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)
,- 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)
,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
, • 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:
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)
,- 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)
,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
, • 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:
