Organogenesis 5 - The Heart PDF

LAYOUT OF THE HEART AND CARDIAC CIRCULATION The heart is mad of 4 compartments —> 2 atria and 2 ventricles separated from one another. The left atrium is connected to the left ventricles by the bicuspid valve (or mitral valve), while in between the right atrium and right ventricle we have the tricu...

LAYOUT OF THE HEART AND CARDIAC CIRCULATION The heart is mad of 4 compartments —> 2 atria and 2 ventricles separated from one another. The left atrium is connected to the left ventricles by the bicuspid valve (or mitral valve), while in between the right atrium and right ventricle we have the tricuspid valve. The right atrium receives blood from the superior and inferior venae cavae and from the coronary sinus (trophic circulation). Blood then goes into the right ventricle (across the tricuspid valve), from which it will be sent to the pulmonary trunk, which then divides into the left and right pulmonary arteries and branches in the lung parenchyma to finally form a capillary network around alveoli, where the gas exchange and oxygenation of blood will take place. From lungs the now oxygenated blood is then brought back to the heart through the 4 pulmonary veins, which open in the left atrium. From the left atrium the blood is sent to the left ventricle (through the bicuspid or mitral valve), and from there it will enter the aorta (divided into ascending, arched and descending aorta) and be brought to the rest of the body. The pulmonary trunk and aorta are separated from the rest of the heart by the semilunar valves. Superior vena cavae —> deoxygenated blood from upper limbs, neck, brain etc Inferior vena cava —> deoxygenated blood from the inferior portion of the body, it has to cross the diaphragm FORMATION OF THE HEART Cells that form the heart originate from 4 different sources: Cardiac crescent (originating from the migration of epiblastic cells) Secondary heart field —> made by mesenchymal cells migrating towards the heart from the mesenchyme of the primordial pharynx (which is dorsal to the heart) Neural crest cells from the most rostral portion of the neural crest Proepicardial region —> cells from the region of the developing diaphragm (septum transevrsum). These cells will contribute to the formation of the epicardium The right ventricle is mostly made by cells coming from the secondary heart field while the left ventricle is mostly made by cells of the primary heart field. Neural crest cells contribute to the separation of the pulmonary trunk and aorta. FROM TWO ENDOCARDIAL TUBES TO ONE While the two endocardial tubes are forming there is also the formation of the cardiac jelly (ECM surrounding the tubes), of the myocardium (from mesenchymal cells in the surrounding) and of the pericardial cavity. The cardiac jelly disappears in the adult. During the 4th week, when the two endocardial tubes come together as a result of the folding, the two sides of the pericardial cavity fuse as well as to form one single pericardial cavity. The tubular heart will now be suspended in the pericardial cavity by the dorsal mesocardium, which will eventually be reabsorbed. In the region where the dorsal mesocaridum is reabsorbed the transverse pericardial sinus originates R (space between the aorta and pulmonary trunk and inferior and superior venae cavae) There is now a single tubular heart (s shaped) originating from the fusion of the two endocardial tubes, which presents an inflow and an outflow portion Inflow portion —> vitelline veins (non oxygenated), umbilical veins (oxygenated) and cardinal veins (non oxygenated) Outflow portion —> aortic sac - pharyngeal arch arteries - dorsal aortae (mixed blood) - segmental arteries, vitelline arteries and umbilical arteries. At the beginning of the 4th week the heart is divided into 5 chambers (inflations): Sinus venosus and horns —> where the three systems of veins communicate with the inflow portion of the heart. It gives rise to the smooth portion of the right atrium and coronary sinus Primitive atrium —> will form the definitive trabeculated portion of the left and right atria Primitive ventricle —> will give rise mostly to the left ventricle of the heart Bulbus cordis —> will give rise mostly to the trabeculated portion of the right ventricle Outflow tract —> divided into conus cordis (proximal part of the outflow tract, it originates from the elongation of the bulbus cordis. It will also give rise to part of the conus arteriosus of the right ventricle and aortic vestibule) and truncus arteriosus (ascending aorta and venesus pulmonary trunk) LOOPING The primitive heart can’t remain a tube, it has to undergo a complex mechanism called