Development of the Heart Flashcards
(51 cards)
1
Q
When do progenitor heart cells appear?
What cell type are they derived from?
A
- the vascular system begins to develop in the middle of the 3rd week (day 16-18) when the embryo can no longer satisfy its requirements from diffusion alone
- progenitor heart cells are derived from the epiblast, immediately adjacent to the cranial end of the primitive streak
2
Q
Where do the progenitor heart cells migrate to and what do they form?
A
- progenitor heart cells (epiblast) invaginate through the primitive streak
- they migrate to the splanchnic layer of the lateral plate mesoderm between days 16-18
- some of the PHCs will form horseshoe-shaped clusters of cells called the primary heart field (PHF)
- these are located cranial to the neural folds
3
Q
What do the cells of the primary heart field give rise to?
A
- the atria
- left ventricle
- part of the right ventricle
- the remainder of the right ventricle and outflow tract (conus cordis & truncus arteriosus) are formed from the secondary heart field
4
Q
How are progenitor heart cells “fate-mapped” as they migrate through the primitive streak?
A
- as the PHCs migrate through the primitive streak, they are specified on both sides from lateral to medial to become the different parts of the heart
- this process occurs around the same time that laterality is being established
5
Q
When does the secondary heart field develop?
Where is this located?
A
- the secondary heart field (blue) forms in the region cranial to the primary heart field
- this still resides in the splanchnic mesoderm but ventral to the pharynx
6
Q
What is the “master gene” for heart development?
Where is this secreted?
A
NKX2.5
- signals from the anterior (cranial) endoderm induce a heart-forming region in the overlying splanchnic mesoderm by inducing NKX2.5
7
Q
What must be secreted and inhibited before the anterior endoderm can secrete NKX2.5?
A
- these signals require secretion of bone morphogenic proteins (BMPs) 2 & 4 secreted by the endoderm and lateral plate mesoderm
- there must also be inhibition of WNT proteins (3a & 8) secreted by the neural tube as these inhibit heart development
8
Q
How is inhibition of WNT proteins acheived?
A
- there is WNT inhibition by CRESCENT*** and ***CERBERUS
- these are produced by endoderm cells immediately adjacent to heart-forming mesoderm in the anterior half of the embryo
9
Q
What combination of factors lead to expression of NKX2.5?
A
- inhibition of WNT proteins by CERBERUS & CRESCENT
- upregulation of BMP 2 & 4 activity
- BMP expression also upregulates activity of FGF8 that is needed for expression of cardiac specfic proteins
- the product of development of the primary heart fied is an endocardial tube surrounded by myoblasts (cardiogenic region)
10
Q
How is the cardiogenic region established following formation of the PHF?
A
- the underlying pharyngeal endoderm signals for cells to form cardiac myoblasts and angiogenic cell clusters / blood islands (will form blood cells / vessels)
- the blood islands unite to form a horseshoe-shaped endothelial-lined tube surrounded by myoblasts
- this is the cardiogenic region - an endocardial tube surrounded by myoblasts
11
Q
How does the heart tube form following formation of the cardiogenic region?
Which regions of this tube receive and pump out blood?
A
- as a result of embryonic folding, the caudal regions of the paired cardiac tube merge (except at their caudalmost ends)
- the central part of the tube expands to form the future outflow tract and ventricular regions
- the heart tube is an expanding tube that consists of an inner endothelial lining** and an **outer myocardial layer
- it receives venous drainage at its caudal pole and begins to pump blood out of the first aortic arch into the dorsal aorta at the cranial pole
12
Q
How is development of the secondary heart field regulated?
How can outflow tract defects arise?
A
- development of the secondary heart field is regulated by neural crest cells (NCCs)
- NCCs proliferate and differentiate to allow the SHF to lengthen and form the outflow tract** and **part of the RV
- disruption to NCCs can result in outflow tract defects
13
Q
How is the SHF involved in lengthening of the heart tube and why is this important?
A
- the heart tube continues to elongate as cells from the SHF are added
- addition of these cells is regulated by NCCs, which are essential for formation of part of the right ventricle and the outflow tract region
14
Q
What is the bulbus cordis and what is it formed from?
