IN THE NAME OF GOD
Development of the Heart and Vasculature 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 Atrioventricular junction 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 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 connections major 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 Development Extraembryonic 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 Hematopoiesis Extraembryonic 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, Liver Liver 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 vasculogenesis
Starts 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 differences differences 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 Veins Gives 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 vessels defects 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