Heart Development Flashcards
1
Q
which embryonic germ layer gives rise to the heart?
A
the mesoderm
2
Q
what structure marks the earliest visible stage of heart development?
A
cardiac crescent
3
Q
what two cell populations does the cardiac crescent consist of? what is the significance of these populations in their adult contributions?
A
consists of 1) first heart field and 2) second heart field
- both contribute to different structures of the heart/ heart chambers
- SHF contributes to separating the common outflow tract into the aorta and pulmonary artery, separating pulmonary and systemic circulations
4
Q
what happens if SHF development is disrupted?
A
abnormalities in the outflow tract or right ventricle may occur
5
Q
what is the role of the proepicardial organ in heart development?
A
it’s a cluster of cells that give rise to the epicardium & contribute to coronary vasculature
6
Q
where are cardiac neural crest cells derived from, and what do they do?
A
derived from the neural tube; contribute to the aorticopulmonary septum which divides the common outflow tract to separate pulmonary and systemic circulations
7
Q
what embryonic structure gives rise to the aorta and pulmonary artery?
A
the outflow tract (derived from the second heart field of the cardiac crescent) - divided by cardiac neural crest cells
8
Q
clinical case: a foetus has a single outflow vessel. what developmental event likely failed?
A
outflow tract septation by neural crest cells
9
Q
which developmental window is most critical for heart formation?
A
weeks 3-10 post-conception
10
Q
describe the embryological origin of the heart. What germ layer is it derived from, and how does this relate to the early structure that forms?
A
heart arises from the mesoderm - mesodermal cells migrate to the anterior part of the embryo and form the cardiac crescent (early structure)
11
Q
after the cardiac crescent forms, what is the next major structural development? how is the heart tube formed, and what are its features?
A
cells from the cardiac crescent migrate and fuse to form a single linear heart tube with two main poles - an arterial pole (cranial) and venous pole (caudal)
the tube consists of an inner endocardial layer, middle cardiac jelly, and outer myocardial layer
12
Q
what is cardiac looping, and why is it essential?
A
looping - process where the linear heart tube elongates and folds rightward (dextral looping)
moves the atrial & ventricular regions towards their adult anatomical positions
13
Q
what causes heart looping?
A
fixed ends (arterial & venous poles) & elongation via addition of SHF cells causes bending
14
Q
in what direction does the heart normally loop in?
A
dextral looping/ rightward
15
Q
how do primitive heart chambers form from the heart tube? what structural changes occur in this stage?
A
heart tube…
- elongates
- loops to establish the correct spatial relationships between future chambers
- balloons at specific regions to form primitive chambers
- septation divides the heart into its respective chambers
16
Q
what is septation, and how does it contribute to functional circulation in the mature heart?
A
septation - formation of walls/ septa that divide the heart into its chambers & separating the aorta and pulmonary artery of the outflow tract
process ensures oxy. and deoxy. blood remain separated
17
Q
outline the major events in heart development in correct chronological order
A
- specification of cardiac mesoderm - heart development originates from the mesoderm at week 3
- cardiac crescent formation - mesodermal cells migrate to the anterior part of the embryo, form a cardiac-crescent cluster of cells consisting of two progenitor populations: the first and second heart fields (FHF, SHF)
- heart tube formation - cardiac crescent cells proliferate and form a single heart cells, with distinct arterial (cranial) and venous (caudal) poles; layers consist of inner endocardium, middle cardiac jelly, and outer myocardium
- heart tube elongation and looping - loops rightward to re-arrange poles & chambers into adult anatomical positions
- chamber ballooning and early chamber formation -specific regions of heart tube balloon to form primitive chambers, now aligned from looping.
- septation of atria, ventricles, and outflow tract - forming septa divides heart into anatomical chambers, and the common outflow tract into aorta & pulmonary artery; ensures different circulations are separate
- final maturation of heart - development of coronary vasculature, alignment of great vessels
18
Q
what is the function of Nkx2.5 in heart development?
