#13346 - Cardiovascular Embryology - Organisation of the Body

THE DEVELOPMENT OF THE HEART-mesodermal derivative

CONGENITAL CARDIOVASCULAR DISEASE

-Account for 20% of the birth defects

-teratogens: lithium/alcohol/retinoic acid/maternal diseases (diabetes)

Common genetic causes:

a) Specification: Formation of cardiac crescent

-cardiac progenitor cells are derived from intraembryonic mesoderm emerging from cranial 1/3^rd primitive streak

-the progenitor cells leave the primitive streak and migrate in a cranial lateral direction to become localized on either side of the primitive streak within the splanchnic lateral plate mesoderm to form a cardiac crescent. Cells in the cardiac crescent form the primary heart field. Expression of Mesp1, Mesp2 are expressed transiently

Cell fate maps/lineage labels- fluorescent dye into cell and see where it migrates, or you can express a green fluorescent protein-this shows the cardiac crescent originates from the cranial 1/3^rd of the primitive streak

-progenitors become specified to become cardiogenic mesoderm once in the splanchnic plate mesoderm. Interaction with the endoderm is required

-The endoderm secretes various signaling molecules. Most important is Bmp 2 stimulates expression of early cardiogenic transcription factors Nkx2.5. Bmp expression occurs in most endoderm but its effects on the mesoderm are limited to cranial region of the lateral mesoderm- inhibitors are released- notochord releases chordin and noggin and neural plate/neural tube ectoderm releases Wnt1- binds to BMP and prevents signaling activity

Mutations in Nkx2.5 result in heart development defects and congenital heart malformations

-within each limb of the cardiac crescent, endocardial tubes form- vessels form by a process of vasculogenesis. Vascular endothelial growth factor derived from the cranial endoderm directs a subset of cells within the cardiac crescent into endothelial/endocardial cell lineage

Lateral endocardial tubes develop in the cardiogenic region and fuse to form the primary heart tube

-onset of contraction occurs in the left and right endocardial tubes coordinated by the pacemaker

-late in third week- cephalic and lateral folding of the embryo- brings the two lateral endocardial tubes into the thoracic region- the two endocardial tubes fuse to form a single tube- the contacting surfaces undergo programmed cell death

If there is no fusion of the two lateral endocardial tubes it leads to cardiac bifida

Four layers of the primary heart tube

-primary heart tube initially layer of endothelium

-day 22- thick mass of splanchopleuric mesoderm attaches to the endothelium and differentiates into two layers- myocardium (heart muscle) + cardiac jelly. Cardiac jelly- thick acellular matrix- hyaluronic acid and proteoglycans- secreted by myocardium and seperates myocardium from fused endocardial tubes

-on the outer surface a final layer of mesoderm surrounds the heart forming the epicardium -serous epicardium- (visceral pericardium)- formed by population of mesothelial cells that are independently derived from the splanchnopleuric mesoderm- migrate to the outside surface of heart from sinus venous

Paired dorsal aortae of the primitive circulatory system form simultaneously with the lateral endocardial tubes

-the primitive heart tube pumps before the fusion of the tubes- after fusion there is a linear heart and blood flows from the caudal end to the primitive aortas

-inflow and outflow tracts of the future heart make connection with the endocardial tubes before they are translocated to thorax and fuse to form heart

-the paired dorsal aortae develop at the same time as the lateral endocardial tubes

-paired dorsal aortae- forms the primary outflow tract of the heart- develop from the dorsal mesenchyme of the embryonic disc either side of notochord- make their connection with the endocardial tubes

-flexion + cephalic folding brings the endocardial tubes into the cervical and then thoracic- the dorsal aortae are pulled ventrally and form dorsal ventral loop- first aortic arch

-inflow of the heart- enters through the sinus venosus through the left and right sinus horns supplied by 6 vessels- 3 vessels either side of the sinus horns

The venous drainage of the embryo develops as three pairs of vessels on the left and right sides of the embryo. The vitelline veins (VV) drain the yolk sac, the cardinal veins the body (CC) and umbilical veins (UV) the developing placenta (oxygenated blood), all drain into the sinus venosus (see below).