looping of the heart. At the end of this process the bulbus cordis will be located caudally and to the right while the primitive atrium will be located dorsocranially and to the left. Despite the bending the atrial and ventricular region will still be in communication through the atrioventricular canal In the adult heart the portion of left atrium we can see from the front is called left auricle DEXTROCARDIA In situs inversus totalis or on its own —> the heart rotates the opposite way around. It is functional if everything is connected the right way EVOLUTION OF THE SINUS VENOSUS Between the 4th and 8th week the left side of the sinus venosus regress, and what remains forms the coronary sinus, while the right side is incorporated in the posterior wall of the right atrium forming the smooth portion of the right atrium (site of venous blood entry in the heart, where the vena cave and coronary sinus enter) Because of all these changes the left umbilical vein will come to drain into the inferior vena cava instead of directly into the heart Here the umbilical veins are still two, but then just one of them will remain. After this happens the umbilical veins enters the inferior vena cava (enveloped by the liver) and then from there to the heart 30 days purple smooth At the beginning there is just one large atrium (not divided) called PRIMORDIAL ATRIUM where we can appreciate a right and a left side. The right atrium has a posterior smooth portion (site of entrance of venous blood) and an anterior trabeculated region (there are trabeculae, it is called true atrium). The left atrium is the same but the posterior smooth portion hosts only one opening originating from the incorporation of the pulmonary veins. The openings will increase as the incorporation progresses (1 to 2 to 4…) The smooth portion takes the name of SINUS VENARUM and it’s called this way in the adult as well 31 days At the level of the opening of the coronary sinus and inferior vena cava there is the appearance of flaps of tissue that surround the openings forming the venous valves, which will disappear in the adult. The openings in the smooth portion of the left atrium are now 2 There is the formation of the crista terminalis, which is a ridge in the smooth portion of the right atrium and it marks the boundaries between the smooth and trabeculated portion of the atrium. Corresponds to the sulcus terminalis on the outside The trabeculated portions on each side elongate and form the left and right auricles (only portions of atria we can see from the front) 32 days By the 32nd day the openings in the smooth portion of the left atrium are 4 SEPTATION OF THE ATRIAL SIDE OF THE HEART FROM THE VENTRICULAR SIDE The septation of the heart requires both a rearrangement of the myocardium and the formation of endocardial cushions. The first septum to form is the septum intermedium (or atrioventricular septum), which separates the atrioventricular canal into two atrioventricular canals, forming the atrioventricular walls. There is a formation of two thickenings in the wall of the canals called ENDOCARDIAL CUSHIONS, that can either be superior (or dorsal) or inferior (or ventral). These endocardial cushions then come together forming the septum. One atrioventricular canal now keeps in communication the left atrium and ventricle and the right atrium ad ventricle. At the level of the communication between each atrium and ventricle we will have the formation of the tricuspid and mitral valves FORMATION OF THE ENDOCARDIAL CUSHIONS It is a very complex mechanism guided by molecular clues. The cells of the myocardium secrete a jelly ECM which triggers the ETM transition of the endocardial cells, which then give rise to a layer of connective tissue. The endocardial cushions will form into the truncus arteriosum (outflow tract, to separate the aorta from the pulmonary trunk) as well but there there will be a big contribution of neural crest cells There can be problems in the developing of the heart due to the wrong migration of the neural crest cells. Things that happen to the mother can lead to problems in the formation of the endocardial cushions —> for example hyperglycaemia (diabetes) or hypoxia REALIGNMENT OF THE CARDIAC CHAMBERS At the initial phase of looping there is not a very good communication between the right/left atrium/ventricles (there is a mismatch) so we need a mechanism of shifting to give the correct alignment to the heart. The ventricles slide a bit to the left while the atria slide a bit to the right SEPTATION OF THE HEART There is so far a right and left side, but their atria and ventricles are connected and are a single chamber. There is