Development of the Heart and

Vasculature

IN THE NAME OF GOD

Overview vascular system appears (middle of 3rd week)

◦ when the embryo is not able to satisfy its nutrition by diffusion

Heart is the first functional organ

◦ beating rhythmically (22nd day)

◦ pumps blood (24-25days)

single heart tube structure

◦ Myocardium

◦ Endocardium

◦ ECM (cardiac jelly)

Heart development Cardiac progenitor cells in epiblast immediately lateral to primitive

streak

◦ Cells migration through the cranial third of streak 1st cranial segments of heart (outflow tract)

then more caudal portions right ventricle, left ventricle, and sinus venosus

◦ The cells position rostral to buccopharyngeal membrane and neural folds

◦ Splanchnic mesoderm layer

◦ They induced by underlying pharyngeal endoderm form cardiac myoblasts

Blood islands also appear in this mesoderm vasculogenesis process

Endothelium

Blood cells

◦ horseshoe-shaped region

Formation of Primitive Heart Tube

Heart Tubes and Dorsal Aorta Lateral folding & Craniocaudal folding Cardiac bifida

Dorsal mesocardium((Transverse pericardial sinus

• three layers Heart

• Endocardium

• Myocardium

• Epicardium (visceral pericardium)

Cardiac Looping

Heart tube elongate and bend on day 23-28

cephalic portion◦ bends ventrally, caudally, and to the right

caudal portion◦ shifts dorsal, cranial and to the left

Mechanisms of cardiac bending and looping

asymmetric differences in ECM composition

Heart tube expansions

During 5-10 weeks

sinus venosus

primitive atrium

◦ L & R atrium

atrioventricular junction

◦ atrioventricular canal

primitive ventricle

◦ Left ventricle

bulboventricular sulcus

◦ primitive interventricular foramen

bulbus cordis

◦ proximal third trabeculated part of the right ventricle

◦ midportion (conus cordis) outflow tracts of both ventricles

◦ distal third (truncus arteriosus) roots and proximal portion of the aorta

and pulmonary arteries

aortic sac

Atrioventricular junction

Abnormalities of Cardiac Looping

Dextrocardia

◦ heart lies on right side of thorax

◦ heart loops to left instead of right

◦ may coincide with Situs inversus complete reversal of asymmetry in all organs

which occurs in 1/7,000 individuals

Heterotaxy

◦ 3 out of 20,000 live births

◦ sidedness is random laterality sequences

predominantly left-sided bilaterally

polysplenia

or right-sided bilaterally

asplenia or hypoplastic spleen

Development of sinus venosus left horn

middle of 4th week

sinus venosus

◦ right and left sinus horns vitelline (omphalomesenteric) vein

umbilical vein

common cardinal vein

Sinus entrance shifts to right

◦ left-to-right shunts of blood 4-5th week: obliteration of

right umbilical vein

left vitelline vein

10th week: obliteration of left common cardinal vein

remnant of left sinus horn

◦ oblique vein of left atrium

◦ coronary sinus

Development of sinus venosus right horn

As a result of left-to-right shunts of blood

right sinus horn veins enlarge greatly

incorporated into the right atrium

◦ Form smooth-walled part of right atrium (sinus venarum)

Development of sinus venosus sinuatrial orifice

right and left venous valves

◦ dorsocranially fusion septum spurium

left venous valve and septum spurium

◦ fuse with developing atrial septum

right venous valve

◦ superior portion disappears entirely (crista teminalis)

◦ inferior portion develops into valve of the inferior vena cava

valve of the coronary sinus

Further Differentiation of the Atria

Right atrium

primitive right atrium

◦ trabeculated atrial

◦ pectinate muscles

incorporated right sinus horn

◦ smooth-walled (sinus venarum)