A
Nkx2.5 - master transcription factor, initiates the cardiac gene regulatory network (triggers expression of other essential TFs like GATA and MEF-2)
19
Q
the “tinman” gene in Drosophila is homologous to Nkx2.5 TF in humans. what does this suggest about evolution?
A
illustrates the evolutionary conservation of heart development — similar genes control cardiac formation across species
20
Q
what is the embryological origin of the cardiac mesoderm, and how does it relate to the primitive streak?
A
embryological origin: during gastrulation (week 3) - mesodermal cells migrate laterally and cranially from the primitive streak
- become fated as cardiac mesoderm
- form bilateral heart-forming regions which then contribute to the cardiac crescent
21
Q
describe how the combination of BMPs and Wnt inhibitors leads to heart formation in the embryo
A
BMPs promote cardiac expression ONLY when Wnt signalling is inhibited by Noggin/Chordin
spatial overlap allows cardiac mesoderm formation in the correct region
integration of BMP signalling & Wnt inhibition activates Nkx2.5 -> initiates cardiac gene regulatory network -> triggers TF expression (GATA4-6, MEF-2, co-factors)
22
Q
what would happen if Wnt signalling remained active in the anterior embryo?
A
persistent Wnt signalling would inhibit cardiac mesoderm formation - failure of heart tissue specification in cranial region
23
Q
name four key cardiac transcription factors downstream of Nkx2.5
A
GATA 4,5,6
HAND1/2
MEF-2
Tbx genes
24
Q
what is the general role of GATA TFs in heart development?
A
specifies cardiac mesoderm
supports fusion of bilateral heart-forming regions
25
what is the role of MEF-2 expression in heart development?
activates *cardiac-specific muscle* genes - drives functional cardiac muscle differentiation
26
compare the roles of GATA & MEF-2 TFs in heart development
GATA TFs help specify cardiac mesoderm & support fusion of bilateral heart-forming regions
MEF-2 activates cardiac-muscle specific genes, driving differentiation into functional cardiac muscle
27
outline the formation of the primitive heart tube from the cardiac mesoderm (and the several structures formed along the way)
1. mesodermal cells migrate laterally and cranially form primitive streak - fated as cardiac mesoderm
2. form bilateral heart-forming regions which contribute to the cardiac crescent (specifically the FHF population)
3. cardiac crescent develops to contain FHF & SHF populations
4. angioblastic cords form within FHF - cords become endocardial tubes
5. endocardial tubes fuse at the midline and form the primitive heart tube
28
in which embryonic structure do angioblastic cords form, and what do they become?
form within the cardiac crescent (specifically the FHF) - fuse to become endocardial tubes, which fuse to form the primitive heart tube
29
what three key molecular signals are involved in defining the cardiogenic region of the embryo?
1. BMP signalling - promotes cardiac fate
2. Wnt inhibitors (Noggin/Chordin) - allows BMP action
3. FGFs - support proliferation & differentiation
30
what is the importance of the spatial overlap between BMP signalling and Wnt inhibition?
defines a specific zone in the cranial mesoderm where Nkx2.5 can activate and cardiac mesoderm can form - without this overlap, heart formation fails
31
which TFs would you expect to be upregulated after Nkx2.5 is activated in cardiogenic mesoderm?
GATA4-6
MEF-2
HAND1/2
Tbx genes
32
why is the conservation of cardiac transcription factors across species important to researchers?
allows us to use model organisms (fruit flies, mice, zebrafish) to study heart development and mutations - conservation of key genes make findings applicable to human biology
33
how do molecular signals coordinate to define the heart field during gastrulation?
spatial overlap of BMP, Wnt inhibitors and FGFs interact in a controlled pattern to induce Nkx2.5 - triggers specification of cardiac mesoderm in the heart-forming region & activates the cardiac gene regulatory network
34
how does the initial cardiac crescent give rise to the heart tube, and what role does embryonic folding play in this process?
