemaker: initially in the caudal part of the heart tube, later taken over by the sinus venosus; its incorporation into the right atrium gives the SA node.
• Ductus arteriosus is kept open by prostaglandins; premature closure can follow NSAID exposure. Its remnant is the ligamentum arteriosum. See fetal circulation.

Most congenital heart defects arise from genetic mutations that disrupt cardiac development; teratogens such as rubella and alcohol also contribute, and lithium is linked to Ebstein anomaly.

• Derivatives: bulbus cordis → trabeculated right ventricle; primitive ventricle → left ventricle; sinus venosus right horn → sinus venarum; truncus → ascending aorta and pulmonary trunk.
• Timing: tubes fuse ~day 22; beat ~day 23; looping complete by day 28; septation days 27–37.
• Septum identification: valve of foramen ovale = septum primum; crescentic fold = septum secundum.
• Defect-embryology matching: TGA (linear septum), truncus (absent septum), AVSD (cushion fusion failure, trisomy 21), ostium primum.
• Gene matching: PITX2 (laterality), TBX5 (Holt-Oram), NKX2-5, 22q11.2 (conotruncal).