the need to form some septa. Again, this requires two main things: Rearrangement of the myocardium (will form the muscular portion of the interatrial and interventricular septa) Formation of the endocardial cushions SEPTATION OF THE ATRIA —> important step in the separation of the systemic and pulmonary circulation. During gestation the separation is PARTIAL and it allows a right to left shunt of blood because most of the oxygenated blood coming from the inferior vena cava (coming from the only remaining umbilical vein) has to bypass the lungs (not functional) and reach the systemic circulation. At this stage of development the lungs should receive the same type of blood as the rest of the body. However, at the moment of birth this separation must be completed very rapidly.  IS 8th feb atrium and fromleft there to the leftventricle Formation of the SEPTUM PRIMUM and SEPTUM SECUNDUM and of the OSTIUM PRIMUM, OSTIUM SECUNDUM and FORAMEN OVALE The septum primum starts to grow between the two atria from the roof with the objective to reach the septum intermedium. While it is growing it always leaves a communication open between the right and left side (ostium primum). When it reaches the septum intermedium it closes the communication completely but there is a process of vacuolisation happening in the rostral part which gives rise to another communication (ostium secundum) While this is happening there is also the formation of another septum (septum secundum) on the right side of the heart, which again grows down towards the intraventricular septum. While its growing it leaves a passageway in its wall called foramen ovalis, which is shifted a bit downward compared to the ostium secundum (which is upper). Most of the blood comes from the inferior vena cava and passes through the foramen ovalis and then to ostium secundum reaching the left atrium, while some of it remains in the right one and goes to the lungs. This process is helped by the valve of the inferior vena cava (flappy connective tissue) The ostium secundum can also be called foramen secundum. The two septa will fuse together at the moment of birth In the adult heart the foramen ovale leaves an imprint called fossa ovalis SEPTATION OF THE VENTRICLES The ventricles have to be separated starting from fetal life. The septum separating the ventricles is called INTERVENTRICULAR SEPTUM. This septum is made of a muscular portion and a membraneous portion (and it remains like this in the adult, the part of the septum in relation with the septum intermedium is made of a membrane). Most of the times the defects in this septum are located in the membranous portion In the adult the membranous part is divided into an atrioventricular part and an interventricular portion Atrioventricular portion —> it partly derives from the septum intermedium Formation of the muscular portion —> at around 44 days of gestation the myocardium undergoes a massive rearrangement and grows in between the two sides of the ventricular cavity forming the muscular portion of the interventricular septum, which doesn’t reach the septum intermediate. It has a sort of crescent appearance (half moon)  Formation of the membranous portion — > it originates from the conotruncal endocardial cushions with the contribution of the atrioventricular endocardial cushions. The conotruncal endocardial cushions are the ones that form in the conus cordis and truncus arteriosus. To understand how the CONOTRUNCAL SEPTUM contributes to the formation of the interventricular septum we have to talk about its formation first —> the cushions start to form rostrally in the truncus arteriosus and then grow caudally towards the septum intermedium while rotating on themselves (very important). If the rotation doesn’t take place correctly then the right ventricle communicates with the aorta and the left ventricle communicates with the pulmonary trunk The two conotruncal cushions (also called swellings) are made of mesenchyme of neural crest origin. The two cushions then grow towards one another and towards the muscular portion of the interventricular septum forming a spiral (rotation along the longitudinal axis of the outflow tract). This septation allows the separation of the outflow tract (truncus arteriosus) into the aorta (connected to the left ventricle) and the pulmonary trunk (connected to the right ventricle). If the formation of this septum doesn’t take place correctly the blood in the heart mixes At the same time we have the formation of the CARDIAC VALVES: Tricuspid Mitral Aortic Pulmonary The pulmonary and aortic valves are also called SEMILUNAR VALVES — > they form at the origin of the aorta and pulmonary