How many live births have congenital heart disease?
-~1% -most common congenital disorder
3 rationales fro studying CV development
1. inherent scientific knowledge 2. understanding the pathogenesis of CHD: dx and prognostic tool development, develop therapies 3. hypothesis: mlc pathways important for CV development are recapitulated during CV disease pathogenesis
5 major processes in cardiac development
1. normal cardiac morphogensis 2. left-right patterning 3. valve formation 4. angiogenesis vs vasculogensis 5. contribution of extra-cardiac cells to heart: epicardium and NC
6 parts of normal cardiac morphogenesis
-myocardial specification -formation of linear heart tube -looping -septation -patterning of great vessels -circulatory changes at birth
where is the cardiogenic (heart-forming) region located in embryo? What is this called?
-initially located at the anterior rim of the embryonic disc very early in development -called the cardiac cresent: epithelial layer of cardiac MULTIpotent progenitor cells that make up myocardium, endocardium, pericardium
As the embryo grows, the developing heart assumes a position where? Then what happens?
-ventral to forming forebrain and foregut; as 2 side tubes -heart progenitors migrate ventrally and medially to form a linear heart tube; attached to rest of embryo by dorsal mesocardium
3 events happening at linear heart tube phase
1. heart begins to beat: intrinsic pacemaker activity (caudal >rostral) 2. blood flow commences: single circulation in series caud to rostral (remember atria on bottom of linear tube) 3.chamber specification due to molecular determination
Atrium location within linear tube
-caudal end! under LV and RV
Chamber-specific transcriptional programs of linear heart tube
-dHAND is RV and eHAND is LV -hey1 is atria and OFT and hey2 is ventricles
T/F: Advanced cariac morphogenesis does not require midline fusion.
Secondary Heart Field
-large parts of RV and OT derived from secondary field of cardiac precursors -these cells migrate into OT and differentiate into muscle from pharynx -diff gene expressions of these cells within cardiac crescent
Secondary Heart Field is associated with ______ and ______ signaling.
-LiCl (Wnt agonist) -Wnt signalling
Secondary Heart Field defects are attributable to ______ variants in 11-18% cases.
-Islet 1 variants
3 events occurring during cardiac looping
-linear heart tube bends to right and anteriorly, thought to be driven by regional differences in myocardial growth rate--first sign of assymetry in heart!! -begin septation: endocardial cushions (OFT and AV canal) and interventricular septum -myocardial trabeculation
2 end results of cardiac looping
-atria assume a more rostral and posterior orientation -advanced regional specification: bulbis cordis (conus cordis becomes cardiac OFT, truncus arteriosus becomes PA and Ao), AV canal (maturation of AV canal and formation of endocardial cushions)
4 septation events
-AV canal septation -Interventricular septation -Interatrial septation -outflow tract septation (TA and CC)
steps of atrial septation
1. septum primum grows from dorsal wall of atrium toward AV cushions 2. initially incomplete (passive): ostium primum= residual connection 3. eventually completely (actively) closed by fushion with cushions 4. new opening in septum primum occurs= ostium secundum (smaller performations up higher) 5. new septum = septum secundum grows from superior atrial wall 6. septum secundum passively closes the ostium secundum
In embryonic circulation, ostium secundum allows for flow from right to left atrium (little pulm circulation). In the adult, septum secundum closes the ostium secundum. Ostium secundum later ______ closes in most, but not all people. What is a variant of this called when the ostium secundum does not close?
-actively -Patent Foramen Ovale: 20-25% of people and potential stroke risk
Ostium Secundum Atrial Septal Defect
-most common type of ASD (larger, constantly lets blood thru) -occurs in center of the septum between LA and RA -due to incomplete formation of septum secundum or incomplete active closure of ostium secundum -variant of this type of ASD is PFO and is very small!
