Cardiac Development

The heart is the first organ to function. By day 22 the linear heart tube is beating; by day 28 it has looped to the right (dextral looping); by week 8 the four chambers, valves, and great vessels are anatomically complete. The complexity comes from stitching together cells from at least three sources (first heart field, second heart field, and cardiac neural crest) under the orchestration of master transcription factors like NKX2-5, GATA4, TBX5, and MEF2C. Most congenital heart disease (CHD) traces back to a defined event in this sequence, which is why CHD is one of the most embryology-dense topics in clinical genetics.

1. Cardiogenic mesoderm specification (week 2–3). Lateral plate mesoderm splits; the splanchnopleure forms two endocardial tubes that fuse into a single heart tube.
2. Heart tube looping (day 22–28). The straight tube loops to the right (dextral). Failure of normal looping → dextrocardia / heterotaxy / situs inversus. Cilia function is required (left-right asymmetry depends on nodal cilia).
3. Chamber septation (weeks 4–8). Atrial and ventricular septa form; endocardial cushions divide the AV canal.
4. Outflow tract septation (weeks 5–8). Cardiac neural crest migrates into the conotruncus and forms the aorticopulmonary septum, dividing the truncus arteriosus into aorta and pulmonary trunk in a spiral.
5. Aortic arch remodeling (weeks 6–8). Six paired aortic arches connect to the dorsal aortae; selective regression and persistence shapes the adult arch anatomy.

• First heart field: forms left ventricle and parts of the atria.
• Second heart field: forms right ventricle, outflow tract (conotruncus), and parts of atria. Tbx1-dependent.
• Cardiac neural crest: divides the outflow tract via the aorticopulmonary septum and contributes to great-vessel walls.

22q11.2 deletion (TBX1) disrupts both the second heart field AND cardiac neural crest, which is why it produces conotruncal lesions specifically (truncus arteriosus, interrupted aortic arch type B, tetralogy of Fallot).

Atrial Septation

• Septum primum grows down from the roof; ostium primum closes as it meets the endocardial cushions; ostium secundum opens within the septum primum.
• Septum secundum grows alongside, creating a one-way flap (foramen ovale) that allows right-to-left shunting in fetal life.
• Patent foramen ovale (PFO): failure of postnatal closure, usually clinically silent.
• Ostium secundum ASD: the most common ASD; deficient septum primum.
• Ostium primum ASD / AV canal defect: deficient endocardial cushions; classically associated with Down syndrome.

Ventricular Septation

• Membranous septum (from endocardial cushions + bulbar ridges) closes last and is the most common location for VSDs.
• Muscular VSDs form lower in the septum and often close spontaneously.

Endocardial Cushions

• Form the membranous IVS, the AV valve leaflets, and divide the AV canal.
• Failure → AV canal defect (ostium primum ASD + inlet VSD + common AV valve). Strong association with trisomy 21 (~40% of Down syndrome have a CHD; AV canal is the classic).

Cardiac neural crest failure or aorticopulmonary septation defects produce a recognizable family of "conotruncal" malformations:

• Truncus arteriosus persistens: failure to septate the truncus → single great vessel.
• Interrupted aortic arch type B: discontinuity between left common carotid and left subclavian; almost pathognomonic for 22q11.2.
• Tetralogy of Fallot: anterior malalignment of the conotruncal septum produces all four features (overriding aorta, RV outflow obstruction, VSD, RVH).
• Transposition of the great arteries (TGA): failure of the spiral arrangement during conotruncal septation → aorta from RV, pulmonary artery from LV.
• Double-outlet right ventricle (DORV): both great vessels arise from the RV.

A right-sided aortic arch (failure of left 4th, persistence of right 4th) is associated with 22q11.2 and tetralogy of Fallot. Aberrant right subclavian is the most common aortic arch variant; often asymptomatic.