CVS Session 3: CVS embryology and congenital heart defects Flashcards
When does the vascular system appear and why?
Middle of week 3 (~day 16)
Need more than diffusion to meet the nutritional requirements
Where are the progenitor heart cells located?
In the epiblast, next to the cranial end of the primitive streak
Describe the 2 sections of cardiac field, located at the cranial end
Primary heart field: cranial to neural folds. Form atria, LV and part of RV
Secondary heart field: remainder of RV and outflow tract
To where do the progenitor heart cells migrate at the start of heart development?
Splanchic layer of the lateral plate mesoderm
Initial cardiac structure?
“Blood islands” that will form blood vessels
These unite, form endothelial-lined tube surrounded by myoblasts: cardiogenic region
At the cranial end these blood islands are primitive heart tube
Intraembryonic cavity over it: later forms pericardium
Dorsal aortae (eventually become descending aorta): other blood islands appear, forming a pair of longitudinal vessels. Develop concurrently with endocardial heart tubes and form a cranial connection with the tubes prior to folding
How is the primitive heart tube formed?
- 2 tubes bilaterally of trilaminar disc at ~day18
- embryo folds laterally so that the caudal regions of the paired cardiac tube merge (except at the caudalmost end)
- cephalocaudal folding brings the tube into the thoracic region: buccopharyngeal membrane pulled forward, heart and pericardial cavity move to thorax
- by day 22 (w4) the primitive heart tube can contract and push blood cranially from sinus venosus
- myocardium thickens, epicardium and pericardium form
What happens at the caudal pole?
Venous drainage
What happens at the cranial pole?
Blood pumped out of first aortic arch
What is the transverse pericardial sinus?
Connect both sides of the pericardial cavity when the dorsal mesocardium disappears
Space behind outflow vessels and in front of inflow vessles (arteries in front of veins)
How are regions of the heart tube tethered?
Cranially and caudally by inflow and outflow
Inflow through sinus venosus and outflow through aortic roots
Sufficient for early embryo
In which direction does the heart tube fuse?
Begins cranially, extends caudally
Facilitated by apoptosis
What happens following fusion of the heart tube?
Constrictions and dilations appear
Form the regions of the early embryonic heart
Blood flows from caudal to cranial. What are the structures through which blood passes, from caudal to cranial?
Sinus venosus Primitive atrium Primordial ventricle Bulbis cordis Truncus arteriosus Aortic roots
What is cardiac looping and when does it occur?
Continued elongation as cells added to cranial end. Allows the tube to form a more complex structure more associated with the adult heart
~Day23 to day 28 (week 4, completed by week 5)
Summary of cardiac looping?
- Straight heart tube begins to elongate with simultaneous growth in the bulbus cordis and primitive ventricle.
- This forces the heart to bend ventrally and rotate to the right, forming a C-shaped loop with convex side situated on the right.
- The ventricular bend moves caudally and the distance between the outflow and inflow tracts diminishes.
The atrial and outflow poles converge and myocardial cells are added, forming the truncus arteriosus.
Hence an S-shape is formed with the first bend of the ‘S’ being the large ventricular bend while the bend at the junction of the atrium and sinus venosus forms the second ‘S’ bend.
Looping of cephalic portion?
Ventrally, caudally and to the right
Looping of cranial portion?
Dorsally, cranially and to the right
What drives the looping process?
The limiting of space
What is the main achievement of looping?
Puts inflow and outflow cranially, with inflow behind outflow
Atrium communicates with ventricle via atrioventricular canal (expansion of AV junction)
What happens to the bulbus cordis during looping?
Bulbis cordis is narrow
Except proximal 1/3–>forms trabeculated part of RV
Midportion (conus cordis) forms ventricular outflow tracts
Distal portion (truncus arteriosus) forms roots and the proximal aorta & pulmonary trunk
Area between the BC and the ventricle becomes the interventricular foramen
Completion of looping?
Smooth walled heart tube begins to form primitive trabeculae
BC smooth walled temporarily
Primitive ventricle now primitive left ventricle
Trabeculated proximal 1/3 of BC is primitive right ventricle
Result of looping allows partitioning:
Primordium of RV put closest to outflow tract
Primordium of LV put closest to inflow tract
Atrium dorsal to BC (i.e. inflow dorsal to outflow)
AV canal narrows junction between A and V zones, but is still continuous at this point
What is the role of the sinus venosus in atrial development?