Ostium Primum ASD
-2nd most common ASD -located in lower portion of atrial septum -due to incomplete active closure of ostrium primum -often associated with a cleft or slit-like defect in anterior leaflets in MV
-Ostium Primum cause and association
-due to incomplete active closure of ostrium primum -often assoc with cleft or slit-like defect in anterior leaflet of MV
Sinus Venosus ASD
-least common of ASD -located in upper portion of atrial septum -due to defect in formation of septum primum -often has an abnormal pulmonary vein connection associated with in -one of PVs abnormally connect to the RA instead of the LA (anomalous PV)
-Location of ASDs in atrial septum from top to bottom
1. top: sinus venosus ASD 2. middle: ostium secundum ASD 3. bottom: Ostium primum ASD
Rank 3 main ASD in order of how common they are
-Ostium secundum is most common -Ostium primum ASD -Sinus venosus ASD
-homeobox gene expressed as soon as heart muscle precursors are specified (paraxial mesoderm) -required from dorsal aorta in flies, looping in mice, and heterozygous mutations in humans with CHD
______ is expressed prior to formation of the midline cardiac tube.
Nkx2.5 mutations in flies, mice, humans
-flies: no dorsal aorta -mice: fatal looping defect -humans: conduction defects (potential link to A. fib/heart block), ASD, tetralogy of fallot
Patterning of the great vessels
-initially, 5 pairs of symmetric aortic arch arteries -some regress while others grow, resulting in the mature asymmetric vascular pattern -signals from pharyngeal endoderm and migrating neural crest are required for this remodeling
What is required for the correct remodeling of the great vessels?
-signals from pharyngeal endoderm and migrating neural crest
Other issues associated with neural crest cell migration
-skin discoloration (melanocytes), parathyroid and thymus issues, facial deformities
Abnormal remodeling of branches may lead to interruption of the __________.
-most common human chromosome deletion syndrome -del 22q11 -CHD, parathyroid deficiency, thymus defect -phenotype similar to animal models of NC ablation -many children with CHD along and nothing else have this deletion
An important gene found within the region deleted within DiGeorge?
-Tbx1 -deletion of 22q11 in DiGeorge
3 main events that are changes in circulatory system at birth
-closure of ductus arteriosus -closure of ductus venosus -closure of foramen ovale
Abnormalities of L-R axis
-mirror image: dextrocardia -discordance between organs: heterotaxy
L-R axis is established very early, as seen by ____________.
-asymmetric expression of signalling mlcs at primitive streak stage -persistence of this program results in asymmetric expression in the developing heart (eHAND vs dHAND)
Defects in sidedness can be due to defects in what process? What in particular is thought to be an etiology of this?
-looping -nodal ciliar abnormalities early in development--reminiscent of Kartagener's which has dextrocardia and immotile cilia
-endothelial cells migrate into "cardiac jelly" (ECM between initial 2 layers of cells) between endothelium and myocardium -undergo a phenotypic switch= epithelial-mesenchymal transformation (EMT) -cellular swellings within cardiac jelly are the endocardial cushions, that mature into valve leaflets
Reciprocal inductive interactions in valve formation
-signals from myocardium required from EMT -signals from endothelium required for myocardium to mature -cross-talk between opposing tissues is a common theme in developmental biology
Where are the endocardial cells that form cushions located?
-AV canal and OFT (think of where the valves are normally formed!!)
What pathway was seen to be important in EMT in valve formation?
Angiogenesis vs Vasculogenesis
-angiogenesis: formation of new blood vessels from pre-existing blood vessels -vasculogenesis: formation of new blood vessels from endothelial precursors (angioblasts)--usually only occurs in embryo
T/F: VEGF is only player in vascular development.
-false: it is potent angiogenic stimuli -but also Notch ligand and semaphorin ligands too
-mediate REPULSIVE signals involved in axon guidance and growth cone collapse -secreted ligands bind to plexin/neuropilin receptors -expressed broadly outside CNS
Epicardium arises from and required for ?
-from proepicardial organ, a derivative of the septum transversum (also gives rise to diaphragm, liver) -EMT again -required for coronary artery development and for myocardial maturation (inductive signals)
Neural crest cells migrate from ________ to _____ and ______.
-dorsal neural tube -pharynx and heart
What do neural crest cells form?
-arterial SMCs, nerve, bone, skeletal muscle, melanocytes, cells of thymus, thyroid, parathyroid
2 things NC cells are required for in heart development. Defects result in?
1. SMC layers of PA, Ao, DA, carotid arteries 2. septation of truncus arteriosus and OFT (Ao and PA) -defects result in cardiac outflow tract defects
What is one possible thought on where aortic dissection entrance and exit points occur?
-embryologic border zones -ascending aortic SMC from NC cells -descending SMCs diff origin
4 broad steps important in normal morphogenesis
1. crescent --> linear tube --> looping --> septation