- cardiac crescent forms bilateral angioblastic cords within FHF
- angioblastic cords coalesce & form paired endocardial tubes
- endocardial tubes fuse at midline to form a single primitive heart tube
- cranial-caudal folding shifts this structure from its cranial position to a thoracic position (adult position)
35
what cardiac-specific transcription factors distinguish SHF from FHF?
FHF - only Nkx2.5
SHF - Islet-1 and Nkx2.5
36
what is the function of Islet-1 in SHF cells? why is its persistence in the adult heart significant?
Islet-1 marks cardiac progenitor cells in the SHF - its persistence in adults suggests potential for cardiac regeneration or repair
37
what transcription factor is required heart development across both heart fields?
Nkx2.5
38
which part of the heart primarily originates from the FHF?
left ventricle
39
what is the one chamber of the heart the SHF doesn't contribute to? what structures does it contribute to?
doesn't contribute to the left ventricle
does contribute to the right ventricle, both atria & inflow tract
40
which transcription factors, alongside Islet-1 and Nkx2.5 expression, regulate the anterior, posterior & most caudal SHF subdomains?
anterior - FGF10
posterior - Tbx5
caudal - Tbx18
41
how do cardiac neural crest cells (CNCCs) interact with the SHF and contribute to heart development?
CNCCs derived from the neural tube migrate into the outflow tract & cardiac cushion mesenchyme
- contribute to *cardiac valve formation and aorticopulmonary septum*
- inhibit FGF signalling in SHF to prevent excessive cell proliferation and refine outflow tract development
42
what structural transformation is dependent on cardiac neural crest cell migration and differentiation?
the division of the common outflow tract into the aorta and pulmonary artery via formation of the aorticopulmonary septum
43
which transcription factor is common to both FHF and SHF lineages?
Nkx2.5
44
why is heart field distinction (FHF vs SHF) important for functional heart architecture?
ensures specific heart regions form from distinct progenitor pools with tailored molecular cues
FHF - only Nkx2.5
SHF - Islet 1 & Nkx2.5 (anterior = FGF10; posterior = Tbx5; caudal = Tbx10)
45
how does inhibition of FGF signalling by cardiac neural crest cells benefit heart development?
helps fine-tune SHF proliferation, ensures proper outflow trach development
46
Which of the following correctly matches a transcription factor with its homolog in another species and its role in heart development?
A. GATA – homologous to Tinman in Drosophila – induces cardiomyocyte apoptosis
B. Nkx2.5 – homologous to Tinman in Drosophila – master regulator of cardiogenesis
C. Tbx18 – homologous to MEF2 in zebrafish – regulates septum formation
D. HAND – homologous to Islet1 – promotes endodermal lineage development
*B. Nkx2.5 – homologous to Tinman in Drosophila – master regulator of cardiogenesis* - essential for initiating cardiac mesoderm and regulating downstream TFs like GATA and MEF-2
47
the cardiac crescent forms as a result of mesodermal migration during:
A. Neurulation
B. Gastrulation
C. Somitogenesis
D. Organogenesis
*B. Gastrulation* - mesodermal cells migrate from the primitive streak during gastrulation and are fated to form cardiac tissue, gives rise to the cardiac crescent
48
which combination of signalling molecules promotes the induction of cardiac mesoderm?
A. High Wnt + BMPs
B. BMPs + Wnt inhibitors
C. FGF + high Wnt
D. Wnt inhibitors + Sonic Hedgehog
B. BMPs + Wnt inhibitors - BMPs promote cardiogenic gene expression, while Wnt inhibitors (e.g. Noggin, Chordin) block posteriorizing signals; overlap induces Nkx2.5 and cardiac mesoderm
49
which of the following transcription factors is uniquely expressed in the SHF and not the FHF?
