Cardiac development van den Hoff

Cardiac development – van den Hoff

Prevalence of congenital cardiac malformation: 8-16 per 1000 life born children

• Many now survive because of surgery, prenatal diagnostics > new population of patients

- Only in 25% of cases cause is known:

• Genetic defect: sporadic or familial

• Environmental factor: teratogen (vitamin A, lithium, alcohol intoxication), disease of mother (diabetes, Rubella) • Combination

Three main themes:

• Error in the building plan
• Cardiomyopathy > cardiomyocytes do not develop well > do not contract/relax properly
• Arrhythmias > electrical impulse too fast/slow

Early development:

• Heart develops from mesoderm
• Cardiogenic mesoderm > endocardial cells + cardiomyocytes

- Signaling pathways involved:

• Wnt > blocks differentiation into cardiomyocytes • Wnt inhibitors • BMP > drives differentiation into cardiomyocytes

• Formation of heart tube by folding of embryonic disc

• Differential growth > ectoderm grows very fast > heart folds from above to ventral

• Defect in folding: ectopia cordis

• Initial heart tube contributes to interventricular septum and apex (only anterior part) 1 / 4

• Differentiation and proliferation > first only at ventricular side > then other cells attracted +

further differentiation and proliferation • After 4 weeks of human development the heart is formed > only needs to grow

- Development of the electrocardiogram:

• Primary heart tube > the peristaltic contraction and uni-directional blood flow implies: ▪ Localized pacemaker activity at one end of the heart tube (>polarity and presence of sinus node function) ▪ Slow conduction owing to poor coupling of the myocardial cells ▪ Poorly developed sarcomeric and SR structures in the myocardial cells • Embryonic heart > the adult-type ECG and uni-directional blood flow imply: ▪ Localized pacemaker activity at one end of the heart tube ▪ Compartments with slow and fast conduction alternate ▪ Compartments with poor and well-developed sarcomeric and SR structures alternate

- Mutations:

• Ion channels and connexins (gap junctions between cardiomyocytes) > channelopathies ▪ E.g. long QT syndrome • Sarcomere > not enough power > hypertrophic cardiomyopathy (HCM) • Cytoskeleton > dilated cardiomyopathy (DCM)

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Cardiac chamber formation:

- Tbox transcription factors:

• Tbx5: chamber development > development into cardiomyocytes

• Tbx2/3: conduction system > transcription inhibitors (prevents chamber formation)

• Tbx18: inflow region > development of sinus node

• Tbx1: outflow region

Cardiac septation:

• Ventricular septation

• Apposition

• Septation of the primary heart tube

• 2 pairs of cushions (in atrioventricular canal (avc) and outflow tract (oft)) > fuse • Bloodstreams are now physically separated 3 / 4

• Development of cushions:

▪ Cardiac jelly produced by primary myocardium (separation from endocardium) > mesenchyme formed by EMT (endothelial-mesenchymal transition) ▪ Myocardialization = mesenchyme is replaced by myocardiocytes > muscular outlet septum

• Alignment defects:

• Atrial septation

• Primary septum:

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