The pattern of the coronary arterial orifices in hearts with congenital malformations of the outflow tracts: a marker of rotation of the outflow tract during cardiac development?

Authors


Correspondence

Lucile Houyel, Hôpital Marie-Lannelongue, CMR-M3C, Université Paris-Sud, 133 avenue de la Résistance, 92350 Le Plessis-Robinson, France. E: l.houyel@ccml.fr

Abstract

Outflow tract defects, including cardiac neural crest defects (so-called conotruncal defects) and transposition of the great arteries, are due to an abnormal rotation of the outflow tract during cardiac development. Coronary orifices are often abnormal in outflow tract defects, particularly in common arterial trunk (CAT). A recent study indicates that abnormal coronary artery pattern in a mouse model with common arterial outlet (Tbx1−/− mouse mutant) could be due to a reduced and malpositioned subpulmonary coronary-refractory myocardial domain. The aim of our study was to demonstrate the relation between coronary orifices pattern in outflow tract defects in human and the abnormal embryonic rotation of the outflow tract. We analyzed 101 heart specimens with outflow tract defects: 46 CAT, 15 tetralogy of Fallot (TOF), 29 TOF with pulmonary atresia (TOF-PA), 11 double-outlet right ventricle with subaortic ventricular septal defect (DORV) and 17 controls. The position of left and right coronary orifices (LCO, RCO) was measured in degrees on the aortic/truncal circumference. The anterior angle between LCO and RCO (α) was calculated. The LCO was more posterior in TOF (31 °), TOF-PA (47 °), DORV (44 °), CAT (63 °), compared with controls (0 °, P < 0.05), and more posterior in CAT than in other outflow tract defects (P < 0.05). The RCO was more anterior in TOF (242 °), TOF-PA (245 °) and DORV (271 °) than in controls (213 °, P < 0.05), but not in CAT (195 °). The α angle was similar in TOF, TOF-PA, DORV and controls (149 °, 162 °, 133 °, 147 °), but significantly larger in CAT (229 °, P < 0.0001). In all outflow tract defects but CAT, the displacement of LCO (anterior) and RCO (posterior), while the α angle remains constant, might be due to incomplete rotation of the myocardium at the base of the outflow tract, leading to an abnormally positioned subpulmonary coronary-refractory myocardial domain. The larger α angle in CAT could reflect its dual identity, aortic and pulmonary.

Introduction

Congenital heart defects affecting the arterial pole of the heart, including cardiac neural crest defects (so-called conotruncal defects) and transposition of the great arteries (TGA), are due to an abnormal rotation of the outflow tract during cardiac development (Bajolle et al. 2006). Coronary artery pattern in outflow tract defects is often different from that found in the normal heart, and constitutes a major risk factor for cardiac-related mortality and morbidity after operation, particularly in common arterial trunk (CAT), tetralogy of Fallot (TOF) and TGA.

Indeed, the surgical significance of the coronary arterial anatomy in CAT depends on a variety of factors: position of the coronary arterial orifices on the truncal circumference and in relation to valvar sinus and pulmonary origin (Adachi et al. 2009); proximity with commissures, configuration of the orifices and branching pattern. In TOF, the surgical consequences of a major coronary artery crossing the right ventricular outflow tract require preoperative recognition. Along the same line, the variety of coronary arterial patterns found in TGA is the major anatomical risk factor of mortality after arterial switch operation.

Increased knowledge in the development of the arterial pole of the heart has raised questions on the intricate fates of the great vessels and the associated coronary artery pattern. Theveniau-Ruissy et al. (2008) hypothesized that the coronary artery pattern in the Tbx1−/− mouse mutant was the consequence of a severely reduced ‘subpulmonary’ coronary-refractory myocardial domain malpositioned in the dorsal/left side of the outflow tract. In these mice exhibiting common arterial outlet, the left coronary artery crosses the ventral surface of the heart, a zone normally refractory to coronary artery development, to connect with the right coronary sinus, adjacent to the right coronary orifice (RCO). Consistent with this hypothesis, the anatomical findings in human outflow tract defects confirm that even in CAT a specific area on the truncal circumference is devoid of coronary orifices (Bogers et al. 1993). We therefore hypothesized that the position of the coronary arterial orifices on aortic/truncal circumference in human outflow tract defects could be described as a consequence of the lack of rotation of the outflow tract on the location of a repulsive myocardial domain that influences the epicardial course of main coronary stems, and their final connection to the aorta.