artery and they’re called semilunar because they’re made of 3 semilunar pieces. They are formed thanks to the reorganisation of the subendocardial tissue of the conotruncal cushions and the formation of other two cushions called intercalated cushions (with contribution of neural crest cells). The semi-lunes of the valves are named anterior (pulmonary), posterior (aortic), left and right (in both). ATRIOVENTRICULAR VALVES They’re between the atria and ventricles and they originate from the endocardial cushions of the AV septum and the process of remodelling of the myocardium. The leaflets of the AV valves are attached to the papillary muscles of the ventricles, which are the thinner of the muscles originating from the myocardium The muscles don’t attach directly to the leaflets of the valve but rather to fibrous chords called chordae tendineae EMT TRANSITION IS NEEDED for the formation of the valves Endocardial cells in the AV cushions and truncoconal cushions undergo epithelial-to-mesenchymal transformation (EMT) and generate mesenchymal cells that populate the cushions. The mesenchymal cushions then remodel and elongate themselves to form primitive valves that mature into thin valve leaflets (shown here for the atrioventricular valves and the semilunar valves). CONDUCTION SYSTEM The heart starts beating when it’s still a simple tube (around the 22nd day of gestation). This happens because some cells of the primitive myocardium become very responsive to electrical signals around them and start to develop some characteristics on their membrane such as channels for Ca++ which gives them the ability to polarise and depolarise cyclically. Histologically they look the same, there is just a difference in electrical properties. In the adult heart they will be histologically different as well This activity is first detected in the inflow portion and then continues toward the rest of the heart. While the changes in shape of the heart take place even the myocardial cells change and become the conductive system of the heart. These myocardial cells will make up the specific myocardium, which sends rhythmic electrical signals to the rest of the myocardium. sinoatrial node - atrioventricular node - bundle of Hiss - Purkinje fibers FETAL CIRCULATION righing 28mm dd Ef.EE The amount of blood coming into the umbilical veins depends on the state of the placenta. The umbilical vein brings a little amount of oxygenated blood from the placenta to the liver, distributing it to the sinusoids, while the rest (most of the blood) proceeds in the ductus venosus of Arantius and drains in the inferior vena cava, which is in communication with the right atrium. The right atrium also receives blood coming from the superior vena cava (non oxygenated, upper portion of the body) and coronary sinus. Because of the direction of the blood flow and the valves, the blood coming from the inferior vena cava goes through the foramen ovalis and foramen secundum. Now it has reached the left atrium, from which it will go to the left ventricle and then to the aorta, being pumped all over the body The right atrium sends blood both from the superior vena cava and inferior vena cava (mixed) to the right ventricle. It is important that the right ventricle receives a good amount of blood so that it can develop correctly. The right ventricle then sends blood in the pulmonary trunk, which divides into left and right pulmonary arteries, reaching the lungs and allowing them to develop correctly. At the level of the pulmonary trunk there is another shunt, the ductus arteriosus of Botallus, which keeps in communication the aorta with the pulmonary trunk. Blood from the lungs then goes back to the left atrium through the pulmonary veins The shunt between the pulmonary trunk and aorta takes place after the vessels that supply the head and upper limbs have originated, otherwise poorly oxygenated blood would be delivered to them. The regions supplied by the branches of the arch of the aorta receive the most oxygenated blood. So far we have 3 shunts —> liver-ductus venosus of Arantius, right-left atrium and pulmonary trunk- aorta. These shunts won’t remain in the adult. AT BIRTH The blood flow in the umbilical veins suddenly decreases (placenta comes out with the fetus and umbilical cord is cut) and so there is less blood supplied to the ductus venosus, inferior vena cava and consequently in the right atrium. There is a drop in pressure in the right atrium and in the left atrium as well. The baby then takes the first breath and as the lungs expand the resistance in its blood circulation decreases. This allows more blood to flow into the lungs parenchyma through