The human heart is the first organ to develop in the embryo and the knowledge of its embryology is essential for interpretation of congenital cardiac malformations. The cardiac development is a complex process that starts as early as 15th–16th day of embryonic age, with migration of cardiogenic stem cells from the primitive streak, formation of paired cardiac crescents and primitive heart tube, with subsequent cardiac looping, convergence, septation and chamber formation, as well as the development of the cardiac conduction system and coronary vasculature. The establishment of left–right asymmetry also is crucial for the developing embryonic heart [2].
It is common in literature that anomalies of the great vessels are more prevalent in patients with CHD than in normal population [1,2,3, 5,6,7,8]. In our study, we observed that CHD are commonly associated with extracardiac abnormalities, of which vascular anomalies were the commonest.
The most common association observed in our study was between the aortic anomalies and conotruncal anomalies (Fig. 5). Also venous anomalies were coincident with septal, conotruncal and heterotaxy anomalies [5, 9].
The most common vascular anomalies observed in our study were the aortic anomalies, as they were found to be associated with CHD in half of patients (50%). Aortic abnormalities were frequently associated with conotruncal anomalies, valvular anomalies, chamber anomalies and to lesser extent with septal anomalies. Similarly aortic arch anomalies were found to be frequently associated (64%) with congenital cardiac defects according to Groun and Oeschslin [10].
Moreover, it was documented that right sided aortic arch with mirror-image branching is usually associated with intracardiac defects (commonly conotruncal malformations as in TOF, pulmonary atresia and truncus arteriosus) [11]. Also high incidence of associated extracardiac vascular anomalies was found in pediatric patients with TOF, 40% of TOF patients had associated aortic anomalies according to El-shimy et al., and they also reported that anomalous coronary arteries were a common association with TOF (20%) [12]. While Hu et al. observed coronary artery anomalies in only (1.26%) of TOF patients [6], Goo reported an incidence of 8.5% [13]. In our series, two cases of coronary arteries anomalies (6.2%) were found, and they were associated with conotruncal anomalies. The detection of an anomalous origin of coronary arteries is of major importance particularly prior to surgery when a ventriculotomy is planned, since incidental coronary passing by right ventricle is fatal. So differences in the topography of the great arteries should be taken into account in diagnosis and treatment of cardiac outflow tract malformations.
Several studies were done to figure out the embryonic basis for the association between vascular anomalies and CHD [1, 3, 8, 14, 15]. This association may be attributed to genetic/ chromosomal defects resulting in both anomalies, as according to Goldmuntz [16] the conotruncal anomaly associated with aortic arch anomalies and ductus arteriosus should raise the suspicion of DiGeorge syndrome (22q11.2 deletion syndrome). Moreover, others observed specific patterns of extra cardiac vascular malformations that coexist with cardiac defects in patients with DiGeorge syndrome (22q11.2 deletion syndrome), including anomalies of the aortic arch and anomalies of the pulmonary vasculature [17].
The associated vascular anomalies could represent a consequence to congenital heart disease, where the hemodynamic theory admitted that the development of heart chambers and resulting vessels is related to the pattern of the fetal blood flow that passes through them [18]. Therefore, a reduction in the blood flow to the left side of the heart leads to decreased flow across the arch and isthmus that may potentiate the development of coarctation and this theory is supported by high prevalence of coarctation of the aorta in patients with CHD with reduced antegrade aortic flow in utero. Also the absence of aortic coarctation in patients with right heart obstruction provides support to the hemodynamic theory of coarctation development [7]. In our study, there were seven cases of aortic coarctation, five of them had bicuspid aortic valve; two cases had TGA (D and L types) (Figs. 6, 7).
Interestingly, several studies were conducted on animal models (chick embryos used as a model to study heart development), where surgical interventions in the form of banding of the outflow tract (to variable extents) were made to alter blood flow conditions in the embryonic chick cardiovascular circulation, these interventions resulted in extensive cardiac malformations which resemble those of human patients with CHD. These studies showed that banding affects the entire embryonic circulation with consequent growth and remodeling that occurred in response to altered hemodynamics resulting in cardiac malformations. These hemodynamic changes occur in a “dose–response” type relationship between the level of blood flow alteration (outflow tract ligation) and manifestation of specific cardiac phenotypes. So hemodynamics plays a critical role in embryonic cardiovascular development, and altered blood flow patterns may lead to congenital heart defects [14].
The second common vascular anomalies observed in our study were the systemic venous anomalies, as they were found in 21.8% of patients with CHD which is nearly similar to another study [3] that observed systemic venous anomalies in 18.1% of patients with CHD in the middle East, others reported prevalence of 12% [6], however Arslan et al. reported that anomalous systemic venous return was prevalent in only 4.5% of patients with CHD [9]. The higher prevalence of systemic venous anomalies in Middle East patients was likely attributed to consanguinity [3]. The systemic venous anomalies encountered in our study were: persistent left superior vena cava (PLSVC), persistent right superior vena cava (PRSVC) in a case of situs inversus totalis, left-sided inferior vena cava (IVC) with interrupted infra-hepatic segment and azygous continuation, congested IVC and hepatic veins. We found that systemic venous anomalies were frequently associated with valvular anomalies, chamber anomalies, septal anomalies and to lesser extent conotruncal anomalies.