Materials

We investigated the position of coronary arterial orifices in human hearts with outflow tract defects, using the heart specimens available in the French Reference Center for Complex Congenital Heart Defects (CMR-M3C). This collection includes more than 1350 heart specimens fixed in 10% formalin. We analyzed 101 hearts with outflow tract defects and two distinct coronary orifices, including 46 CAT, 15 TOF, 29 TOF with pulmonary atresia (TOF-PA) and 11 double-outlet right ventricle with subaortic ventricular septal defect (DORV). In addition, we examined six hearts with outflow tract defects, and only one or two contiguous, coronary orifices (2 TOF, 1 TOF-PA, 3 DORV). We chose to exclude hearts with TGA or double-outlet right ventricle with subpulmonary ventricular septal defect, as these defects are supposed to be related with distinct embryological mechanisms. Seventeen hearts with dilated or restrictive cardiomyopathy without any associated congenital heart defects were used as controls.

Methods

Positioning of the coronary arterial orifices on the aortic/truncal circumference

Hearts were placed in an anatomical position with the base of the left and right atrial appendages on the intersecting line of a horizontal and vertical plane, as previously described (Bogers et al. 1993). Each heart was then photographed. For each specimen, the position of the left coronary orifice (LCO) and RCO was measured in degrees on a circle relative to a sagittal plane (Bogers et al. 1993) using Perfect Image V7.6 software (Fig. 1a). This plane was defined by three points localized on the aortic/truncal valve circumference (Fig. 1b). We chose to calculate the anterior angle between the two coronary orifices (α), which represents the area devoid of coronary arterial orifices. For the hearts with CAT, we additionally measured the position of each commissure in degrees over the aortic circumference, in order to study the position of LCOs and RCOs relative to the commissures and the valvar sinuses.

Figure 1.

Position of the coronary orifices over the aortic/truncal circumference, expressed in degrees: technique of measurement. (a) The heart is placed in anatomical position with the base of the left and right atrial appendages on the intersecting line of a horizontal and vertical plane (red arrow). (b) The position of left and right coronary orifices (LCO and RCO) is measured in degrees on a circle relative to a sagittal plane. CAT, common arterial trunk; CD, right coronary orifice; CG, left coronary orifice; PA, pulmonary artery.

Configuration of the coronary arterial orifices

We described in each specimen the size and configuration of the coronary orifices: normal, diminutive or pinpoint, tangential, intramural, slit-like, orificial ridge (Fig. 2). Their location relative to the commissures was described as normal, paracommissural, supracommissural or intracommissural. We also described their location relative to the sinotubular junction: normal, too low or too high. For the hearts with CAT, we additionally described the anatomical type of CAT, the number of truncal cusps, the relation between the mitral valve and the truncal valve (continuity or discontinuity), and the position of the CAT relative to the ventricles (above both ventricles, or predominantly over the right or left ventricle).

Figure 2.

Examples of abnormal configuration of the coronary orifices. (a) Pinpoint coronary orifice (arrow); (b) slit-like coronary orifice (arrow); (c) slit-like and supracommissural coronary orifice (arrow); (d) orificial ridge (arrow). PA, pulmonary artery; VSD, ventricular septal defect.

Statistical analysis

Statistical analysis was performed with Statview 5.0. The statistics were descriptive and expressed as mean ± SD. An anova test with Fisher's PLSD test was used for comparison of values between the different outflow tract defects and controls. Pearson's correlation test was used for studying the association between the position of the coronary orifices and the commissures in CAT. A P-value < 0.05 was considered statistically significant.

Results

Positioning of the coronary orifices on the aortic/truncal circumference

The position of LCOs and RCOs over the aortic/truncal circumference is shown in Fig. 3. Despite the great variability in the angles of LCOs and RCOs relative to the aortic/truncal circumference, there was some degree of clustering that allowed to perform statistical analysis.

Figure 3.

Position of the coronary orifices on the aortic/truncal valve circumference. (a) Position of the LCO, measured in degrees. (b) Position of the RCO, measured in degrees. CAT, common arterial trunk; DORV, double-outlet right ventricle with subaortic ventricular septal defect; TOF, tetralogy of Fallot; TOF&PA, tetralogy of Fallot with pulmonary atresia.

