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Embryology of heart and lung
- 2. EMBRYOLOGY OF HEARTAND LUNG Princy Francis M IInd Yr MSc (N) JMCON
- 3. Definition Embryology: Embryology isthe branch of biology that studies the prenatal development of gametes, fertilization, and development of embryos and fetuses. Heart :Heart is a hollow muscular organ that pumps the blood through the circulatory system by rhythmic contraction and dilation. Lungs : The lungs are a pair of spongy, air-filled organs located on either side of the chest (thorax) which remove carbon dioxide from and bring oxygen to the blood.
- 4. EMBROYOLOGY OF THEHEART Day 18 – 12 weeks of intrauterine life 1. Primitive heart tube formation 2. Looping 3. Wedging 4. Septation of the atria 5. Development of the atrioventricular valves 6. Development of the aortic and pulmonic trunks 7. Development of the aorta and its branches
- 5. 1. Primitive hearttube formation • Mesoderm. • Day 18: anterolateral plate of mesoderm present over the yolk sac, connecting stalk and the body of the embryo differentiates to form angioblasts. • Angioblasts form endothelial cell clusters called angiocytes. • These spread in a cephalic direction and unite anteriorly to form a horse shoe shaped plexus of small blood vessels.
- 6. • Two lateralgroups than fuse ventrally in the midline to form the primary or primitive heart tube. • It has an inner endocardium and an outer myocardium separated by the cardiac jelly.
- 7. • Between 21stand 24th day, the primitive heart tube subdivides from below upwards into right and left horns of sinus venosus, sinus venosus proper, primitive atrium, primitive ventricle and bulbous cordis. • Into each horn of sinus venosus 3 bilateral venous systems drain. • From lateral to medial they are the cardinal, the umbilical and the vitelline veins.
- 8. ABNORMAL DEVELOPMENT DURING FORMATIONOF HEART TUBE •Embryonic death
- 9. 2. LOOPING • Theheart is the first organ to break the bilateral symmetry of the early embryo. • A differential growth begins which allows a posterior leftward slow growth and anterior rightward fast growth. • This leads to rightward or dextro-looping due to which the future right ventricle comes to the front and right of future left ventricle.
- 10. • Further disproportionategrowth occurs resulting in bending of the heart tube at atrioventricular junctions. • Eventually inflow tract and future left ventricle are posterior and to the left. The outflow tract and future right ventricle remain anterior and to the right.
- 11. Abnormal development duringlooping • Dextrocardia Dextrocardia may coincide with situs inversus, a complete reversal of asymmetry in all organ. • Levolooping : Abnormality of looping alone. Normal development of outflow tract results in ventricular inversion. i.e, right ventricle receives from left atrium and vice versa
- 12. • Abnormality oflooping as well as outflow tract development may lead to corrected transposition of great vessels. Both ventricular inversion as well as transposition of the great vessels. RA – LV-PA-LA- RV- Aorta.
- 13. 3. WEDGING • Theprimitive ventricle grows centrifugally from the greater curvature of the cardiac loop. • At this point the inflow tract has access only to the left ventricle, where as right ventricle has access only to the outflow tract.
- 14. processes • Convergence :The inflow constriction (future AV canal) and bulbous cordis converge more towards each other. Simultaneously, the atria are expanding centrifugally and AV canal septation is taking place. • Wedging : The septated AV canal moves to the right and each orifice lies over its future respective ventricle. The bulbous cordis shift leftwards such that a part of outlet sits over the left ventricle and rest sits over right ventricle. • After convergence and wedging, each ventricle has gained access to both inflow and outflow tracts.
- 15. Ventricular septum development •The interventricular septum grows upwards from the floor of the bulboventricular cavity. • The bulbar septum grows downwards to partially reach the interventricular septum. • Still, a gap remains between the two which is eventually filled by growth of atrioventricular cushions.
- 16. Abnormal development • Abnormalitiesof looping and convergence can result in inflow malalignment- double inlet left ventricle or outflow malalignment- double outlet right ventricle.
- 17. • Only abnormalwedging results in double outlet right ventricle. • Ventricular septal defects originate during this stage.
- 18. 4. SEPTATION OFTHE ATRIA Before atrial septation begins, 2 events must take place 1. Transfer of the original 3 paired bilaterally systemic venous inflow systems to the right side of the heart. 2. Incorporation of pulmonary venous inflow to left atrium.