A
- the bulbus cordis consists of the truncus arteriosus and the conus arteriosus
- together these form the outflow tract of the heart, which is derived from NCCs
15
Q
What is the purpose of cardiac looping?
When does it start and end?
A
- cardiac looping begins on day 23 as the outflow tract lengthens
- it is complete by day 28
- it occurs in preparation for the heart dividing into 4 chambers
16
Q
How do the bulbus cordis, primitive ventricle and primitive atrium move during cardiac looping?
A
Bulbus cordis:
- moves caudally, ventrally and to the right
Primitive ventricle:
- is displaced before moving back to the midline
Primitive atrium:
- moves cranially, dorsally and to the left
- all the primitive chambers are connected, so if one moves caudally then it will push the other side cranially
17
Q
Which transcription factor of the laterality pathway is important for cardiac looping?
A
- cardiac looping is dependent on several factors, including expression of *PITX2* in lateral plate mesoderm on the left side
- PITX2 plays a role in the deposition and function of extracellular matrix molecules that assist in looping
18
Q
How is NKX2.5 involved in cardiac looping?
A
- NKX2.5 upregulates expression of HAND1 and HAND2
- these transcription factors are expressed in the primitive heart tube before later becoming restricted to the future left (HAND1) and right (HAND2) ventricles
- downstream effectors of these genes participate in looping
- HAND1 & HAND2, under the regulation of NKX2.5, also contribute to expansion and differentiation of the ventricles
19
Q
What transcription factor is important in lengthening of the outflow tract by the SHF?
A
SHH
- lengthening of the outflow tract by the SHF is in part regulated by SHH
- SHH is expressed by the pharyngeal arch endoderm and acts through its receptor patched (PTC) to stimulate proliferation of cells in the SHF
- PTC is expressed by SHF cells
20
Q
How is retionic acid involved in cardiac development?
A
- the venous portion of the cardiac tube is specified by retinoic acid (RA)
- RA is produced by mesoderm adjacent to the sinus venosus and atria
- after exposure to RA, these structures are able to make their own RA and are committed to becoming caudal cardiac structures
- lower concentrations of RA in the ventricles and outflow tract commits these to becoming cranial cardiac structures
21
Q
What types of defects result from disruptions in laterality pathways?
Which 2 drugs have been linked to these?
A
- septal defects
- outflow tract defects
- isomerisms
- inversions
- SSRIs and retinonic acid have been linked to heart defects
22
Q
Do heart defects tend to be more environmental or genetic?
A
- most heart defects are caused by a complex interplay between genetic and environmental influences (multifactorial)
- around 2% of cases are caused by environmental agents
23
Q
What are some known causes of congenital heart defects?
A
- alcohol intake during pregnancy
- maternal diabetes
- genetic defects
- drugs (e.g. retinoic acid, SSRIs)
- infections (e.g. rubella)
- disruption of neural crest cells (development, migration, differentiation)
24
Q
In simple terms, what 3 broad categories do all CHDs fall into?
A
Hole in the heart:
- abnormal communication between 2 chambers that allows blood to flow between them
- clinical effects depend on the size of the defect
Laterality defect / outflow tract defect:
- e.g. a common outflow tract opposed to a separate aorta / pulmonary trunk if septation fails
- the aorta may arise from the RV and pulmonary trunk from the LV
Valve abnormalities:
- may be stenoses (valves fail to function correctly) or atresia (valves fail to close properly)
25
What is meant by cyanotic and acyanotic CHDs?
this classifies CHDs depending on whether or not the patient has **_normal O2 saturations_**
**_Cyanotic CHD results if the defect:_**
* results in **reduced pulmonary blood flow**
* allows for the **mixing** of oxygenated and deoxygenated blood
* carries **deoxygenated blood** into the systemic circulation
**_Acyanotic CHD results if the defect:_**
* involves a **left-to-right shunt** of blood
* does **_not_** allow for **significant mixing** of blood
* results in **increased pulmonary blood flow**
* *although, this can be damaging to pulmonary vasculature*
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27
What is the ductus arteriosus and when should it usually close?
