Development of the Heart Flashcards

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
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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
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3
Q

What do the cells of the primary heart field give rise to?

A
  1. the atria
  2. left ventricle
  3. 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
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
  1. alcohol intake during pregnancy
  2. maternal diabetes
  3. genetic defects
  4. drugs (e.g. retinoic acid, SSRIs)
  5. infections (e.g. rubella)
  6. 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
Q

What is meant by cyanotic and acyanotic CHDs?

A

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
26
Q
A
27
Q

What is the ductus arteriosus and when should it usually close?

A
  • 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
Q

What is patent ductus arteriosus?

A
  • 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
Q

What are the symptoms of patent ductus arteriosus?

A
  • 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
Q

Why can NSAIDs be given in individuals with PDA?

When is this contraindicated?

A
  • 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
Q

What infant may be at a greater risk of PDA?

A
  • premature newborns are more likely to have PDA due to underdevelopment of the heart and lungs
32
Q

What 4 defects are present in tetralogy of Fallot?

Is this cyanotic or acyanotic?

A
  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
Q

Why does RV hypertrophy occur in Tetralogy of Fallot?

A
  • 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
Q

What causes Tetralogy of Fallot?

What other presentations / conditions may also be present?

A
  • 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
Q
A
36
Q

What are the typical symptoms of Tetralogy of Fallot?

A
  • 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
Q

What is meant by hypoplastic left heart syndrome?

What is thought to be the underlying cause?

A
  • 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
Q

What is the immediate management for hypoplastic left heart syndrome?

What are the symptoms and associated risks later in life?

A
  • 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
Q

What is an atrial septal defect and who is more likely to be affected?

What are the 2 main reasons why this occurs?

A
  • 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
Q

What is meant by Eisenmenger’s syndrome resulting from an ASD (including patent foramen ovale)?

A
  • 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
Q

What is meant by total anomalous pulmonary venous return (TAPVR)?

A
  • 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
Q

What needs to be present to prevent TAPVR from being fatal?

A
  • 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
Q

What is meant by transposition of the great vessels and why does it occur?

A
  • 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
Q

What are the 2 types of VSD and which is more severe?

A
  • 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
Q

What is meant by common truncus arteriosus?

Why does this occur and what is it always associated with?

A
  • 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
Q

What usually accompanies transposition of the great vessels?

What is thought to be the underlying cause of this condition?

A
  • 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
Q

How does someone with a ASD high in the septum (foramen secundum) tend to present?

How is this different to a low septal defect?

A
  • 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
Q

What is the difference in severity between a muscular and membranous VSD?

How do they present?

A
  • 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
Q

What is the only way in which a child with hypoplastic left heart syndrome can survive?

When do symptoms appear?

A
  • 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
Q

What steps are taken to treat heart failure in babies?

A
  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
51
Q
A