- 19. • Initially 2anastomotic channels develop to transfer blood from left side of the body to the right. a. Brachocephalic vein in the head, which transfers all blood from left cardinal to right cardinal vein b. Ductus venosus in the body, transfers blood from left umbilical vein to the right vitelline vein and eventually to sinus venosus.
- 20. • Simultaneously, thereoccurs regression of both distal vitelline systems, both proximal umbilical veins, proximal left vitelline vein and distal right umbilical vein. • The sinoatrial junction shifts rightwards to open into right half of common atrium. This results in regression of left sinus horn, which eventually becomes the coronary sinus. • The pulmonary venous system develops from the left posterior wall of the left atrium initially as a single primary pulmonary vein. It then extends towards the developing lung buds, the lung buds are posterior to the heart and derive blood from the splanchnic plexus.
- 21. • The pulmonaryvein grows posteriorly and superiorly towards the intrapulmonary venous plexus and once contact occurs, blood flows into left atrium. • The earlier connection with the splanchnic plexus is then lost. • The left atrium grows by incorporating the primary pulmonary vein itself back onto the posterior wall. • Eventually, four pulmonary veins draining into left atrium are formed.
- 22. Septation of atria •At the end of 4th week of development a thin crest shaped septum goes from the cranial aspect of primitive atrium • It represents the first portion of septum primum. • The opening between the lower rim of the septum primum and endocardial cushion is called the ostium primum.
- 23. • This ostiumprimum gradually gets obliterated when the growing septum primum fuses with endocardial cushion. • Before the septum primum fuses with endocardial cushions, several perforations develop in its mid portion that enlarge and coalesce to form a single large opening the ostium secundum
- 24. • Another septum,septum secundum then develops along the cranial and posterior wall of the right atrium. • This septum which also has a crescent shaped leading edge extends midway along septum primum and its crescent shaped lower margin from the foramen ovale. • Usually the septum secundum covers the ostium secundum. • This septum formation is completed in 34 days.
- 25. Abnormal development • Completefailure of atrial septation results in development of a common atrium often with both systemic and pulmonary veins appearing bilaterally. • Failure of development of septum primum results in large secundum defects. • Failure of fusion of septum primum with the endocardial cushions results in primum ASD. • Failure of fusion of septum secundum with the sinus venosus results in the development of a sinus venousus ASD, with or without anomalous pulmonary venous drainage.
- 27. • Failure ofdevelopment of upper connecting brachiocephalic vein results in bilateral superior venacava or persistence of left superior venacava draining into the coronary sinus. • Failure of connection between the primitive pulmonary vein and the intrapulmonary venous complex results in various forms of total or partial anomalous pulmonary venous return.
- 28. Total anomalous pulmonaryvenous return.
- 29. • Defective incorporationof the primitive pulmonary vein into the left atrial wall results in cor triatriatum. • Ectopia cordis is a rare anomaly in which the heart lies on the surface of the chest. It is caused by failure of the embryo to close the ventral body wall.
- 30. 5. DEVELOPMENT OFAV VALVES • Particulates known as ADHERONS accumulate in the cardiac jelly in the region of atrioventricular and conotruncal valve formation. • These adherons stimulate the endocardial cells to transform cardiac jelly into mesenchyme. • This mesenchyme forms dorsal and ventral out pouches. • It further differentiates to form fibrous connective tissue which finally forms the valves.
- 31. • Simultaneously cavitationand septation of ventricular chambers are occurring. • Papillary muscles develop and attach to the valve leaflets through chordae tendinea.
- 32. Abnormalities • Atresia ofone of the valves (tricuspid atresia) and Ebstein’s anomaly • Atrioventricular septal defect • Abnormalities of papillary muscular attachments.
- 33. 6. DEVELOPMENT OFAORTIC AND PULMONIC TRUNKS • The conus truncus which is the common outflow tract, has to separate into aortic and pulmonic outflow tracts swelling appear from right and left sides and not from dorsal and ventral wall. • Similar transformation, as in development of atrioventricular valves follows and results in the formation of separate valves.
- 34. • Neural crestcells migrate to the site of formation of outflow septum. • The septum develops from distal to proximal and meets the endocardial cushions below to separate the two semilunar valves. • The septum is formed in a spiral manner to provide the final anatomy of the great arteries.