* the ductus arteriosus **connects the pulmonay artery to the aorta** in foetal circulation
* *it allows blood to bypass the lungs and enter the aorta*
* contraction of its muscular wall following birth should lead to its closure to form the **_ligamentum arteriosum_**
* anatomical closure takes **1 to 3 months**
28
What is patent ductus arteriosus?
* when the **ductus arteriosus fails to close** after birth
* this allows **oxygenated blood from the _aorta**_ to pass through the patent ductus arteriosus and into the _**pulmonary artery_** (L-R shunt)
* this allows for **oxygenated blood to return to the lungs**
29
What are the symptoms of patent ductus arteriosus?
* symptoms are **uncommon at birth** and usually appear in the **first year of life**
* there is an **_increased work of breathing**_ and _**failure to gain weight_** at a normal rate
* over time, untreated PDA leads to **pulmonary hypertension** followed by **right-sided heart failure**
30
Why can NSAIDs be given in individuals with PDA?
When is this contraindicated?
* NSAIDs **inhibit prostaglandin synthesis**
* **_prostaglandin E2_** is responsible for keeping the ductus arteriosus **open**
* in **transposition of the great vessels**, prostaglandins are given to **keep the PDA open** as this is the only way oxygenated and deoxygenated blood can mix
31
What infant may be at a greater risk of PDA?
* premature newborns are more likely to have PDA due to underdevelopment of the heart and lungs
32
What 4 defects are present in tetralogy of Fallot?
Is this cyanotic or acyanotic?
1. VSD (of the membranous part)
2. pulmonary stenosis
3. overriding aorta
4. right ventricular hypertrophy
* it is cyanotic as the VSD allows for the mixing of oxygenated and deoxygenated blood
* an overriding aorta involves expansion of the aorta to allow blood from both ventricles to enter
33
Why does RV hypertrophy occur in Tetralogy of Fallot?
* pulmonary stenosis results in a **narrowed pulmonary trunk**, which increases the pressure within the RV
* the VSD allows for **more blood to enter the RV** from the left, further increasing the pressure
34
What causes Tetralogy of Fallot?
What other presentations / conditions may also be present?
* caused by **unequal division of the conus**, resulting from **anterior displacement of the conotruncal septum**
* may involve mutations in **JAG1 or NOTCH** that regulate NCCs forming the conotruncal septum of the outflow tract
* individuals often also have:
* problems with the liver
* broad prominent forehead
* deep set eyes
* small pointed chin
35
36
What are the typical symptoms of Tetralogy of Fallot?
* at birth, symptoms can range from severe to asymptomatic
* later in infancy, **episodes of cyanosis** due to lack of sufficient oxygenation are seen
* ***"tet" spells*** occur when babies cry or have a bowel movement
* become cyanotic
* difficulty breathing
* may become limp
* may lose consciousness
* heart murmur
* finger clubbing
* easy tiring on breastfeeding
37
What is meant by hypoplastic left heart syndrome?
What is thought to be the underlying cause?
* a condition in which the **_left side of the heart is underdeveloped_** and some structures have failed to form properly
* the **left ventricle will be small**
* the aorta may be **atretic** or **stenotic**
* the **left atrium may be reduced in size**
* this is likely to be due to an adverse effect on **_specification of the left cardiac progenitor cells_** at an early stage of heart development
38
What is the immediate management for hypoplastic left heart syndrome?
What are the symptoms and associated risks later in life?
* the **_ductus arteriosus is kept open_** otherwise **cyanosis** and **respiratory distress** result, which can lead to cardiogenic shock and death
* early symptoms include **poor feeding** and **cyanosis** that does not respond to oxygen administration
* **extremities are cool** and **peripheral pulses are weak**
* even after treatment, individuals are at a **_greater risk of heart failure as an adult_** and often experience **neurodevelopmental and motor delay**
39
What is an atrial septal defect and who is more likely to be affected?
What are the 2 main reasons why this occurs?