Left atrium

primitive left atrium

◦ trabeculated atrial

◦ incorporated pulmonary veins

◦ smooth-walled part of the adult atrium

Cardiac Septa Formation

(Remodeling and differentiation growth)

major septa formed between 27-37th days

◦ Endocardial cushions

(synthesis and deposition of ECM and cell migration and proliferation) Single or Two growing cushion

atrioventricular and conotruncal regions

atrial septa

ventricular (membranous portion) septa

atrioventricular canals and valves

aortic and pulmonary channels

◦ narrow tissue strip of wall fail to grow

Septation of Common Atrium

At the end of the 4th week

Septum primum

◦ sickle-shaped crest from roof extend toward endocardial cushions of atrioventricular canal

◦ its opening: ostium primum Occlusion

ostium secundum

Septum secundum

◦ overlap the ostium secundum

◦ its opening: oval foramen

valve of oval foramen

◦ Remnant of septum primum

After birth: oval fossa

◦ lung circulation begins

◦ pressure in left atrium increases

probe patency of oval foramen

◦ In about 20% of cases

Atrioventricular Canal Septation

At the end of 4th week

Initially atrioventricular canal gives access only to the primitive left Ventricle

◦ bulbo(cono) ventricular flange to left Along base of superior endocardial cushion

superior and inferior atrioventricular endocardial cushions

Near the end of 5th

Two lateral atrioventricular cushions

Atrioventricular Valves

each atrioventricular orifice surrounded by proliferations of mesenchymal tissue

◦ bloodstream hollows out and thins ventricular surface of these proliferations valves form and remain attached to ventricular wall by muscular cords

papillary muscles

chordae tendineae

Truncus Arteriosus Septation

During the fifth week

pairs of truncus swellings (cushions)

◦ right superior truncus swelling grows distally and to the left

◦ left inferior truncus swelling grows distally and to the right

growing swelling toward the aortic sac

◦ twist around each other

After complete fusion

◦ aorticopulmonary septum Aortic channel

pulmonary channel

Conus Cordis Septation

During the fifth week conus cordis swellings (cushions)

◦ right dorsal wall◦ left ventral wall

grow toward each other and distally unite with the truncus septum

the septum divides the conus into◦ Anterolateral (outflow of right ventricle)◦ posteromedial (outflow of left ventricle)

Ventricles Septation

By the end of 4th week two primitive ventricles begin to expand by◦ continuous growth of myocardium on outside◦ continuous diverticulation and trabeculation on inside

medial walls of expanding ventricles◦ apposed and gradually merge

muscular interventricular septum interventricular foramen

◦ outgrowth of tissue from inferior endocardial cushion◦ membranous part of interventricular septum

Semilunar Valves

When partitioning of truncus is almost complete

semilunar valves primordia become visible

◦ as small tubercles

Then tubercles hollow out at their upper surface

◦ semilunar valves

neural crest cells contribute to formation of these valves

Heart Conducting System

Pacemaker node◦ Initial pacemaker

caudal part of left cardiac tube cluster of cells in sinoatrial region, which derived from

right common cardinal vein or right sinus venosus

◦ Later pacemaker sinus venosus

◦ Definitive pacemaker (sinuatrial node)

atrioventricular node and bundle◦ cells in left wall of sinus venosus◦ cells from atrioventricular canal

Atrial septal defect (ASD) incidence of 6.4/10,000 births

◦ premature closure of oval foramen massive hypertrophy of right atrium and ventricle

underdevelopment of left side of heart

Ventricular septal defect (VSD)

most common congenital cardiac malformation (12/10,000 births)

often associated with abnormalities in conotruncal partitioning

Tetralogy of Fallot

most frequently abnormality of conotruncal region (9.6/10,000 births)

unequal division of conus

◦ (a) pulmonary infundibular stenosis

◦ (b) large defect of interventricular septum

◦ (c) overriding aorta arises directly above septal defect

◦ (d) hypertrophy of right ventricle

Persistent truncus arteriosus

conotruncal ridges fail to fuse and descend toward the ventricles (0.8/10,000 births)

undivided truncus overrides both ventricles

Transposition of great vessels

conotruncal septum fails normal spiral course and runs straight down (4.8/10,000 births)