A. Nkx2.5
B. MEF-2
C. Islet-1
D. Tbx5
C. Islet-1 - marker for SHF cells. Nkx2.5 is in both FHF and SHF; Tbx5 is posterior SHF; MEF-2 is broadly cardiac.
50
the aortic and pulmonary trunks are separated by:
A. Epicardial outgrowths from the proepicardium
B. Downregulation of Nkx2.5 in the SHF
C. Fusion of angioblastic cords
D. Cardiac neural crest cell-derived septation
D. Cardiac neural crest cell-derived septation - CNCCs spiral through outflow tract, contributing to aorticopulmonary septum
51
which of the following transcription factors is most directly responsible for inducing cardiac-specific muscle gene expression in differentiating cardiomyocytes?
A. GATA4
B. MEF-2
C. Tbx5
D. Nkx2.5
B. MEF-2 - directly responsible for activating muscle-specific cardiac genes
52
a mutation in FGF10 would most directly disrupt development of which heart region?
A. Left atrium
B. Right ventricle
C. Aorticopulmonary septum
D. Epicardium
B. Right ventricle - FGF10 is expressed in the anterior SHF, which contributes to the right ventricle and outflow tract
53
Which of the following best describes the role of proepicardial cells in heart development?
A. Form part of the interventricular septum
B. Contribute to the myocardium
C. Migrate to form the epicardium and coronary vasculature
D. Separate atrial and ventricular compartments
C. Migrate to form the epicardium and coronary vasculature
54
Why is Wnt signalling inhibited during cardiac mesoderm induction despite being important in other mesoderm derivatives?
A. It promotes lateral plate differentiation
B. It activates pro-neural genes
C. It prevents cardiogenic fate and posteriorizes tissue
D. It suppresses BMP signalling, which is needed for heart development
D. It suppresses BMP signalling, which is needed for heart development - Wnt signalling encourages posterior (non-cardiogenic) mesoderm
55
what is dextrocardia? when does it result in clinical problems?
dextrocardia - leftward looping of the heart tube; heart ends up on the right
if it occurs as part of situs inversus (complete reversal of LR asymmetry), it often causes no clinical problems
causes clinical problems when it occurs in isolation
56
from what structure do angioblastic cords arise, and what do they become?
arise from the cardiac mesodermal cells in the cardiac crescent - arises specifically from FHF cells
become endocardial tubes which fuse & form the primitive single heart tube
57
how is the linear heart tube elongated?
addition of SHF cells at both arterial and venous poles
58
how is the left-right (LR) asymmetrical heart morphogenesis established in the embryo? what role do cilia play? what signals are involved?
1. motile cilia at the embryonic node generate a leftward flow of ECF, creating a leftward flow of signalling molecules that sets up asymmetry
2. non-motile (sensory) cilia on the left detect this flow - trigger intracellular signalling cascades, activates Notch signalling
3. Notch, Lefty & BMP activated - trigger Pitx2 expression in left lateral plate mesoderm
4. Pitx2 direct asymmetric morphogenesis - induces rightward heart looping & asymmetric development of structures (pulmonary and systemic veins)
59
what is the potential outcome if LR asymmetry during heart morphogenesis fails?
dextrocardia - heart on the right due to leftward-looping
60
how do the aortic arch arteries from during development from the pharyngeal arches?
- aortic arch arteries form within the pharyngeal arches (1-6), develop sequentially
- older pharyngeal arches degenerate as new aortic arch arteries form & development progresses
- only parts of arches 3, 4, 6 persist; remodelled to contribute to major adult arteries (aorta & pulm. artery)
61
the atrioventricular region is divided by atrioventricular septation - how does this occur during development?