* 2:1 prevalence in **female** to male infants
* there is a **communication present between the right and left atria**, allowing for the **_mixing of blood_**
* the most significant defect is the **_ostium secundum defect,_** which can be caused by:
* excessive cell death and resorption of the septum primum
* inadequate development of the septum secundum
* depending on the size of the defect, **_considerable L-R shunting occurs_**
40
What is meant by Eisenmenger's syndrome resulting from an ASD (including patent foramen ovale)?
* if an ASD is not corrected, **pulmonary hypertension progresses** until the **pressure in the _right side_ of the heart _exceeds that of the left side_**
* this causes **_reversal of the shunt from L-R to R-L_**
* after this reversal, a portion of oxygen-poor blood is shunted to the left side of the heart and ejected into the systemic circulation, producing **signs of cyanosis**
41
What is meant by total anomalous pulmonary venous return (TAPVR)?
* in this condition, **_all 4 pulmonary veins_** connect to and drain into the **_superior vena cava_**
* this abnormal connection means that **oxygenated blood is _not_ returning to the left atrium**, but to the **_right atrium_** instead
* within the right atrium there is **mixing of oxygenated and deoxygenated blood**
42
What needs to be present to prevent TAPVR from being fatal?
* a patent foramen ovale
* a patent ductus arteriosus
* or an ASD
* need to be present or else this condition is fatal due to lack of systemic blood flow
43
What is meant by transposition of the great vessels and why does it occur?
* occurs when the **conotruncal septum fails to follow its normal spiral course** and runs **_straight down_** instead
* this results in the **_aorta arising from the right ventricle**_ and the _**pulmonary artery from the left ventricle_**
44
What are the 2 types of VSD and which is more severe?
* VSD involves a defect in either the **_muscular or membranous portion_** of the ventricular septum that allows for the **mixing of blood**
* 80% occur in the **muscular portion** of the septum and can **_resolve as the child grows_**
* **membranous VSDs are more severe** and result from abnormalities in partitioning of the conotruncal region
* depending on the size of the opening, pressure in the pulmonary artery can be 1.2-1.7x that of the aorta
45
What is meant by common truncus arteriosus?
Why does this occur and what is it always associated with?
* the **conotruncal ridges fail to form** so **_no division of the outflow tract occurs_**
* the ridges also participate in formation of the interventricular septum, so there is always also a **_defective interventricular septum_**
* the undivided truncus **overrides both ventricles** are **_receives blood from both sides_**
46
What usually accompanies transposition of the great vessels?
What is thought to be the underlying cause of this condition?
* usually accompanied by a **patent ductus arteriosus**
* sometimes associated with a **membranous VSD**
* cells of the **_SHF and NCCs_** contribute to formation and septation of the outflow tract, so insults to these cells result in defects involving the outflow tract
47
How does someone with a ASD high in the septum (foramen secundum) tend to present?
How is this different to a low septal defect?
* symptoms are **rare** in infancy, may become **_breathless on exertion_**
* they tend to present in their **_30s / 40s_** with **heart failure, pulmonary hypertension** and **atrial arrhythmias**
* low septal defects are associated with **atrioventricular valve abnormalities** and tend to present with **_heart failure in infancy_** / childhood
48
What is the difference in severity between a muscular and membranous VSD?
How do they present?
* symptoms of a **_muscular VSD_** tend to **improve with age** as the **_defect can repair itself_**
* **membranous septal defects require surgery** and cannot fix themselves
* large defects result in **failure to thrive, breathlessness when crying / feeding** and **heart failure**
49
What is the only way in which a child with hypoplastic left heart syndrome can survive?
When do symptoms appear?
* underdevelopment of the left side of the heart results in a **reduced cardiac output**
* survival is only possible in the presence of a **_patent ductus arteriosus**_ and _**patent foramen ovale_**
* *this allows some mixed blood to reach target organs*
* symptoms develop after the **first few days of life** when the **_PDA and PFO close_**
50
What steps are taken to treat heart failure in babies?
1. oxygen
2. nasogastric feeding
3. keep the child positioned upright
4. diuretics (furosemide)
5. maintaining the PDA in cyanotic duct-dependent defects with prostaglandins
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