It was found that persistent left superior vena cava (PLSVC) was more frequently associated with CHD than in the general population, with reported incidence of 4.4 and 0.3 respectively [2]. Other caval malformations that are reported to be frequently observed in patients with CHD include PRSVC in situs inversus, interrupted IVC with azygous continuation. They also confirmed that caval malformations have a higher prevalence in patients with complex congenital heart disease (such as atrio-ventricular septal defect (AVSD), TOF, DORV, TGA, hypoplastic left heart) compared to simple malformations (such as ASD, VSD, pulmonary stenosis, patent foramen oval, coarctation of the aorta, PDA) [4].
Congenital cardiac defects and associated venous anomalies might be attributed to the same factors (genetic and/or environmental) that affect the development of both cardiac structures and the systemic veins, since that the development of the caval veins happens during the 5th to the 8th week of pregnancy, which is a critical time for the developing heart, as the cardiac looping and septation occurs.
The venous flow into the developing heart might play part in its development, so defect or failure of connection might lead to mal-development of cardiac structures, and vice versa. The close association in timeline of the developing structures might explain that any disturbance of the development of the cardiac structures might also interfere with the venous system [9].
On the basis of this concept two theories were postulated for development of PLSVC, one theory “the obstructive theory” hypothesize that PLSVC would reduce blood flow into the left ventricle restricting its growth. Another theory “low left atrial pressure theory” proposes that presence of atrial anomalies (such as AVSD) would reduce left atrial pressure and size, predisposing for PLSVC [8].
In our series, 3 cases of PLSVC were found, they were associated with ASD, AVSD, and heterotaxy (in one patient) and DORV and a case of PRSVC in case of situs inversus totalis.
Also studies conducted on animal models confirmed that venous obstruction (performed via vitelline vein clipping led to alterations in the venous return and patterns of intracardiac laminar blood flow, with secondary effects on the mechanical load of the embryonic myocardium, these effects produced cardiac malformations similar to those observed in human babies with CHD [15].
Heterotaxy syndromes are also a common cause for cardiac and extracardiac anomalies involving the great vessels and thoraco-abdominal organs. Aberrations in normal left–right axis determination during embryogenesis lead to a wide range of abnormal internal laterality phenotypes, including situs inversus and situs ambiguous. Many cardiac defects (such as AVSD, conotuncal, TGA) and extracardiac vascular defects were observed in laterality defects including systemic venous anomalies (PLSVC, interrupted IVC with azygous continuation) or anomalous pulmonary venous drainage (partial or total) [19]. Three cases of situs abnormalities were found in our study; a case of situs inversus totalis and a case of left isomerism both had AVSD with associated systemic venous anomalies, the third case show situs inversus with TOF and associated left-sided aortic arch (Fig. 8).
In this study, PDA and collaterals were found in 18% and 15% of patients respectively, which is nearly similar to another study that observed PDA in 22% and collaterals in 13% of patients with CHD [6].
Identification of extracardiac anomalies is not only limited to detection of vascular anomalies but also demonstration of possible associated extracardiac thoracic and abdominal aberrations. These findings can alter the patients’ management. The prevalence of these extra cardiovascular findings was 43% in our study; however, it varies greatly in several studies [20] ranging from 7.8% to 83% according to the different definitions, modalities, techniques and different CT machines (using contrast and non-contrast studies and 16-slice MDCT or EBCT or 64-channel MDCT scanners).
The most common extracardiac thoracic findings in our study were pulmonary consolidation patches as a complication to congenital heart disease. Other findings in the abdomen were related to situs anomalies and liver congestion, the remaining were incidental findings. Whereas Malik et al., found that atelectasis, collapse, liver congestion and laterality defects were the most common non-cardiovascular findings encountered in their study [20].
One of the major roles of MDCT in patients with CHD is structural assessment of extracardiac vascular anatomy involving the thorax and upper abdomen, the lungs and major airways with high sensitivity and specificity [6, 12, 20]. It is mandatory for the assessment of MAPCAS, pulmonary slings and pulmonary infections. In addition the scan coverage of the upper abdomen is crucial for evaluation of atrio-visceral situs, heterotaxy syndromes, infra-diaphragmatic total anomalous pulmonary venous drainage and depiction of anomalous abdominal vessels as IVC anomalies, and abdominal aortic coarctation.
This study is limited by relatively small number of cases; similar studies on larger number of patients are required. Our study was performed in a large tertiary children’s hospital; therefore, our results may not be readily replicated in smaller institutions, however most cases of complex congenital heart diseases are referred to tertiary hospitals. Third, confirmatory reference standard tests were not available for reported extracardiac findings; however, no additional evaluation or work-up is usually necessary in children in whom vascular, pulmonary and abdominal findings are diagnosed on CT basis.