◦ aorta originates from right ventricle

◦ pulmonary artery originates from left ventricle

sometimes is associated with a defect in membranous part of the interventricular septum

usually accompanied by an open ductus arteriosus

Valvular stenosis

Development of the Vascular system

Heart-Vasculature connectionsmajor vessels develop at same time as

endocardial tube

Inflow (right and left sinus horns)

◦ 3 paired vessels common cardinal veins

vitelline veins

umbilical veins

Outflow Three pairs of aortic arch arteries and

the paired dorsal aortae that circulate blood to the head and trunk

4th and 5th weeks

At day 22

◦ primitive bilateral symmetric circulatory system

Vasculature DevelopmentExtraembryonic vasculature

From 17th day

◦ splanchnic mesoderm of yolk sac hemangioblastic aggregates

Primitive hematopoietic stem cells

endothelial precursor cells

By end of 3rd week blood network completely vascularizes yolk sac, connecting stalk, and chorionic villi

Intraembryonic vasculature

On day 18

◦ splanchnic mesoderm of embryonic disc

◦ later in paraxial mesoderm

Vasculogenesis (primary embryonic vasculature formation )

◦ de novo blood vessel formation Endothelial precursors differentiate into endothelial cells

organize into networks of small vessels

Grow and invade other tissues

Angiogenesis

◦ primitive vasculature expansion and remodeling

◦ Budding and sprouting from existing endothelial cords

HematopoiesisExtraembryonic hematopoiesis

Primitive HSCs of yolk sac (up to 60th day)

◦ exclusively erythropoietic cells primitive erythrocytes

nucleated erythrocytes

containing embryonic hemoglobin

◦ some pluripotent progenitor cells Megakaryocytes

primitive macrophages

intraembryonic hematopoiesis

primitive HSCs colonize some organs

◦ liver, spleen, thymus, bone marrow

Hematopoiesis, LiverLiver is first organ to be colonized by HSCs

main hematopoietic organ until initiation of bone marrow hematopoiesis near birth◦ two waves of colonization

first beginning about day 23 Primitive HSCs from yolk sac

primitive nucleated erythroblasts

embryonic hemoglobin

Second beginning about day 30 Definitive HSCs from AGM

All hematopoietic cell lineages

both myeloid and lymphoid progenitor cells

enucleated (definitive) erythrocytes

fetal hemoglobin

Hematopoiesis, Bone marrow

as early as 10.5 weeks

definite HSCs come to colonize bone marrow

◦ But hematopoietic mainly carried by liver until birth

Definitive HSCs from splanchnic mesoderm of AGM

◦ In the ventral floor of the dorsal aorta appears at 27th day

increase to thousands cells by 35th day

Disappear by 40th day

Hematopoiesis Site of hematopoiesis

phases of hemoglobin synthesis

intraembryonic vasculogenesisStarts on day 18

blood vessels begin developing in intraembryonic splanchnic mesoderm

◦ Unlike blood extraembryonic and AGM region is not coupled with hematopoiesis

only EPCs (angioblasts) develops Vasculogenesis

Blood network grows and spreads by

◦ (1) continued formation, migration, and coalescence of EPCs (new vasculogenesis)

◦ (2) angiogenesis budding and sprouting of new vessels from existing endothelial cords

◦ (3) vascular intussusception (nonsprouting angiogenesis) existing vessels are split to generate additional vessels

◦ (4) intercalation of new EPCs into the walls of existing vessels

Vasculogenesis & Angiogenesis

level of oxygenation mediates angiogenesis by altering levels of Vegf

Under hypoxic conditions

Vegf is released

Arteries and veins differencesdifferences in directions of blood flow, morphology and physiology

Flow dynamics in capillary-sized vessels

◦ Flow increases (arterial vessels)

