Common Types of Heart Defects | American Heart Association
According to the relationship between the VSD and the blood vessels, DORV is that of normally committed great arteries, i.e., posterior and right-sided aorta. In the normal heart the pulmonary trunk passes anterior and to the left of the aortic root. The aorta and pulmonary trunk ascend in spiral relationships with the . of the great arteries (TGA), rotating high long-axis view. (RHLAV). Introduction of normal versus abnormal great artery relationships is not always definitive.
Another example is the remodelling of the PAA in chick embryos where the right 4th PAA forms the aortic arch instead of the left as in humans and mice.
d-Transposition of the Great Arteries | American Heart Association
However, the formation of a set of bilaterally symmetrical arteries connecting the primitive heart with the paired dorsal aorta, which are then remodelled into the great vessels to correctly bring blood in and out of the heart, occurs overall in the same fashion in all mammals.
Imaging studies have revealed that the formation and patterning of the PAAs in mouse Bamforth et al. Although the timing slightly differs due to the short pregnancy in mice, the remodelling process occurs in the same way. Additionally, the genetics underlying this process in mice also appears to be similar to humans, making the mouse a good model for the study of PAA development in CCVM.
The ability to selectively manipulate the mouse genome to model human disease has provided valuable insight into the genetic processes underlying human developmental disorders. The use of transgenic mouse models to study the development of the PAAs and malformations affecting the great arteries has provided key information to understanding the pathology of PAA-related abnormalities Kameda, ; Scambler, This has been the case for 22q11 deletion syndrome.
Affected individuals display a wide variety of abnormalities including craniofacial dysmorphology, cleft palate, immune deficiency, cardiovascular defects and mental retardation.
The abnormal regression of the left 4th PAA, or a complete failure of its formation, leads to an interrupted aortic arch, a disruption in the connection between the ascending and descending aorta, consequently breaking off the supply of oxygenated blood to the rest of the body upon closure of the ductus arteriosus after birth. Patients with 22q11DS harbour either a 3Mb or 1.
Within this region, more than 30 genes are commonly deleted, but TBX1 is thought to be the main gene involved in causing the 22q11DS cardiovascular phenotype Jerome and Papaioannou, ; Lindsay et al. TBX1 belongs to a family of T-box binding transcription factors that play key roles during embryonic development for the formation of many tissues. TBX1 has been shown to be particularly important for cardiovascular development, as deletion of the Tbx1 gene in transgenic mouse models leads to cardiovascular defects similar to those seen in 22q11DS patients Jerome and Papaioannou, ; Lindsay et al.
In this context, Tbx1-null embryos present with abnormal patterning of the pharyngeal arches where the 1st and 2nd arches are hypoplastic and the 3rd, 4th and 6th pouches are absent. Moreover, the PAAs are not formed in Tbx1-null embryos and a single artery connects the aortic sac with the dorsal aorta instead, and all pups die soon after birth. Examination of the developing PAA system by injection of india ink into the E This indicates that some form of recovery occurs during the remodelling of the PAAs Lindsay and Baldini, ; Papangeli and Scambler, Tbx1 is expressed in the ectoderm, mesoderm and endoderm of the pharyngeal arches but not in the neural crest cells Chapman et al.
Tbx1 expression is induced and sustained by Sonic hedgehog Shh expression in the pharyngeal endoderm Garg et al. The required expression of Tbx1 in the different tissues of the pharyngeal arches for correct arch artery development has been shown using conditional-knockout models to delete Tbx1 specifically from the mesoderm Zhang et al.
In this context, conditional deletion of Tbx1 from the mesoderm or the endoderm causes abnormal patterning of the pharyngeal arches, subsequently affecting the development of the PAA, and displaying abnormalities similar to those seen in the global Tbx1-null embryos. Furthermore, Tbx1 expression in the pharyngeal ectoderm was shown to be required to control cardiac neural crest cell migration through Gbx2 expression Calmont et al.
Timed conditional inactivation of Tbx1 revealed its requirement at a precise time frame between E7. Later deletion of Tbx1 at E Reduced levels of Tbx1 mRNA mainly affects the development of the 4th PAAs and the septation of the outflow tract, and the severity of the cardiovascular defects observed increase with further reductions in the levels of Tbx1 expression.
The cardiovascular defects seen in Tbx1-null mice are largely due to a significant reduction in the proliferation of second heart field cells, where Tbx1 is also expressed.
Such reduction in proliferation is caused mainly by down-regulation of Fgf8, a direct target of Tbx1 Vitelli et al. Further studies have found that Tbx1 interacts with Six1-Eya1 transcription factors which in turn regulate Fgf8 expression, and loss of either Six1, Eya1 or both lead to cardiovascular defects similar to those in Tbx1 mutant mice and 22q11DS patients Guo et al. It has also been suggested that Tbx1 may promote proliferation of second heart field cells by directly interacting with Smad1, and therefore preventing Bmp4 signalling Fulcoli et al.
However, Tbx1 does not only regulate heart and PAA development by promoting proliferation of progenitor cells, but also by regulating their differentiation. Furthermore, expression of many other genes is affected by loss of Tbx1, as demonstrated by microarray analysis of Tbx1-null embryo tissue Ivins et al.