1. heart tube has elongated, looped and undergone ballooning
2. endocardial cells (part of inner layer of heart) undergo EMT - makes them migratory
3. migratory endocardial cells invade cardiac jelly (extracellular matrix layer between endocardium & myocardium) - forms basic AV cushions
4. anterior & posterior AV cushions grow & fuse - separates atria from ventricles fully, contributes to AV valves & septa formation
62
what is the sequence of events involved in forming the interatrial septa that separates the atria?
primary and secondary septa form between atria - grow towards & fuse, fully separating right and left atria
- temporary openings like foramen ovale allow blood shunting (left-to-right) during foetal life
63
how is the interventricular septum formed?
grow upwards from ventricular base towards AV cushions - fuses with cushions to fully separate ventricles
64
what cells are primarily involved in outflow tract septation?
cardiac neural crest cells
65
how are cardiac neural crest cells involved in OFT septation?
CNCCs migrate into the OFT - populate the cardiac jelly & form OFT cushions
cushions help divide the common trunk into the aorta and pulmonary artery - contribute to septations
66
what are the two types of septation that divide the heart tube?
muscular walls
(endocardial) cushions
67
there are two types of septation - muscular walls & endocardial cushions. what structural septations do they contribute to? what are they derived from?
muscular walls
- form interventricular & interatrial septa
- originate from myocardial cells in heart wall (formed form muscular tissues)
(endocardial) cushions
- form OFT & AV valves and septa
- formed from endocardial cells; undergo EMT, infiltrate cardiac jelly & form cushion structures
68
what is cardiac jelly? why is it critical during heart development?
cardiac jelly - acellular extracellular matrix produced & released by myocardium; layer between inner endocardium and outer myocardium
- structural support for early heart
- promotes EMT (for cushion/septal formation)
- OFT & AV valves and septa formation
69
what are the three layers of the heart tube (-cardium)? (outer-inner)
epicardium
myocardium
endocardium
70
what signals and factors induce the formation of endocardial cushions in the heart?
growth factors - BMP4, TGF-B1-3
- secreted by restricted AVC & OFT myocardial regions
- interact with endocardial receptors
- initiate EMT in endocardial cells which migrate & populate the cardiac jelly to form cushions
71
where is endocardial cushion formation restricted in the developing heart, and why?
restricted to the atrioventricular canal (AVC) and OFT
due to restricted signalling from myocardium in these regions (by TGFB1-3, BMP4) - induces EMT & cushion formation specifically in these regions
72
what role does TBX20 play in endocardial cushion formation?
TBX20 expressed in atrial & ventricular regions limits cushion formation outside AVC and OFT
73
what triggers the epithelial-to-mesenchymal transition (EMT) in endocardial cells? what does this lead to?
EMT triggered by growth factor signals - BMP4, TGFB1-3 - interacting with receptors on endocardial cells
causes endocardial epithelial cells to become migratory mesenchymal cells - populate cardiac jelly & begin forming endocardial cushions
74
how do the endocardial cushions remodel during heart development?
mesenchymal cells form the initial cushion structure - later remodel into OFT & AV valves and septa
75
what distinguishes semilunar valves (pulmonary and aortic) from AV valves in terms of formation and structure?
semilunar valves don't require tendinous cords anchoring them to myocardium - supported by structural shape & attachment to arterial walls of heart
AV valves (tricuspid + bicuspid/mitral) form from AV cushions, tethered to myocardium by chordae tendinea
76
describe the formation of endocardial cushions, and their significance in heart septation
77
role of the atrioventricular (AV) septum in heart development?
separates left and right atrioventricular canals - divide atria from ventricles
78
what developmental event triggers AV valve formation?
the formation & division of AV septum initiates AV valve development
79
what happens in a complete AV septal defect (AVSD)?
AV septum fails to form and fuse - leaves a common opening between all chambers and significant mixing of oxygenated and deoxygenated blood
80
what characterizes a partial AVSD?
incomplete formation of AV septum - leaves a small communication between the left and right heart chambers
81
AVSDs are commonly associated with which genetic condition?