Receives blood from the placenta, yolk sac and body (umbilical, vitelline and common cardinal veins)
Has two sinus horns (L and R): initially same size
The entrance shifts right when the right shunt of blood occurs (w4-5)
Left sinus horn recedes: R. umbilical and L. vitelline veins are obliterated
Enlarging R. atrium absorbs the R. sinus horn
How does the right atrium develop?
Most of primitive atrium and the right horn of the sinus venosus
Receives venous drainage from venae cavae (body) and coronary sinus (heart)
How does the left atrium develop?
A small portion of the primitive atrium absorbs the proximal parts of the pulmonary veins
Receives oxygenated blood from the lungs
What are the auricles?
Rough remainders of the primordial atria, present in the adult heart
What is the oblique pericardial sinus and where can it be located on a prosection?
Formed as the left atrium expands and absorbs the pulmonary veins
With the heart in the palm of the hand, fingers are in a “cul de sac”
Describe the foetal circulatory shunts (more in next lecture)
Lungs are non functional, so circulation bypasses these: this must change immediately after birth. This is to avoid oxygenated blood damaging the developing lung tissue
Process:
1. Oxygenated blood from mother enters placenta
2. In foetus, bypasses liver and travels to IVC where it enters the RA
3. Bypasses the RV, PT, goes straight to LA, drains into LV, then into aorta
4. Most blood passes through ductus arteriosus into descending aorta, mixes with blood from proximal aorta
5. Oxygenated blood circulates around foetal body, then returns to the placenta when the oxygen has been used to be returned to the mother
Describe the two mechanisms of blood vessel development
- Vasculogenesis: vessels grow through coalescence of angioblasts
- Angiogenesis: vessels sprout from existing vessels (major vessels)
Guided by VEGF
Aortic arches?
Early arterial system begins as a bilaterally symmetrical system of arched vessels, then remodelling creates major derivations
Creates 5 pairs of arches
Arches 1,2,3,4 and 6: each has its own cranial nerve and own artery
Why is there no aortic arch 5?
Aortic arch 5 has no derivatives in humans
Where are the aortic arches positioned?
Mesenchyme of pharyngeal arches
Terminate in the R and L dorsal aortae
Appear in a cranial to caudal sequence
4th aortic arch?
Right: proximal part of the right subclavian artery
Left: arch of the aorta
6th aortic arch?
Recurrent laryngeal nerve
Right: right pulmonary artery
Left: left pulmonary artery and ductus arteriosus
What is the relevance of the recurrent laryngeal nerves?
Supply each arch
Right descends to T1-T2, left descends to T4-T5
Factors influencing course of nerve on left and right sides:
1. Caudal shift of developing heart and expansion of neck
2. Need for a foetal shunt between the PT and aorta
As the heart descends the nerve hooks around the 6th arch and turns back on itself
End result of looping?
NOT yet 2 pumps in series configuration
Primitive chambers must be divided
Purpose of septation and when does it occur?
To create the 4 chambers and achieve selective outflow
Major septa formed d. 27-36 (w. 4-6)
2 general methods in which septation may occur?
- Two acitvely-growing tissue masses approach each other until they fuse
- Active growth of tissue continues to expand until reaches the other side of the lumen (endocardial cushions)
Septation of the AV canal?
Two endocardial cushions form on the dorsal and ventral surfaces of the AV canal (superior and inferior resp)
Tissue in this region expands while mesenchymal cells from the endocardium invade the cushions, allowing them to grow and fuse
Fusion divides the common AV canal into the right and left canals, hence partially separating the primitive atrium and ventricle
Two smaller endocardial cushions also form on the lateral walls of the AV canal, which later help to form the mitral and tricuspid heart valves.
How do endocardial cushions form?
Synthesis and deposition of ECM and proliferation/migration of cells
In AV cushions: endocardial cells
In conotruncal cushions: cells from neural crest cells
What is the clinical relevance of endocardial cushions?