Position of the LCO

The LCO was more posterior in outflow tract defects compared with controls: the mean angle was 0 ° in controls, 31 ° in TOF (P < 0.005), 47 ° in TOF-PA (P < 0.0001), 44 ° in DORV (P = 0.0002) and 65 ° in CAT (P < 0.0001; Fig. 4).

Figure 4.

Position of the RCO over the aortic or truncal circumference in outflow tract defects compared with controls. Mean angle in degrees. CAT, common arterial trunk; DORV, double-outlet right ventricle with subaortic ventricular septal defect; TOF, tetralogy of Fallot; TOF&PA, tetralogy of Fallot with pulmonary atresia.

The LCO was significantly posteriorly displaced in CAT compared with all other outflow tract defects (P < 0.05).

Position of the RCO

The RCO was more anterior in TOF, TOF-PA and DORV compared with controls: the mean angle was 213 ° in control, 242 ° in TOF (P < 0.03), 245 ° in TOF-PA (P < 0.005) and 271 ° in DORV (P < 0.0001). The RCO was significantly more anterior in DORV than in TOF and TOF-PA (P < 0.05; Fig. 5).

Figure 5.

Position of the LCO over the aortic or truncal circumference in outflow tract defects compared with controls. Mean angle in degrees. CAT, common arterial trunk; DORV, double-outlet right ventricle with subaortic ventricular septal defect; TOF, tetralogy of Fallot; TOF&PA, tetralogy of Fallot with pulmonary atresia.

However, the mean angle in CAT (195 °) was not significantly different from controls.

Anterior intercoronary angle α

The α angle was similar in TOF (149 °), TOF-PA (162 °), DORV (133 °) and controls (147 °). It was significantly larger in CAT than in controls and other outflow tract defects (229 °, P < 0.0001), reflecting the posterior displacement of the LCO (Fig. 6).

Figure 6.

Measure of the anterior intercoronary angle α in various outflow tract defects. CAT, common arterial trunk; DORV, double-outlet right ventricle with subaortic ventricular septal defect; TOF, tetralogy of Fallot; TOF&PA, tetralogy of Fallot with pulmonary atresia.

Association between the position of the coronary orifices and the commissures in CAT

In the overall group of CAT, no correlation was found between the position of the LCO and the posterior commissure (r = 0.037, P = ns), nor between the position of the RCO and the right commissure (r = 0.28, P = ns). In CAT with a three-leaflet truncal valve, a correlation was found between the position of the RCO and the right commissure (r = 0.48, P = 0.02), but not between the position of the LCO and the posterior commissure (r = 0.12, P = ns).

Position of single, or two contiguous, coronary orifices

Two hearts with TOF had a single coronary orifice located anteriorly and to the left (20 ° and 30 °, respectively), supplying all three main coronary arteries. One heart with TOF-PA had two contiguous coronary orifices supplying, respectively, the right and left coronary arteries, located anteriorly (30 °). One heart with DORV had an anterior single coronary orifice (36 °), another had a posterior and left single coronary orifice (−22 °) with the right coronary artery coursing behind the aorta, and the last one had two posterior contiguous orifices supplying the right and left coronary arteries (−45 °).

Anatomy of the coronary orifices

CAT

We found at least one abnormal coronary orifice in 87% of the 46 heart specimens with CAT. The LCO was significantly more often abnormal than the RCO with regards to its shape or size (72% vs. 42%, P < 0.01; Table 1). The LCO was more often supracommissural than the RCO (17% vs. 2%, P < 0.05). There was no difference for the respective position of the coronary orifices relative to the sinotubular junction.

Table 1. Anomalies of the LCO
 CAT (= 46)TOF (= 15)TOF-PA (= 29)DORV (= 11)CTRL (= 17)
  1. CAT, common arterial trunk; CTRL, control hearts; DORV, double-outlet right ventricle with subaortic ventricular septal defect; TOF, tetralogy of Fallot; TOF-PA, tetralogy of Fallot with pulmonary atresia.

Shape/course
Normal1312261015
Pinpoint100100
Slit-like (orificial ridge)16 (2)02 (1)01 (1)
Tangential (intramural)7 (0)3 (2)01 (1)1 (0)
Location relative to commissures
Normal2115271017
Paracommissural160200
Supracommissural80010
Intracommissural10000
Location relative to sinotubular junction
Normal2613291116
Low situated40000
Above132000
Same level30001

Controls and other outflow tract defects

Coronary orifices anomalies were less commonly observed in controls and other outflow tract defects compared with CAT: 23.5% in controls had at least one abnormal coronary orifice, 17.2% in TOF-PA, 20% in TOF and 9% in DORV. The most frequent anomaly was tangential origin of one or both coronary arteries in six hearts with vertical intramural course in four (Table 2). There was no difference between LCOs and RCOs anomalies.