- 35. Abnormalities • Complete absenceof neural crest migration results in persistence of truncus arteriosus • Partial absence of neural crest migration produces double outlet right ventricle, TOF and double inlet left ventricle. • Asymmetrical division of the outflow tract orifice may result in stenosis of one of the valves.
- 36. 7. DEVELOPMENT OFAORTA AND ITS BRANCHES • Early in development, there are 2 paired lateral dorsal aorta which fuse to form the descending aorta. • Simultaneously the pharyngeal arches are growing and each arch has a pair of aortic arch arteries. • The first, second and fifth arches disappear. • The third, fourth and sixth arches from the major components of central cardiovascular system
- 37. Abnormal development • Failureof migration of neural crest cells into the aortic arch arteries result in a wide variety of phenotypes. • DiGeorge syndrome, velcardiaofacial syndrome, catch 22, interrupted aortic arch, truncus arteriosus, TOF, isolated ventricular septal defects aberrant subclavian artery and other subtle arch anomalies are the result of third or fourth aortic arch defects.
- 38. DEVELOPMENT OF THEPACEMAKER AND CONDUCTION SYSTEM • The rhythmic electrical depolarization waves that trigger myocardial contraction is myogenic, which means that they begin in the heart muscle spontaneously and are then responsible for transmitting signals from cell to cell. • Primitive ventricle acts as initial pacemaker. • But this pacemaker activity is actually made by a group of cells that derive from the sinoatrial right venous sinus. • These cells form an ovoid sinoatrial node (SAN), on the left venous valve.
- 39. • After thedevelopment of the SAN, the superior endocardial cushions begin to form a pacemaker as known as the atrioventricular node. • With the development of the SAN, a band of specialized conducting cells start to form creating the bundle of His that sends a branch to the right ventricle and one to the left ventricle. • The human embryonic heart begins beating approximately 21 days after conception
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- 42. • The lungsbegin to develop in the fourth week and begin to mature just before birth. • The respiratory tree originates as a foregut Diverticulum that undergoes a controlled series of branching. • The first rudiment of the lung, a keel- shaped ventral outpouching of the endodermal foregut called the respiratory diverticulum or lung bud, appears on day 22. • The lung bud begins to grow ventrocaudally through the mesenchyme surrounding the foregut.
- 44. • On days26 to 28 it undergoes a first bifurcation, splitting into right and left primary bronchial buds. These buds are the rudiments of the two lungs. • Between weeks 5 and 28, they branch an additional 16 times to generate the respiratory trees of the lungs. • The stem of the respiratory tree proximal to the first bifurcation becomes the trachea and larynx and the stems of the right and left primary bronchial buds become the right and left primary bronchi. • The third round of branching, which occurs early in the fifth week, yields three secondary bronchial buds on the right side and two on the left. • These buds give rise to lung lobes: 3 in the right lung and 2 in the left lung.
- 45. • During thesixth week, a fourth round of branching yields 10 tertiary bronchi on both sides; these become the bronchopulmonary segments of the mature lung. • By week 16, after about 14 more branching’s, the respiratory tree produces small branches called terminal bronchioles. • Between 16 and 28 weeks, each terminal bronchiole divides into 2 or more respiratory bronchioles, and the mesodermal tissue surrounding these structures become highly vascularised. • By week 28, the respiratory bronchioles begin to sprout a final generation of stubby branches. These branches develop in craniocaudal progression, appearing first at more cranial terminal bronchioles.
- 46. • By week36, the first formed wave of terminal branches is invested in a dense network of capillaries and are called terminal sacs (primitive alveoli). • Limited respiration is possible at this point, but the alveoli are still so few and immature that infants born at this age may die of respiratory insufficiency without adequate therapy. • Additional terminal sacs continue to form and differentiate in craniocaudal progression both before and after birth, possibly until as late as 8 years.