◦ Floe decreases (venous vessels)

before blood flow

◦ endothelial cells of capillary beds not identical arterial specification

venous specification

◦ Also endothelial cells have plasticity in their ability based on their local environment

Arteries and veins differences

Development of Aortic Arches

In the human embryo, 5 pairs of mesenchymal condensations develop on pharynx

pharyngeal arches

◦ Correspond to branchial arches 1, 2, 3, 4, and 6 of fish ancestor

5 pairs of Aortic arches from Aortic sac

◦ first pair formed between 22-24th days Dorsally, connect to left and right dorsal aortae

dorsal aortae

remain separate in the region of the aortic arches

they fuse together from 4th T to 4th L segment (during 4th week)

◦ Between days 26 and 29 aortic arches 2, 3, 4, and 6 develop

◦ Neural crest cell play a significant role in the normal development of aortic arch

Aortic Arches (1, 2, 3)

First aortic arches

◦ portions of maxillary arteries

second aortic arches

◦ part of the hyoid and stapedial arteries

segments of dorsal aorta connecting 3rd and 4th arch

(carotid duct) disappear

third aortic arches

◦ common carotid arteries

◦ proximal portion of internal carotid arteries distal portion derived from cranial extensions of dorsal aortae

external carotid arteries sprout from the common carotids

Aortic Arches (right 4th)By the 7th week

right dorsal aorta

◦ loses its connections with midline dorsal aorta

right sixth arch

◦ remaining connected to right fourth arch

◦ Acquires right seventh cervical intersegmental artery

right subclavian artery

◦ (1) right fourth arch

◦ (2) short segment of right dorsal aorta

◦ (3) right seventh intersegmental artery.

region of aortic sac connected to right fourth artery

◦ brachiocephalic artery

Aortic Arches (left 4th)

left fourth aortic arch + small segment of aortic sac

◦ aortic arch

◦ most cranial portion of descending aorta

left seventh intersegmental artery

◦ left subclavian artery

Aortic Arches (6)

right and left 6th arches arise from proximal end of aortic sac

By the 7th week◦ right 6th arch

disappears distal connection with dorsal aorta

◦ left sixth arch remains complete

distal portion forms ductus arteriosus

ligamentum arteriosum

left and right recurrent laryngeal nerves

originally arise below the level of 6th arch

Dorsal Aorta and ventral Branches

Dorsal aorta

Left dorsal aorta

Merged left & right aorta (T4-L4)

vitelline system

blood vessels arising from yolk sac wall

◦ As yolk sac shrinkage right and left vitelline plexuses coalesce

Anastomoses with vascular plexuses of future gut

ventral surface of dorsal aorta

◦ Cranial to the diaphragm (5 pairs) supply thoracic esophagus

◦ Caudal to the diaphragm (3 pairs) celiac artery (abdominal foregut)

initially at C7, finally at T12

superior mesenteric artery (midgut) Initially T2, finally L1

inferior mesenteric artery (hindgut) initially T12, finally L3

Dorsal Aorta and umbilical arteries

umbilical arteries develop in connecting stalk early in the 4th week

(earliest embryonic arteries to arise)

◦ initially connected with paired dorsal aorta

◦ secondary connected with branch of dorsal aorta (common iliac artery)

After birth

◦ proximal portions of umbilical arteries internal iliac

superior vesical arteries

◦ distal parts obliterated medial umbilical ligaments

Dorsal Aorta and Lateral Branches

suprarenal glands

Form between T6-12

◦ vascularized mainly by pair of lateral aortic branches at upper lumbar level (suprarenal arteries) also acquire branches from

renal artery and inferior phrenic artery

presumptive gonads become vascularized by gonadal arteries

◦ arise initially at T10

◦ As gonads descend origin of the gonadal arteries becomes fixed L3-4

definitive kidneys arise in the sacral region

As they migrate, vascularized by transient aortic branches

final pair of arteries in upper lumbar region become definitive renal arteries

Dorsal Aorta and Intersegmental

Branches At the end of the 3rd week arise from posterolateral surface of

descending aorta and vascularize somite derivatives from cervical through sacral levels

cervical, thoracic, and lumbar regions

◦ dorsal branch developing neural tube

Epimeres (deep muscles of neck and back)