Abnormalities can cause ASDs, VSDs and great vessel defects
Outline the steps in atrial septation
- Crest in common atrium (SEPTUM PRIMUM) grows down towards the fused endocardial cushions in the AV canal
- OSTIUM PRIMUM: first opening before the septum primum fuses with the endocardial cushions
- OSTIUM SECUNDUM: apoptosis causes perforations in septum primum, forming the ostium secundum (before ostium primum closes)
- Lumen of right atrium expands due to incorporation of sinus horn
- New crescent-shaped fold appears: SEPTUM SECUNDUM
- Hole within septum secundum: FORAMEN OVALE
Significance of ostium secundum?
Ensures free blood flow from right to left primitive atrium for the foetus
1 sentence to describe atrial septation?
Division of the common atrium by the creation of 2 septa with 3 holes
Describe passage between the two atrial cavities
An obliquely elongated cleft (staggering of the two holes)
Blood from the right atrium enters the left atrium: RIGHT TO LEFT SHUNT
How do the atria enlarge?
RA: absorbs sinus venosus
LA: expands by the pulmonary vein: sprouts it then grows to absorb it
What are auricles?
Tissue on both atria derived from the primitive atrium
Atrial septation summarise
Membranous tissue forming the septum primum grows from the roof of the atrium, dividing it into left and right halves. The space between the septum primum and the endocardial cushions is referred to as the foramen primum. Apoptosis-induced perforations appear in the centre of the septum primum to produce the foramen secundum. At this time the strong, muscular septum secundum grows immediately to the right of the septum primum and gradually overlaps the foramen secundum during the fifth and sixth weeks of development. The incomplete partition of the atrium by the septum secundum forms the foramen ovale.
Blood flow after septation?
Blood flows from the right atrium through the foramen ovale and foramen secundum to the left atrium, forming a right-to-left shunt. The remaining portion of the septum primum acts as the valve of the foramen ovale. Blood cannot flow in the opposite direction, as the muscular strength of the septum secundum prevents prolapse of the septum primum.
What is the fossa ovalis?
The adult remnant of the shunt used in utero to bypass the lungs
Can see in a dissection
When and how do the primitive ventricles begin to expand?
End of W4
Continuous growth of myocardium on the outside
Continuous diverticulation and trabeculae formation on the inside
Describe the process of ventricular septation
- Primordial muscular interventricular ridge develops on the floor of the primitive ventricle
- Muscular part of septum (majority) grows UPWARDS towards the fused endocardial cushions
- Medial walls of expanding ventricles gradually merge, forming IV SEPTUM
- Membranous septum formed by endocardial cushions to ‘fill the gap’ as muscular portion doesn’t quite reach cushions
- This portion closes the IV foramen, by growing DOWNWARDS
What is the primary interventricular foramen?
Muscular part of septum growing upwards does not quite reach cushions: small gap between septum and fused cushions allows communication between ventricles: INTERVENTRICULAR FORAMEN
Closed by growth of the membranous portion of the septum
What is the conotruncal septum and when does it form?
Septation in the outflow tracts (truncus arteriosus and conus cordis)
W5
What is the role of cardiac neural crest cells in conotruncal septation?
Migrate through pharyngeal arches 3,4 and 6 into outflow region
Contribute to endocardial cushion formation in the conus cordis and truncus arteriosus
Briefly outline conotruncal septation?
- Endocardial cushions appear in truncus arteriosus
- Grow towards each other and twist, forming a spiral structure
- Fuse, forming the aorticopulmonary septum which divides the TA into an aortic and pulmonary channel
- Cushions appear along the R. dorsal and L. ventral walls of CC, grow towards and distally to unite with truncus septum
- The two conus swellings fuse, causing division of the septum into the outflow of the right ventricle (anterolateral) and outflow of the left ventricule (posteromedial)
Summary of outflow tract septation
Active proliferation of neural crest mesenchymal cells in the bulbus cordis during the fifth week creates bulbar ridges which are continuous in the truncus arteriosus. The neural crest cells migrate through the primordial pharynx and over the aortic arch arteries to reach the outflow tract (pictured below). The bulbar ridges undergo a 180° spiral to create the helical aorticopulmonary septum. As the ridges grow and develop myocardium they fuse in a distal-to-proximal direction. Fusion occurs during the sixth week, allowing for cleavage of the aorta and pulmonary trunk. The spiralling nature of the ridges causes the pulmonary trunk to twist around the aorta.