- 47. • The lungis a composite of endodermal and mesodermal tissues. • The endodermal of the lung bud gives rise to the mucosal lining of the bronchi and to the epithelial cells of the alveoli. • The vasculature of the lung and the muscle and cartilage supporting the bronchi are derived from the foregut splanchnopleuric mesoderm, which covers the bronchi as they grow out from the mediastinum into the pleural space. • The endoderm of the lung formed in each lung before birth • The total number terminal sacs in the mature lung is 300 – 400 million
- 48. STAGES OF HUMANLUNG DEVELOPMENT Embryonic 26 days to 6 weeks The lung bud arise as a ventral outpouching of the foregut endoderm and undergoes 3 initial rounds of branching, producing the primordia successively of the two lungs, the lung lobes and the bronchopulmonary segments. Pseudo glandular 6- 16 weeks The respiratory trees of the lungs undergo 14 more generations of branching, resulting in the formation of terminal bronchioles. Canalicular 16 – 28 weeks Each terminal bronchiole divides into 2 or more respiratory bronchioles. The respiratory vasculature begins to develop.
- 51. Developmental abnormalities • Pulmonaryagenesis : lung bud fails to split into right and left bronchi and to continue growing. • Pulmonary hypoplasia a reduced number of pulmonary segments or terminal air sacs. It reduces the volume of the pleural cavity and thus restricts growth of the lungs.
- 52. • Respiratory distresssyndrome :- premature infants show rapid, laboured breathing which arises due to hyaline membrane disease on account of surfactant deficiency. • Congenital lung cysts : These are formed by dilatation of the terminal bronchi where in the lungs show honeycomb appearance on radiograph.
- 53. • Accessory lung:This is located at the base of left lung and does not communicate with tracheobronchial tree although it has systemic blood supply. • Lobe of azygous vein : the lobe appears in the right lung , which develops when the apical bronchus grows superiorly, medial to the arch of azygous vein, instead of lateral to it. Consequently, the vein lies at the bottom of a fissure in the upper lobe producing a linear marking on the radiograph of the lungs.
- 54. JOURNAL ABSTRACT 1. Newapproaches under development: cardiovascular embryology applied to heart disease Research in stem cell biology, the cardiomyocyte lineage, and the interactions of the myocardium and epicardium have opened the door to new approaches for healing the injured heart. The normal roles that epicardium and epicardial-derived cells (EPDCs) play in development may have important implications for therapeutic approaches to adult heart disease. Direct conversion of EPDCs to cardiomyocytes appears to occur rarely in development but may be induced by thymosin-β4 after injury.
- 55. Cardiac fibroblastsderive from embryonic epicardium and can be induced to transdifferentiate into cardiac muscle by transcription factors (TFs) or miRNAs. The epicardium is a necessary source of growth factors for normal development of the myocardium. EPDCs may also produce growth factors that could be used therapeutically to enhance cardiomyocyte regeneration. (cardiac CFU fibroblasts) cCFU-Fs are a population of epicardial-derived cells within the heart that have the ability to differentiate to a number of cell types in vitro, including cardiomyocytes.
- 56. Human lung development:recent progress and new challenges A key line of investigation has been the cloning of mutant genes from human patients with congenital lung disease and mechanistic investigation of gene function using genetically altered mice. For example, the transcription factor Nkx2-1 is the first factor to be expressed in the region of the embryonic foregut endoderm that will bud into the lung. Mouse Nkx2-1 mutants fail to make lungs and Nkx2-1 has been shown to be required throughout mouse lung development and in the adult.
- 57. Mutations in NKX2-1are associated with congenital lung disease, leading to the hypothesis that NKX2-1 plays very similar mechanistic roles in mouse and human lung development. Similarly, genes that are mutated in human neonatal respiratory distress syndrome, such as those encoding surfactant proteins B and C, ABCA3 and the transcription factor FOXM1, have been shown to play key roles in alveolar development in mice
- 58. ASSIGNMENT • Recent advancesin finding embryological abnormalities of heart and lung development.
- 59. REFERENCES • Larsen JL.Human embryology. 3rd edition. USA: Churchilllivingstone; 2001 • Satpathy M. Clinical diagnosis of congenital heart disease. Newdelhi: Jaypeebrothers; 2008. • Moore LK, Persaud NVT. The developing Human. Clinically oriented embryology. 6th edition. Noida : Thompson Press; 1999. • Sadler WT. Langman’s Medical embryology. Ninth edition. USA: Lippincott publication; 2004. • Singh I. Human embryology 6th edition. Delhi: Macmillan ; 1996 • Dixit D. Human Embryology. Delhi: CBS publishers; 2004.