Down's syndrome (trisomy 21)
82
outline the process of interatrial septation
1. *primary interatrial septation* - initiates septation of atria, grows downwards towards AV cushions
2. *formation of foramen ovale* - after primary septum extends down & fuses with AV cushion, its trailing edge degenerates to form the foramen ovale
3. *secondary interatrial septum (septum secundum)* grows adjacent to primary interatrial septum - covers foramen ovale & creates flap-valve mechanism regulating left-right blood flow
4. *post-natal changes* - closing of foramen ovale as LA pressure exceeds RA pressure, leaves fossa ovale as remnant
83
what is the significance of the foramen ovale in the foetal interatrial septum?
allows for right-to-left shunting of blood between atria (oxy. blood from RA > LA) as foetal lungs aren't developed
84
what is the significance of the ductus arteriosus? what post-embryonic remnant does it leave behind?
connects pulmonary trunk to aortic arch - allows blood to bypass lungs and enter systemic circulation
duct closes after birth & leaves behind ligamentum arteriosum
85
what is the significance of the ligamentum arteriosum?
embryological remnant of ductus arteriosus - a duct connecting the pulmonary artery & aortic arch; used to shunt oxy. blood from RV into systemic circulation, bypassing the lungs
86
function of the septum secundum in atrial septation?
grows adjacent to the primary interatrial septum, forms a flap-valve to regulate RA > LA shunting via the foramen ovale
87
what is a persistent foramen ovale? what type of heart defect is it?
ASD (atrial defect) - patent foramen ovale due to incomplete sealing of flap-valve after birth
usually asymptomatic
88
what causes an ostium primum defect?
failure of primary interatrial septum to grow & fuse with AV cushions - leaves a small interatrial gap at the lower end
89
what causes an ostium secundum defect?
incomplete overlap of septum secundum over the foramen ovale - leads to persistent left-to-right shunting between atria
90
what type of blood shunting occurs in atrial septal defects (ASDs)?
left-to-right - higher pressure in LA > RA
91
are ASDs typically cyanotic or acyanotic? why?
acyanotic - left-to-right shunting doesn't mix deoxy. blood into systemic circulation
92
differentiate perimembranous and muscular VSDs
perimembranous - near membranous part of interventricular septum, close to AV cushions, more common
muscular - in muscular portion of IVS, smaller defects
93
what type of shunting occurs in VSDs and why?
left-to-right shunting - higher LV pressure
94
are VSDs typically cyanotic or acyanotic? why?
acyanotic - left-to-right shunting increases pulmonary flow & no deoxy. blood in systemic circulation
95
what is the truncus arteriosus in early heart development?
single outflow tube that later divides into the aorta and pulmonary artery
96
how do spiralling cushions help divide the truncus arteriosus during outflow septation?
two spiralling cushions form within truncus arteriosus & grow towards the heart - physically divide the OFT into aorta and pulmonary artery
fuse into aortopulmonary septum
97
where do the neural crest cells involved in OFT formation come from? how do they contribute to OFT septation?
migrate from dorsal neural tube into pharyngeal arches and OFT
contributions:
- populate spiralling cushions allowing cushions to grow
- help form aortopulmonary septum
- influence remodelling of aortic arch arteries
98
what two structures help form the aortopulmonary septum in OFT septation?
1. spiralling cushions - provide structural framework to divide OFT, cushions fuse into AP septum
2. neural crest cells - migrate into cushions, help guide growth and fusion of AP septum to form properly
99
what is the functional significance of the spiralling arrangement of the OFT cushions?
creates asymmetrical blood flow - ensures correct direction for aorta & pulm. artery
100
what are the key aortic arch arteries involved in OFT remodelling?
arches 3, 4, 6
101
what three aspects of OFT septation do NCCs contribute to?
1. aortic arch remodelling (from pharyngeal arches 3,4,6)
2. spiralling cushions - populate cushions, help growth and fusion with AP septum
3. formation of AP septum
102
what three signals are involved in NCC induction & migration for OFT septation?