the pulmonary trunk and thus more blood is sent to the left atrium through the pulmonary veins, then to the left ventricle and then to the aorta. Now the pressure in the left atrium is higher than the pressure in the right atrium. At the same time there is a decrease in blood pressure of the ductus arteriosus POSTNATAL CIRCULATION In time the closure between the right and left atrium becomes a morphological closure (initially its just a physiological one due to a change in pressure), meaning that the septum primum and the septum secundum fuse together. At the same time the ductus venosus of Arantius becomes the ligamentum venosus of the liver, while the remnants of the umbilical vein become the round ligament of the liver (or ligamentum teres). The ductus arteriosus of Botallus becomes the the ligamentum arteriosum. maybeincomplete adf.EEEa aEaE If there is an atresia or stenosis of the tricuspid valve then the exampeestenotic son right ventricle doesn’t work and the baby dies very quickly as the lungs don’t receive any blood. resits.EE f causes Some congenital defects may be compatible with the fetal survival but not with the newborn’s one torch Patent foramen ovalis = the foramen remains open = too much blood in the lungs = pulmonary hypertension maternal obesity and defects Signs and symptoms of heart congenital defects depend on number, type and severity. Some heart defects cause few or no symptoms, unless something else develops in life and causes a manifestation of it Usually there might be rapid breathing, cyanosis, fatigue, poor blood circulation but NO chest pain. Children affected might struggle to gain weight and might tire easily or have shortness of breath Many congenital heart defects can cause heart failure Symptoms of heart failure —> shortness of breath fatigue with physical activity buildup of fluid in the lungs swelling in the ankles, feet, legs, abdomen and veins in the neck PATENT OVAL FORAMEN 25% of people have a probe patent foramen ovale. It is an incomplete adhesion of the septum primum with the septum secundum. It is not clinically significant unless it is associated to other pathologies (like hypertension or myocarditis) that change the resistance or pressure in the chambers of the heart. OSTIUM SECUNDUM DEFECT It affects 6 in 10.000 people. There is an excessive resorption of the septum secundum so that it does not cover the foramen secundum. Some blood in the left atrium goes to the right atrium —> more oxygenated blood to the lungs. At birth, pressure becomes higher in the left ventricle. Blood is shunted from the left to the right atrium. At the beginning asymptomatic. Later: enlargement of the right side of the heart, pulmonary hypertension (excessive blood flow in the lungs), debilitating atrial arythmias (in the right atrium we have the SA node, which is the pacemaker of the heart, so if the atrium is damaged there might be problems in the conductive system as well) This condition is compatible with many years of normal life, but with time there is hypertrophy of the right atrium and pulmonary hypertension. If the pressure in the right atrium raises above that in the left atrium there is a reversal of the shunt and cyanosis occurs because the pulmonary circulation is bypassed (before the condition was acyanotic) VENTRICULAR SEPTAL DEFECTS It’s the most frequent congenital defect and affects 12 in 10.000 people. Almost 70% of ventricular septal defects occur in the membranous part of the septum. Initially there is just a left-to-right acyanotic shunting of blood flow, but then right ventricular hypertrophy develops, causing pulmonary hypertension and reversal of the shunt. With time it becomes cyanotic TETRALOGY OF FALLOT It is the most common cyanotic congenital malformation and it originates from a defect in the septation of the truncus arteriosum that favours the aorta (which enlarges while the pulmonary trunk is stenotic) and causes defects in the membranous portion of the interventricular septum. This defect is mostly due to problems in the migration of neural crest cells (1) stenosis of the pulmonary trunk, (2) ventricular septal defect, (3) overriding aorta (the aorta overrides the septum: Latrion rightward displacement of the aorta, so Ratrium that the vessel receive blood from both ventricles), and (4) an enlarged right ventricle. A patent ductus arteriosus is also present. This condition is cyanotic because less blood goes to the pulmonary circulation due to the stenosis and because of the communication between the left and right ventricles bypassing the pulmonary circulation. This defect can be observed during fetal life and surgery can be performed to solve it