The central role of TBX1 and its multiple genetic interactions and intersections with different signalling pathways could be the basis for the wide spectrum of phenotypes seen in 22q11DS patients, where mutations in other genes directly or indirectly interacting with TBX1 may determine the phenotype.
Human PAA development parallels closely the formation and remodelling that is seen in the mouse, making transgenic mouse models an ideal research tool to analyse the effects of genetic mutations on this process.
The transcription factor TBX1 has been identified as the gene most likely to be responsible for causing the cardiovascular defects found in 22q11DS patients, primarily through research using transgenic mice. However, given the wide spectrum of phenotypes observed in 22q11DS, with the majority of patients having the same deletion, the basis for such a wide spectrum of abnormalities still needs to be elucidated.
As exemplified above, the expression of many genes and different signalling pathways are affected by a 22q11 deletion, potentially contributing to the variety of phenotypes. Further understanding of such genetic and signalling interactions may provide helpful tools for a complete diagnosis and prognosis, as well as potentially treating 22q11DS patients in the future. The human pharyngeal arches.
Coronal section of the pharyngeal arches, obtained by high resolution episcopic microscopy of a Carnegie stage 15 human embryo.
Each artery is found within the centre of each pharyngeal arch and connects the aorta ao and pulmonary trunk ptwhich is septated by this stage. Remodelling of the pharyngeal arch arteries. The symmetric PAA undergo a complex remodelling process in which most of the right dorsal aorta regresses dotted lines as well as the carotid duct on both sides. The 3rd PAA yellow forms the common carotid arteries. The right 4th orange forms part of the right subclavian artery while the left 4th forms the central part of the aortic arch.The Heart and Major Vessels - PART 1 - Anatomy Tutorial
The right 6th purple regress almost completely, while the distal part of the left 6th forms the ductus arteriosus dawhich closes white dotted lines after birth. The pulmonary arteries arise from the proximal part of the 6th PAA.
d-Transposition of the Great Arteries
The 7th intersegmental artery forms the left subclavian artery and the distal part of the right subclavian artery following remodelling and regression of the dorsal aorta. PAA are numbered; ao, aorta; cd, carotid duct; pa, pulmonary arteries; pt, pulmonary trunk.
Figure courtesy of Dr Simon Bamforth. Development of the heart: Inactivation of Tbx1 in the pharyngeal endoderm results in 22q11DS malformations. Clarification of the identity of the mammalian fifth pharyngeal arch artery. Clin Anat 26, Cold Spring Harbor Protocols Tbx1 controls cardiac neural crest cell migration during arch artery development by regulating Gbx2 expression in the pharyngeal ectoderm.
Expression of the T-box family genes, Tbx1-Tbx5, during early mouse development. Dev Dyn Transcriptional Control in Cardiac Progenitors: PLoS Genet 8, e Transformation of the aortic arch system during the development of the human embryo. Contrib Embryol 68, Tbx1 regulates the BMP-Smad1 pathway in a transcription independent manner. PLoS One 4, e Tbx1, a DiGeorge syndrome candidate gene, is regulated by sonic hedgehog during pharyngeal arch development. The most prevalent anatomic arrangement observed in DORV is that of normally committed great arteries, i.
Then, from the highest to the lowest frequency, it is followed by subaortic VSD without pulmonary obstruction, doubly-committed or non-committed VSD, and the extremely rare subpulmonary VSD 2,3. Subpulmonary VSD is the most frequently encountered anomaly in cases where the aorta and the pulmonary trunk are side by side or when the aorta is anterior and right-sided an arterial arrangement observed in complete transposition of the great arteries. Occasionally, subaortic or non-committed VSD can be found.
Actually, depending on the degree of overriding of the pulmonary valve in the trabecular region of the ventricular septum, different types of anomalies can be encountered, ranging from double outlet to transposition of the great arteries.
Some authors prefer to call this group of malformations Taussig-Bing anomaly. In this group of conditions, the defects most frequently encountered are obstructive lesions of the aortic arch, bilateral insertion of the mitral chordae or both 2. When the arterial arrangement is represented by an anterior and left-sided aorta, which is undoubtedly one of the rarest arterial arrangements encountered in DORV, the most frequently found VSD is the subaortic, although it can be doubly-commited, subpulmonary or non-commited.
This kind of arrangement is generally associated with subpulmonary stenosis and juxtaposition of the atrial appendages 2,3. The arterial arrangement in which the aorta is anterior to the pulmonary trunk is extremely rare. In this case, the VSD may be subpulmonary or non-committed. Bidimensional echocardiography has significantly contributed to the diagnosis and knowledge of the anatomic variations of DORV through the accurate assessment of the intracardiac abnormalities, many times making hemodynamic studies unnecessary, except in cases where a total surgical correction is suggested 1,4.
This report describes one of the rarest forms of DORV, i. Report of the case A white male infant aged 18 days and weighing 3kg was referred to a pediatric cardiologist for the assessment of a heart murmur.
On physical examination, the infant showed tachypnea and slight cyanosis.
His second heart sound had a normal intensity and showed no splitting. His pulses were symmetrical and had a normal amplitude. His electrocardiogram showed right ventricular hypertrophy. His chest X-ray revealed an enlarged cardiac silhouette due to enlarged right cavities, flat pulmonary trunk segment and increased pulmonary vasculature.