Pax3
c-kit (growth factor)
PDGFa
103
what three signals are involved in NCC induction & migration for OFT septation? their specific roles?
1. Pax3 = NCC specification & induces migration into OFT
2. c-kit & PDGFa = growth factors; ensure NCCs stay undifferentiated during migration for proper OFT formation
104
what transcription factor is involved in LR heart asymmetry?
Pitx2
105
what two signals are involved in pharyngeal arch development & remodelling of aortic arch arteries?
FGF8
Tbx1
106
what two signals are involved in pharyngeal arch development & remodelling of aortic arch arteries? what are their specific roles?
FGF8 = supports NCC migration through pharyngeal arches, promotes aortic arch remodelling
Tbx1 = modulates FGF8 activity, corrects pharyngeal arch and OFT formation
107
Tbx1 is involved in modulating FGF8 activity, ensuring proper OFT and pharyngeal arch development. mutations in Tbx1 are linked to which genetic syndrome?
DiGeorge syndrome - linked to heart problems
108
what two signals are involved in joining of the great vessels to the heart?
retinoic acid
TGF-beta2
109
what two signals are involved in joining of the great vessels to the heart? what are their specific roles?
retinoic acid = guides septal ridge alignment, positions great vessels for outflow
TGF-beta2 = works with retinoic acid to stabilize OFT alignment and septation
110
what is patent ductus arteriosus?
ductus arteriosus fails to close after birth - oxygenated blood re-enters lungs, increasing pulmonary circulation
111
in what direction does blood shunting occur in patent ductus arteriosus? does this have a cyanotic/acyanotic effect?
left-to-right shunting; acyanotic effect (may cause pulmonary overload due to increased pulmonary circulation)
112
what is common truncus (OFT defect)? cause?
failure of the OFT to divide into aorta & pulmonary artery - associated with abnormal NCC migration
113
what is transposition of the great arteries? how does this affect circulation?
congenital defect - aorta arises form the right ventricle; pulmonary artery arises from left ventricle
deoxy. blood pumped into systemic circulation (RV > aorta); oxy. blood into pulmonary circulation (LV > pulm. artery)
114
does transposition of the great arteries have a cyanotic or acyanotic effect?
(lethal) cyanotic - deoxy. blood in systemic circulation, oxy. blood back to lungs
115
what causes the abnormal arterial arrangement in TGA (transposition of the great arteries)?
failure of the aorticopulmonary septum to spiral properly and abnormal OFT cushion formation
116
what are the 4 features of tetralogy of fallot?
ventricular septal defect
pulmonary stenosis
right ventricular hypertrophy
overriding aorta
117
why is tetralogy of fallot a cyanotic defect?
VSD 9hole between ventricles) causes mixing of oxy. and deoxy. blood between ventricles - overriding aorta is positioned just above VSD
overriding aorta receives mixed blood from right-to-left shunt - leads to cyanosis
118
why do children with ToF often squat during cyanotic episodes?
squatting increases peripheral resistance
- raises left heart pressure
- encourages left-right shunt
- improves oxygenation
119
causes of tetralogy of fallot?
idiopathic
associated with genetic syndromes - Down's DiGeorge
120
what is the cardiac conduction system?
specialized network of myocardial cells that initiates and coordinates the heartbeat using electrical impulses
121
functions of the SA & AV nodes in the cardiac conduction system?