◦ Cutaneous branches dorsal skin

◦ ventral branch developing hypomere and associated skin

in the thoracic region intercostal arteries

cutaneous branches

in the lumbar and sacral regions lumbar and lateral sacral arteries

short continuation of caudal dorsal aorta beyond its bifurcation

◦ median sacral artery

Dorsal Aorta and Intersegmental

Branches in the cervical region

intersegmental branches anastomose with each other◦ paired vertebral arteries

secondarily lose their intersegmental connections to aorta

◦ deep cervical

◦ ascending cervical

◦ superior intercostal

◦ internal thoracic

◦ superior and inferior epigastric arteries

Upper limb vasculatures

Arteries of developing upper limbs◦ 1. mainly from 7th cervical intersegmental artery

◦ 2. axis artery develops along central axis of limb buds

brachial artery

anterior interosseous artery

deep palmar arch

sprouts of axis artery Radial

Median

Ulnar

Lower limb vasculatures

Arteries of developing lower limbs

◦ mainly from 5th lumbar intersegmental artery Proximal segment

common iliac artery

Distal segment internal iliac arteries

also give rise to external iliac arteries.

◦ axis artery Primitive axial artery

(distal continuation of internal iliac artery) largely degenerates

Its remnants

sciatic (ischiadic) artery

segment of popliteal artery

section of peroneal artery

definitive axial artery (external iliac artery)

all other arteries develop as sprouts of external iliac artery

Embryonic venous system

Initial bilaterally symmetric System

◦ vitelline system Drains gastrointestinal tract and derivatives

◦ umbilical system carries oxygenated blood from the placenta

◦ cardinal system Drains head, neck, and body wall

shift of systemic venous to right atrium remodeled to adult patterns

Vitelline VeinsGives Rise to Liver Sinusoids, Portal System, and a Portion of Inferior Vena Cava

vitelline veins arise from capillary plexuses of yolk sac

form part of vasculature of developing gut and derivatives

Initial pair of vitelline veins

◦ vitelline plexuses in septum transversum surrounded by growing liver cords

liver sinusoids

Ductus venosus

left vitelline vein diminishes by sinus horn regression

Right vitelline vein

◦ cranial portion (between liver and heart) hepatocardiac portion of inferior vena cava

◦ Segment caudal to developing liver and anastomoses portal system

portal vein

superior mesenteric vein

Umbilical Veins

During second month◦ right umbilical vein completely obliterated

◦ left umbilical vein persists with formation of liver

loses its connection with left sinus horn

forms a new anastomosis with ductus venosus

Cardinal Veins

During 4th week

Anterior, posterior and common cardinals

During 5-7th week

subcardinal veins

◦ sprout from base of posterior cardinals (end of 6th week)

◦ mainly drain kidneys

supracardinal veins

◦ Drain body wall via intercostal veins

Anterior cardinal veins

cranial portions of anterior cardinal veins

◦ internal jugular veins

external jugular veins

◦ capillary plexuses in face become connected Internal jugular veins

anastomosis between the anterior cardinal veins

◦ left brachiocephalic vein

superior vena cava

◦ right common cardinal vein

◦ proximal portion of right anterior cardinal vein

Anterior cardinal veins

Posterior cardinal veins

become obliterated over most of their length

proximal portion of left posterior cardinal vein

◦ entering into the left brachiocephalic vein left superior intercostal vein

receives blood from 2 an 3rd intercostal spaces The.

most caudal portions of posterior cardinals (Sacrocardinal)

(including a large median anastomosis)

