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