Heart, Aorta and Aortic Valve Development and Cardiovascular Malformations
Human Genetics & Embryology
Introduction In vertebrates, the heart is the first organ to develop and takes shape during the third week of embryogenesis. The earliest evidence of a heart structure can be identified beginning from day 15 of pregnancy. Stem cells in the anterior-lateral mesoderm become specific cardiac precursor cells and align in a horseshoe shape. In the third week of pregnancy these heart precursor cells that are previously arranged in bilateral symmetrical manner move medially to unite and form a single
... rimitive heart tube. This straight heart tube consists of an inner cell layer (endocardium), an outer cell layer (myocardium), and the extracellular matrix (ECM) separating the other two layers also known as the heart jelly. The developmental stage that follows is a right-hand rotation of the heart leading to the first left-right non-symmetry in the embryo. Because of this rotation, the segments of the heart tube that later form the atria are positioned above the segment that forms the ventricles. The atria, ventricles, and truncus arteriosus originate through local extensions of the heart tube during heart loop shaping. Simultaneously, the ECM within the outflow tract and the future atrioventricular channel expand to form so-called endocardial cushions. Heart-tube segmentation into atria, ventricles, and the outflow tract is accomplished by these cushions. By further growth and additional fusions, they form septum-and valve-structure precursors, separating the developing ventricles from each other. During the sixth and seventh week of pregnancy, the heart and the common outflow tract (truncus arteriosus) are chambered by the septa to divide into four distinct ventricles, the aorta, and the pulmonary artery. This results in the formation of a separate pulmonary and systemic circulation. The aorta and its respective segments originate from diverse embryonic structures. The ascending part of the aorta, the aorta ascenders is formed by the division of the truncus arteriosus as described above; however, the aortic arch and supra-aortic vessels originate from the third and fourth branchial arch arteries. The fivecomplete branchial arch artery pairs are also designated as aortic arches and originate from the truncus arteriosus, connecting it with the right and left dorsal aorta, which are also a part of the embryonic circulation. When the heart develops into the heart tube, valve morphogenesis also begins. The ECM in regions around the outflow tracts and between the atria and ventricles expand to form endocardial cushions, contributing to the formation of all four heart valves. During the next few days interactions between diverse endocardial and myocardial signals occur, which are of crucial importance for the transition remodeling of the endothelium and the mesenchyme. Following this transformation, mesenchymal cells proliferate and support further swelling of the endocardial cushions. In addition, myocardial cells infiltrate the edges of the endocardial cushions now containing mesenchymal cells      . In the truncus arteriosus, this growth of cushions supports the division of the outflow tract into the aorta and pulmonary artery and takes part in the formation of the aortic and pulmonary valves, each consisting of three leaflets. If during this stage of valvulogenesis, the original semilunar valve fails to separate and remain fused at the valve commissures; it results in the development of a bicuspid aortic valve [2,6-9]. Neural Crest Cells Influence the Heart Development Induced by growth factors, a bulge of the epithelial cluster, the neural plate, develops in the embryo's cranial region, in the ectoderm dorsal to the notochord. This plate's median groove is called the neural groove. Further proliferation of the neural plate's lateral edges results in the formation of neural folds, which fuse dorsomedial forming a tubular structure called as neural duct. Later, the central nervous system develops from the cephalic part of neural tube whereas the spinal cord develops from the caudal part. The neural crest cells originate from the neural folds (the border region between the neurectoderm and the ectoderm) and are pluripotent and able to differentiate into many different cells such as melanocytes, nerve cells, connective tissue, and smooth muscle cells. These cells show high migratory activity on predefined tracks through the entire embryo. The cardiac neural crest cells originate from the most caudal part of the cranial neural crest located between the (midotic) placoderm and the third somite. They migrate via the pharyngeal arches III, IV, and VI, colonizing these as well as the aortic arches, the heart outflow tract, and the large proximal vessels. Influenced by the neural crest cells, the aortic arches undergo remodeling during development to finally form a part of the vessels mentioned above, such as the fourth branchial arch artery and the arcus aortae. Furthermore, the neural crest cells participate in the formation of the endocardial cushions within the truncus and the membrane sections of the interventricular septum. They also contribute to the septation and arrangement of the large vessels as well as the development of the semilunar valves. Studies using quailchicken chimera revealed that neural crest cells could be found in all three aortic and pulmonary valve leaflets . not unexpected and implies potential valve malformation by deficient valvulogenesis or by dysplasia of other cardiovascular system elements. Other CVMs like ventricle septum failure, aortic isthmus stenosis, hypoplastic left heart syndrome, abnormal mitral valve, aortic root dilatation, and tetralogy of Fallot were found to be related to BAV. Following is a description of four of the most important genetically inheritable diseases or syndromes showing CVMs along with their characteristic presenting symptoms. It comprises the heart, the valve, and aortic arch malformations along with the above-mentioned ones  . Fallot Tetralogy The Fallot tetralogy was first described in 1988 by the French physician Etienne Fallot and accounts for 10% of all congenital heart defects. It consists of a combination of the following four components: pulmonary stenosis, ventricular septum defect, right ventricular hypertrophy, and rightward displacement of the aorta, which "rides" over the ventricular septal defect and receives blood from both ventricles. Presumably, this malformation results from a misalignment of the aorticopulmonary septum, which separates the bulbous cordis from the truncus arteriosus to the ventral side during embryonic development. In this way, the aorticopulmonary septum fails to fuse with the ventricular septum. The bulbus cordis develops in to the conus arteriosus, which corresponds to the funnel-shaped portion of the outflow path of the right heart, and opens into the pulmonary trunk. The truncus arteriosus, on the other hand, is the distal part of the heart-tube, from which the root of the ascending aorta and the pulmonary artery develop in the later stages of differentiation. The cause of this malformation of the heart appears to be an autosomal aberration or a heterozygous microdeletion on the long arm of the chromosome 22 (22q11), which is autosomal dominant  .