Lecture 45: CV Development, Congenital Heart Disease Flashcards
What are the critical events in cardiac development?
- Initial formation of straight heart tube with evolution into dual parallel circulations and a 4 chambered heart
- Formation of a brached vasculature and pump that is a low pressure circuit in utero but at birth has a requirement for high P systemic circulation to be separated from low P pulmonary circulation
- The heart must function before morphogenesis is complete
What are the steps of cardiac morphogenesis?
- myocardial specification and formation of linear heart tube
- looping
- septation
- patterning of the great vessels
- circulatory changes at birth
What is the cardiac crescent?
An epithelial layer of cardiac progenitor cells
Progenitors for myocardium, pericardium, endocardium
Located at the anterior rim of the embryonic disc
As the embryo grows, the developing heart assumes a position ventral to forebrain and foregut
How do the tubes of the heart first start forming?
Forms as two tubes
Heart progenitors migrate ventrally and medially to form a linear heart tube
What happens once the linear heart tube is formed?
Heart begins to beat -intrinsic pacemaker activity Blood flow commences -single circulation in series caudal to rostral Chamber specification
What is the secondary heart field?
Large parts of the RV and OT derive from a secondary field of cardiac precursors
Cells migrate into the outflow Tract and differentiate into muscle
A new formulation of secondary heart field disorders is in evolution
What are the potential types of secondary heart field defects?
Hypoplastic right heart Some forms of DORV DiGeorge Syndrome Ebstein’s anaomaly Abnormality in Wnt signaling and association with LiCl
What is the significance of Islet1 gene?
11-18% of secondary heart field CHD can be traced back to ISL1 mutations
So screening of ISL1 may be appropriate for families with SHF-CHD
What is looping?
Linear heart tube bends to the right and anteriorly
Direction driven by regional differences in myocardial growth rate
Beginning of septation
-endocardial cushions (OFT and AV canal)
-interventricular septum
Myocardial trabeculation
Ventricle shifts left as bulbus cordis enlarges
Significance: first sign of asymmetry of heart
What are the effects of cardiac looping?
Atria assumes more rostral and posterior orientation
Aortic root and bulbis cordis is still pointed upwards (bulbis cordis is the yellow guy)
What is the bulbis cordis?
A region that is comprised of
i. the conus cordis (CC)
ii. truncus arteriosus
Thus bulbus cordis leads to Cardiac OFT, Pulmonary artery and aorta
What does conus cordis (CC) lead to?
Cardiac OFT
Part of bulbus cordis
What does the truncus arteriosus lead to?
Pulm artery
Aorta
Part of bulbus cordis
What is septation?
Building walls between chambers (to form 4 chambers and 2 circulations) Does so by 1. AV canal septation 2. interventricular septation 3. interatrial septation 4. Outflow tract septation (TA and CC)
What are the two types of mechanisms for septation?
- Passive
2. Active
What are Passive mechanisms of septation?
- septum secondum
- muscular ventricular septum
- Aorticopulmonary
Septum primum = passive then active
What are active mechanisms of septation?
- AV canal
- Conal septum
- Truncal septum
(outflow tracts for 2 and 3)
What are the stages of atrial septation?
- Septum primum grows from dorsal wall of atrium towards AV valves (dorsal is superior here in the picture)
- ostium (hole) primum is the hole between LA and RA present when septum primum is growing
- ostium primum is closed actively by fusion of cusions
- However, an ostium secundum is then in the superior aspect of septum primum
- The septum on the superior aspect of atrial wall is now the septum secundum
- The septum secondum will passively close over the ostium secundum when the time comes
- Ostium secundum allows for flow from RA to LA during fetal development
- At birth, septum secundum will close and block off ostium secundum (or foramen ovale)
What is the septum?
The blockage of flow
What is the ostium?
The hole that allows hole to go through
What is the significance of the ostium primum?
Allows some fluid to still flow as you are putting a wall between them
What is the most common ASD?
Ostium secondum atrial septal defect
A problem with the second hole
What are the characteristics of secundum ASD?
Most common type of ASD
Occurs in center of septum between RA and LA
Due to incomplete formation of septum secundum
OR
Incomplete active closure of ostium secundum
Example: PFO
What is the difference between Ostium secondum ASD and PFO?
Ostium secundum ASD = much bigger hole
PFO is smaller hole
What is ostium primum atrial septal defect?
Second most common ASD
Located in lower portion of atrial septum
Due to incomplete active closure of the ostium primum
Associated with a cleft or slit-like defect in anterior leaflet of the mitral valve
What is the sinus venosus atrial septal defect?
Least common type of ASD
Located in the upper portion of the atrial septum
Due to a defect in formation of the SEPTUM primum
Often has an abnormal pulm vein connection associated with it
One of the pulm veins can abnormally connect to the RA instead of the LA (anomalous pulm vein)
What is Nkx2.5?
Homeobox gene
Conserved among worms, flies, mice and men
Expressed as soon as heart muscle precursors are specified in the paraxial mesoderm
Required for dorsal aorta in flies (“Tinman”)
Required for looping in mice
Heterozygous mutations in humans with CHD
When is NKx2.5 expressed?
Prior to formation of the midline cardiac tube
What is expressed prior to formation of midline cardiac tube?