◦ Form new anastomosis with supracardinal veins common iliac veins

caudalmost (sacral portion) of IVC

Subcardinal veins

By 7-8th weeks sprout from base of posterior cardinals

subcardinal veins

◦ lateral anastomoses with posterior cardinals

◦ median anastomoses left renal vein

by the 9th week

left subcardinal vein

◦ Regress distal portion remains as left gonadal vein

right subcardinal vein

◦ loses its original connection

◦ develops a new anastomosis with segment of right vitelline vein renal segment of the inferior vena cava

Supracardinal veins

with obliteration of major portion of posterior cardinal veins

supracardinal veins assume a greater role in draining the body wall (segmental intercostal veins)

The veins sprout from base of posterior cardinals

right supracardinal vein

◦ Cranial portion 4th to 11th right intercostal veins

Main portion of azygos vein

◦ abdominal portion anastomoses with right subcardinal vein

segment of IVC just inferior to kidneys

azygos vein

◦ right supracardinal vein

◦ portion of posterior cardinal vein

left supracardinal vein

◦ 4th to 7th intercostal veins hemiazygos vein

inferior portion obliterated

Sacrocardinal

(caudal segment of post. Cardinal) veins

their anastomosis

◦ left common iliac vein

Left sacrocardinal vein

◦ Cranial portion Regress

right sacrocardinal vein

◦ Cranial portion sacrocardinal segment of inferior vena cava

◦ Caudal portion Right common iliac vein

Inferior Vena Cava

(1) right vitelline vein

(2) right subcardinal vein

(3) right supracardinal vein

(4) caudal portions of posterior cardinals

Venous System Defects

A, double inferior vena cava

◦ Preservation of left supracardinal vein

B, double superior vena cava

◦ Preservation of left anterior cardinal left superior vena cava empties into coronary sinus

Venous System Defects

Double inferior vena cava

◦ Preservation of left sacrocardinal vein

Absent inferior vena cava

◦ lower half of body drained by azygos vein

◦ hepatic vein enters heart at site of IVC

Lymphatic System

lymphatic channels arise by vasculogenesis and angiogenesis from mesodermal precursors after 5th week

pair of jugular lymph sacs

◦ collect fluid from lymphatics upper limbs, upper trunk, head, and neck

four additional lymph sacs

◦ cysterna chyli initially drains into symmetrical pair thoracic lymphatic ducts

both of these ducts obliterated

definitive thoracic duct derived from caudal portion of right duct

cranial portion of left duct

median anastomosis

◦ posterior lymph sacs

Endocardial Cushions and Heart Defects

Atrial, ventricular septal and great vesselsdefects

DiGeorge sequence◦ abnormal neural crest development. facial defects

thymic hypoplasia

parathyroid dysfunction

cardiac abnormalities outflow tract

Arterial System Defects

double aortic arch

◦ failure of right dorsal aorta regression

◦ esophagus and trachea enclosed in double arch

Arterial System Defects

right subclavian artery anomalous

◦ Retention of right dorsal aorta at level of 7th intersegmental artery

◦ abnormal regression of right 4th aortic arch

Arterial System Defects Coarctation of the aorta

◦ A. Preductal type

◦ B. Postductal type

caudal part of body supplied by large internal thoracic and intercostal arteries

Arterial System Defects

Right aortic arch

Circulation Before Birth

Saturated & desaturated blood mixing

◦ in the liver By blood from portal system

◦ in the IVC By blood from lower extremities, pelvis, and kidneys

◦ In right atrium By blood from head and limbs

◦ in the left atrium by blood from lungs

◦ in the descending aorta at entrance of ductus arteriosus

Circulation Before and After Birth

Circulatory Changes at Birth

by cessation of placental blood flow and the beginning of respiration

Closure of umbilical arteries

◦ medial umbilical ligaments

◦ proximal portions superior vesical arteries

Closure of umbilical vein

◦ ligamentum teres hepatis

Closure of ductus venosus

◦ ligamentum venosum.

Closure of ductus arteriosus

◦ ligamentum arteriosum

Closure of oval foramen