SA node - primary pacemaker; initiates electrical signal that causes atrial depolarisation (P wave)
AV node - delays impulse conduction to allow ventricular filling before systole (P-Q waves)
122
where does the cardiac conduction system originate from during development?
from specialised myocardial cells of the developing heart tube
123
heart myocardium originates from the cardiac mesoderm. describe the development of the layers & final organisation of the ventricular myocardium
starts with outer epicardium, thin myocardial layer, cardiac jelly ECM in between, then inner endocardium
1. formation of compact & trabecular structures
COMPACT LAYER - epicardium produces signals (RA, FGFs, Shh) = promote myocardial cell proliferation & formation of compact layer
TRABECULAR LAYER - induced by signals (Notch, BMP10, ephrins, chromatin and histone modifications) = finger-like projections extend into ECM cardiac jelly & form trabeculae
- epicardium must envelop heart; produces signals that influence myocardial development
2. final organisation
- proper orientation and organisation of cardiomyocytes in myocardium for efficient heart function
- regulated by PCP pathway
124
what are the layers of the early heart tube?
outer epicardium
thin proliferating myocardial layer
acellular ECM (cardiac jelly)
inner single-cell endocardial layer
125
how do the compact and trabecular layers of myocardium form?
proliferating myocardial cells thicken the compact layer (signals from outer epicardium induce formation)
finger-like projections of myocardial cells into ECM form trabeculae
126
what signals and factors regulate trabeculae development? (4)
Notch signalling = initiates trabeculation
BMP10 & ephrins = support trabecular growth
chromatin & histone modifications
127
what is the epicardium’s role in myocardial development?
produces signals - RA, FGFs, Shh - that influence myocardium, essential for compact myocardial growth via proliferation & trabecular organisation
128
which pathway regulates cardiomyocyte orientation?
PCP pathway - ensures organised structure & efficient contraction of cardiomyocytes
129
what signals does the epicardium produce that influence the myocardium into compact & trabecular layer formation?
retinoic acid
FGFs
Shh
130
what signal is essential for epicardial formation?
thymosin beta-4
131
where does the epicardium originate from?
proepicardial organ - cells migrate to cover myocardium
132
describe the formation of the epicardium from its origin
1. originates from proepicardial organ - cells migrate and surround myocardium of heart tube
2. under mainly RA signalling, epicardial cells undergo EMT - become epicardial-derived progenitor cells (EDPCs)
3. EDPCs express thymosin-beta4 - differentiate into 1) angiogenic & 2) smooth muscle cells which contribute to vessel structure
133
which signals are essential for epicardial development?
retinoic acid pathway
- regulates EMT in epicardial cells, become epicardial-derived progenitor cells
- later differentiate into angiogenic & smooth muscle cells (contribute to vessel growth)
thymosin-beta4
- key regulator of epicardium formation
134
what role does thymosin beta-4 play in epicardial development?
regulates epicardial cells EMT
gives rise to epicardial-derived progenitor cells
135
what types of cells do epicardial-derived progenitor cells differentiate into?
angiogenic cells & smooth muscle cells - contribute to vessel structure
136
what happens to epicardial development if thymosin-beta4 is knocked out?
1) endothelial cells regress = unstable vessels
2) disorganised trabeculae & impaired compact layer growth - epicardium influences myocardium via RA, Shh, FGFs
137
what does the Ballooning Model describe in heart development?
describes how the primary heart tube gives rise to chamber myocardium by ballooning out of specific regions
creates functionally distinct fast-conducting chambers; retains slow-conducting primary myocardium in others
138
how do primary and chamber myocardium differ? (function/conduction, gene expression)
primary myocardium
- slow conduction
- expresses Tbx2 & 3 with Nkx2.5
- forms future conduction system
chamber myocardium
- fast conduction
- expresses Tbx5 with Nkx2.5
- forms atria and ventricles
139
what is the role of Tbx 2 & 3 in primary myocardium?
represses chamber-specific genes - maintains slow-conduction by preventing chamber myocardium features
140
what Tbx gene do chamber forming regions of the Ballooning Model myocardium express?
Tbx5 (with Nkx2.5)
141
what structural and functional pattern results from ballooning?
central conduction system from the slow-conducting primary myocardium, surrounded by fast-conducting chambers for efficient contraction and circulation
142
what two TFs are universally expressed in the two types of myocardium of the Ballooning Model?
Nkx2.5
GATA4