Nkx2.5
What happens when you have a mutation in Nkx2.5?
- Inactivation in flies no dorsal aorta
- Inactivation in mice looping defect and embryonic lethality
- Homozygous deficiency in humans not described (cuz probably dead by then)
- Heterozygous deficiency leads to conduction defects, ASD , Tetralogy of Fallot, cardiomyopathy
Conduction defect can be there if you have a hole (physical block) and no hole (no conduction due to loss of gene function)
What is the Tetralogy of Fallot?
A congenital heart defect that involves 4 abnormalities
- pulmonary infundibular stenosis
- overriding aorta
- VSD
- RV hypertrophy
How does one pattern the great vessels?
Initially there are 5 pairs of symmetric aortic arch arteries
Some regress while others grow, resulting in mature assymetric vascular pattern
Signals from pharyngeal endoderm and migrating neural crest are required for this remodeling
You have 3rd, 4th and 6th arches in aorta (slide 45)
What is the function of the cardiac neural crest?
They allow vessels to differentiate
Form the outflow tract
Slide 46 he describes it
Since you have a left and right 4th aortic arch at embryonic development, what happens as fetus grows?
The right one regresses
Left one persists and becomes the descending aorta
What happens when both the left and right aorta regresses?
You get no blood flow in descending aorta
Pictures below (type A-C) have no descending aorta
Examples of what happens when too many parts of the aorta regress abnormally
What are the characteristics of DiGeorge syndrome?
Most common human chromosome deletion syndrome
Deletions on 22q11
1. CongenitalHD
2. Parathyroid deficiency
3. thymus defect
Caused by neural crest dysfunction of migration
Many children with CHD alone have 22q11 deletions
PDA doesn’t close in DiGeorge Syndrome
What is the most commonly deleted gene in DiGeorge Syndrome?
TBX1
What are the circulatory changes at birth?
- closure of ductus arteriosus
- closure of ductus venosus
- closure foramen ovale
What is dextrocardia?
Situs Inversus
Mirror image of body
What is discordance between organs?
When some organs are flipped but others are not
Heterotaxy!
What is heterotaxy?
When there is a discordance between organs in some being flipped and some being in same direction
When is LR axis established?
Very early as soon as primitive streak stage
What are abnormalities of sidedness?
Situs invertus
How is L-R axis established in heart?
Cilia operating at different rates
What are the key characteristics of valve formation?
- endothelial cells migrate into the “cardiac jelly”
- between endothelium and myocardium
- undergo a phenotypic switch = epithelial-mesenchymal transformation (EMT)
- Cellular swellings within cardiac jelly are the endocardial cushions, that mature into valve leaflets
What is different from epithelium and mesenchymal cells?
Former has sidedness to its cell
Mesenchymal cells doesn’t have cell orientation
What induces the formation of mesenchyme and myocardium?
Signals from myocardium and signals from endothelium respectively
Can have cross talk
What is the significance of the Ras Pathway and CHD?
Involved in the epithelial-mesenchymal transition
Growth factors bind to Ras receptor and fuck with E-M transition
Implicated in shitload of congenital heart disease
Specifically valve defects
Noonan syndrome and Costello syndrome, etc
Can predispose one to hypertrophy
What is angiogenesis?
Formation of new blood vessels from pre-existing blood vessels
Happens in the embryo
What is vasculogenesis?
Formation of new blood vessels from endothelial precursors (angioblasts)
What are examples of factors that promote angiogenesis?
- VEGF
- Notch
- Semaphorins
What are the key factors in angiogenic stimulation?
VEGF and VEGF receptors
What is the significance of Notch ligands and receptors?
Determines artery vs vein and of “tip” cells which mediate branching at the leading age of a developing vessel
What is the significance of semaphorins?
Mediates repulsive signals involved in axon guidance and growth cone collapse
Secreted ligands bind to Plexin/neuropilin receptors
Expressed broadly outside the CNS
How does the epicardium form?
Arises from the proepicardial organ, a derivative of the septum transversum that also gives rise to diaphragm and liver
Required for coronary artery development and myocardial maturation
Makes a epithelial-mesenchymal transformation
What happens when you interfere with epicardium formation?
Coronary vessels don’t develop
Where is the muscular wall of the aorta derived from?
Neural crest cells
How do neural crest cells contribute to heart formation?
Migrate from dorsal neural tube to pharynx and heart
Pluripotent cells, form arterial smooth muscle, bone, skeletal muscle, melanocytes, thymus, thyroid and parathyroid cells
Required for SMC layers of PA, Ao, DA, carotid arteries
Required for septation of the truncus arteriosus and cardiac outflow tract
Defets results in cardiac outflow tract defects
What is DA?
Ductus arteriosus
How do neural crest cells contribute to aortic formation?
Neural crest cells become SMCs of tunica MEDIA of pharyngeal arch arteries
What gene defect is present in pulmonary HTN?
BMP
What gene defect is present in DiGeorge Syndrome?
Tbx1
What gene defect is present in Alagille syndrome and Bicuspid Ao valve?
Notch
What are the most common cardiac defects due to DiGeorge?
- PDA
- Interupted aortic arch
- Tetralogy of Fallot (TOF)
- Double outlet RV
- VSD