Bubis cordis in adult?
Accounts for the smooth conus arteriosus (or infundibulum) in the right ventricle and the aortic vestibule in the left ventricle
Function of foramen ovale?
Shunt built in to atrial septum, so blood passes from the right to left atrium, bypassing the non-functional lungs
What happens to the foetal shunts at birth?
- LA pressure much higher than RA so forces foramen ovale shut (septum primum pushed against septum secundum)
- Ductus arteriosus contracts and becomes fibrotic
- Ductus venosus shuts as is no longer receiving blood from the placenta
- Recurrent left pharyngeal nerve hooked around the remnant of the ductus arteriosus
State the fates of the following foetal shunts:
- Foramen ovale
- Ductus arteriosus
- Ductus venosus
- Umbilical vein
- Fossa ovalis
- Ligamentum arteriosum
- Ligamentum venosum
- Ligamentum teres
What is the fate of the following foetal structures and briefly state how the transformation occurs:
- Sinus venosus
- Foetal atrium
- Foetal ventricle
- Bulboventricular sulcus
- Bulbus cordis
i. Proximal 1/3
ii. Conus cordis
iii. Truncus arteriosus
- Right atrium (except left horn) -absorbed by developing atria
- Auricles of definitive atria -during atrial septation
- Left ventricle -during ventricular septation
- 1^o interventricular foramen-during ventricular septation
- i. Trabeculated right ventricule- during ventricular septation
ii. Outflow tracts of both ventricles-division of ventricular septum by the conus swellings
iii. Roots and proximal aorta and pulmonary trunk-truncus arteriosus forms aorticopulmonary septum
When do congenital heart defects usually arise?
After foetal shunts close
Why do skin and mucous membranes appear blueish in cyanotic defects?
Build up of deoxy haemoglobin
In which direction does blood flow in cyanotic defects?
Right to left
Poorly oxygenated blood from the right atrium is shunted to the left atrium, bypassing the lungs
Describe where acyanotic heart defects can occur
Intracardiac stenosis
Vascular stenosis
Valvular regurgitation
Left to right shunt (pulmonary pressure increases)
Aetiology of congential heart defects
- Genetic: Down’s, Turner’s and Marfan’s syndromes
- Environmental: teratogenecity from drugs, alcohol etc
- Maternal infections: rubella, toxoplasmosis etc
May not become apparent until adulthood
Describe left to right shunts
Require a hole
Blood from left heart is returned to the lungs rather than the body
This itself isn’t damaging, but the increased PA or PV pressure is
Describe right to left shunts
Require a hole AND a distal obstruction
Pressure in RV is higher than in LV, so this is the direction of blood shunting. Deoxygenated blood bypasses the lungs
List some acyanotic congential heart defects
Ventricular septal defect Atrial septal defect Ostium primum ASD Ostium secundum ASD Patent foramen ovale Patent ductus arteriosus BUT CAN BE CYANOTIC IF REVERSES Coarctation of the aorta Aortic stenosis Pulmonary stenosis
List some cyanotic congenital heart defects
Tetralogy of Fallot
Tricuspid atresia
Transposition of the great vessels
Hypoplastic left heart
Ventricular septal defect? most common
Location: usually in membranous part
Shunt: left to right
Effects: LV volume overload, pulmonary venous congestion, more blood in pulmonary artery than aorta
Complications: pulmonary hypertension, shunt can be reversed causing cyanosis
Atrial septal defect? second most common, twice as many females as males
Location: atrial septum
Shunt: left to right (low pressure, doesn’t normally damage pulmonary resistance)
Effects: increased pulmonary blood flow, RV volume overload
Complications: pulmonary hypertension (rare), right heart failure
Types of ASD?