-venous blood supply from the body of the embryo enters through pair of vessels- common cardinal veins- formed by the confluence of paired posterior cardinal veins draining the trunk and the paried anterior cardinal veins draining the head region

Constrictions and expansions subdivide the primary heart tube

-day 21- constrictions (sulci) and expansions- appear in the primitive heart tube- forms heart chambers

-inferior end/inflow end of the heart tube- the sinus venous consists of left and right sinus horns into with common cardinal veins drain

-Cranial to the sinus horns are the primitive atrium (gives rise to both left and right atrium) atrial myosin heavy chain AMCH1 is selectively expressed within the atrial cells- when excess retinoic acid added to the embryonic chicken it causes atrialisation due to the expression of AMCH1- To ensure that retinoic acid acts locally retinaldehyde dehydrogenase 2 is expressed only in the caudal part of the primitive tube

-cranial to the atrium is the ventricle (gives rise to the left ventricle)- ventricular myosin heavy chain 1 separated by atrioventricular sulcus

1) Familial hypertrophic cardiomyopathy

-autosomal dominant disease-mutation in the B-cardiac myosin heavy chain gene

thickening of ventricular walls and interventricular septum/ disorganisation of muscle fibrils-arrythmias

-the ventricle separated from the next expansion, bulbus cordis by the buloventricular sulcus/ interventricular sulcus

-inferior part of the bulbus cordis will form the inferior part of the right ventricle

-superior part of the bulbus cordis- forms the conotruncus- region of the heart that forms distal outflow regions of the left and right ventricles – conus cordis + truncus arteriosus

-truncus arteriosus forms the asencing aorta + pulmonary trunk. Truncus arteriosus connected to aortic sac- aortic sac is continuous with the first aortic arch and with the 4 aortic arches

Transverse pericardial sinus- rupture of the dorsal mesocardium

-the primary heart tube suspended in the pericardial cavity by dorsal mesoderm- formed by the foregut splanchopleuric mesoderm

-dorsal mesoderm ruptures leaving heart suspended in primitive pericardial by attached vasculature

-the region where the dorsal mesoderm ruptures- known as the transverse pericardial sinus

-the primitive heart tube lengthens at both ends, especially at the arterial end through addition of cardiac progenitors from secondary heart field mesoderm

Heart tube folds and loops to establish spatial relationship of the future heart chambers

-day 23- heart tube elongates by differential proliferation- bends into C shape extending to the right- break down of the mesentery- allows further looping- S shape

The atria move cranially and come to lie rostral to the developing ventricular system.

-ventricle enlarges swings to the midline displaced to the left- covers the atrium and the great veins

-bulbus cordis is displaced inferiorly, ventrally and to the right

Before the looping of the heart was thought to be due to haemodynamic forces but when the primitive heart tube was isolated it automatically folded into a loop, suggesting that it was under intrinsic control.

-the folding of the loop is mainly due to differential proliferation- the rate of proliferation can be measured through using radioactively labelled nucleotides, BRDU

-dextrocardia- primitive heart tube folds to the right instead of the left- however if all the organs are affected it leads to situs inversus which is due to the cilia in the primitive node

-looping of the heart tube profound effect on direction of blood flow through heart tube-morphological sign of L/R asymmetry in embryo

-the primitive node induces left and right differences- differential gene expression in the left and right ventricles- HAND1 left and HAND 2 right ventricle

Co-ordinated remodelling of primitive vasculature produces the systemic and pulmonary circulations

Day 22- heart and primitive circulatory system are bilaterally symmetrical

-right and left cardinal veins drain the two sides of the body- blood from the heart is pumped into the right and left aortic arches and dorsal aortae

-paired dorsal aortae fuse from T4-L4 in 4^th week to form single midline dorsal aorta

-venous system remodelling- all systemic venous blood enters the right sinus horn – superior vena cavae (right and left common cardinal vein) and inferior venae cavae (right and left umbilical and right vitelline veins). As venous inflow shifts to the right the left sinus horn ceases to grow- coronary sinus

-right sinus horn and venae cavae enlarge due to growth of heart

-right side of the sinus venosus incorporated with the right posterior wall of the right atrium – this displaces the right arterial wall ventrally and to the right

-portion of the atrium that is incorporated with the sinus venosus is called the sinus venarum- atrium that is not directly fused with the sinus venosus becomes the right auricle- flap that is rough as it contains pectinate muscles whereas the sinus venosus is smooth walled

-intussusception of the right sinus venosus the openings of the superior and inferior...