- Ostium secundum ASD (most common)
- defect at foramen ovale due to excess cell death and resorption of septum primum, or inadequate development of SS - Ostium primum ASD (less common)
- inferior portion of septum, endocardial cushions partially fuse, defect in atrial septum but IV septum closed
- usually combined with a cleft in anterior leaflet of tricuspid valve - Cor triloculare biventriculare (most serious)
- complete absence of atrial septum
- i.e. 1. and 2
Patent foramen ovale? (not a true asd)
Location: separates right from left atrium. In 25% of people, usually only apparent when higher pressure
Shunt: none except on coughing (usually silent)
Effects: left atrial pressure higher than right so usually causes closure of the flap valve
Complications: if pressure on right heart increases: venous embolism could reach systemic circulation: paradoxical embolism
Also linked to decompression sickness and migraine
Patent ductus arteriosus
Location: ductus arteriosus fails to close after birth (used in foetus to shunt blood from PA to aorta) normally becomes ligamentum arteriosum when PA pressure decreases as lung perfused
Shunt: left to right
Effects: blood flow from aorta to PA after birth
Complications: if not treated there is vascular remodelling of pulmonary circulation, causing increase in pulmonary resistance until it exceeds that of systemic circulation, so shunt reverses - Eisenmenger syndrome
Hear mechanical murmur consistently in systole and diastole as pressure in aorta always higher than in PA
What is Eisenmenger syndrome?
In chronic PDA, vascular remodelling of the pulmonary circulation takes place, increasing pulmonary resistance > systemic resistance, so L-R shunt reverses as pressure in the right heart increases
Becomes cyanotic
Coarctation of the aorta? (Common in Turner’s syndrome)
Location: narrowed aortic lumen in ligamentum arteriosum
Effect: increased afterload on left ventricle. Normal supply to head and upper limb as proximal to coarctation, but blood to rest of body decreases (severity depends on degree of coarctation)
Signs: hypertension in right arm and hypotension in legs, weak and delayed femoral pulses
Complications: can cause left ventricular hypertrophy. Infants can die if severe from heart failure
Congenital aortic stenosis?
NO SHUNT-obstructive lesion
1/5 also have coarctation of aorta
Narrowed aortic valve with 2 cusps rather than 3, so less blood gets through as it doesn’t fully open, so can’t leave left ventricle
LV pressure increases to push blood into aorta, so LV hypertrophy
Often asymptomatic until adult. May need surgery to remove obstruction
Congenital pulmonary stenosis?
NO SHUNT-obstructive lesion
Narrowing in RV outflow tract/PA, so impaired outflow from RV, so increased RV pressure causing RV hypertrophy
Untreated leads to right heart failure
Often asymptomatic, may need treatment by valvuloplasty
List the main cyanotic heart defeects
Tetralogy of Fallot Tricuspid atresia Transposition of the great vessels Hypoplastic left heart syndrome Eisenmenger syndrome
Tetralogy of Fallot?
Shunt: right to left (increased pressure on RH, VSD & OA)
Defect: abnormal anterior and cephalic displacement of the outflow tract of the IV septum
Abnormalities:
1. VSD (malaligned IV septum)
2. PULMONIC STENOSIS (obstruction from narrowed RV outflow)
3. OVERRIDING AORTA (above septal defect, receives blood from LV and RV)
4. RV HYPERTROPHY (due to high RV pressure)
Correction with surgery
Tricuspid atresia?
Location: lack of development of tricuspid valve
Effect: no inlet to RV: absence or fusion of tricuspid valve. Also causes VSD or PDA to allow blood to flow to the lungs
Shunt: complete R-L shunt of all blood returning to RA
Always associated with:
1. PFO
2. VSD
3. Underdeveloped RV
4. LV hypertrophy
Transposition of the great vessels? (commonest cause of cyanosis in neonates)
Location: conotruncal septum doesn’t develop normally, causing aorta to originate from RV and PA to originate from LV
Effect: 2 unconnected parallel circulations instead of 2 circulations in series. Deoxygenated blood forced from systemic venous system to RV then to systemic via aorta without getting O2 from lungs. Oxygenated blood from PV goes through LV and back to lungs via PA without giving O2 to body
Complications: not compatible with life unless surgical shunt
Hypoplastic left heart syndrome? (rare)
Problem: very small LV and aorta, aorta may be stenosed. PFO and ASD also present
Lethal unless surgery
Why do patients with tetralogy of Fallot develop right ventricular hypertrophy?
Pulmonary stenosis: increases resistance of blood flow to lungs so right ventricle must increase in size to compensate
Ventricular septal defect: decrease in the pressure that the right ventricle is able to create to pump blood to the lungs, so must increase in size to compensate for the loss