Table 2. Anomalies of the RCO
 CAT (= 46)TOF (= 15)TOF-PA (= 29)DORV (= 11)CTRL (= 17)
  1. CAT, common arterial trunk; CTRL, control hearts; DORV, double-outlet right ventricle with subaortic ventricular septal defect; TOF, tetralogy of Fallot; TOF-PA, tetralogy of Fallot with pulmonary atresia.

Shape/course
Normal2612251117
Pinpoint80100
Slit-like (orificial ridge)10 (1)02 (0)00
Tangential (intramural)1 (0)3 (2)1 (1)00
Location relative to commissures
Normal2915261116
Paracommissural140301
Supracommissural10000
Intracommissural20000
Location relative to sinotubular junction
Normal3315261117
Low situated50000
Above50300
Same level30000

Anatomical characteristics of the outflow tract defects

CAT

The different types of CAT were regrouped according to the dominance of either the systemic of pulmonary components of the CAT (Van Praagh, 1987; Jacobs, 2000; Russell et al. 2011).

  • Thirty-six CATs with aortic dominance with confluent pulmonary arteries (Type A1-2 of the modified Van Praagh classification).
  • Three CATs with aortic dominance with discontinuous pulmonary arteries (Type A3 of the modified Van Praagh classification).
  • Seven CATs with pulmonary dominance and interruption of the aortic arch (Type A4 of the modified Van Praagh classification).

The truncal valve had three leaflets in 36 cases, four leaflets in seven cases, two leaflets in the remaining three. Six hearts exhibited a complete muscular subtruncal infundibulum with mitral-to-truncal valve discontinuity. The CAT was entirely or predominantly above the right ventricle in 10 specimens, and entirely or predominantly above the left ventricle in five. We found no correlation between the position of the coronary orifices over the truncal circumference and the anatomical type of CAT, the number of leaflets of the truncal valve, and the degree of overriding of the truncal valve above the ventricles. The LCOs and RCOs were located in different sinuses in all hearts, except for one with a two-leaflet truncal valve, in which the two coronary orifices were contained in the posterior valvar sinus. When the truncal valve had four leaflets, the coronary orifices were located in opposite sinuses in all hearts but one.

Other outflow tract defects and controls

All specimens had a three-leaflet aortic valve. TOF-PA was divided into three groups according to the anatomy and morphology of the pulmonary circulation (Barbero-Marcial & Jatene, 1990; Tchervenkov & Roy, 2000).

  • Twelve TOF-PA with native pulmonary arteries and no major aortopulmonary collateral arteries (MAPCA).
  • Thirteen TOF-PA with both native pulmonary arteries and MAPCA present.
  • Four TOF-PA with no native pulmonary arteries, and MAPCA only.

No correlation was found between the position of the coronary orifices over the aortic circumference and the anatomical type of TOF-PA.

Discussion

Position of the coronary orifices on the aortic/truncal circumference

The position and the anatomy of coronary orifices have been extensively studied in CAT (Van Praagh & Van Praagh, 1965; Crupi et al. 1977; Shrivastava & Edwards, 1977; Anderson et al. 1978; Suzuki et al. 1989; De la Cruz et al. 1990; Bogers et al. 1993; Chiu et al. 2002). It appears from the different series that the positions of LCOs and RCOs are not randomly distributed over the aortic circumference but clustered leftward and posteriorly for the LCO, rightward and anteriorly for the RCO. Our present findings are concordant with what has been previously described in CAT.

In TOF, TOF-PA and DORV with subaortic ventricular septal defect, the anomalies of epicardial course and branching of coronary arteries are well described because of their surgical implications. Still, the position of the coronary orifices themselves has rarely been studied. Li et al. (1998) showed that the LCO was more posterior in TOF than in normal hearts, and attributed this finding to the anterior and rightward displacement of the aorta. Along the same line, the dextroposition of the aorta could explain the more anterior position of the RCO and potentially the abnormal branching of the left anterior descending coronary artery to the right coronary artery, with crossing of the subpulmonary infundibulum (Dabizzi et al. 1980; Li et al. 1998). Chiu et al. (2000) proposed that the position of the coronary arterial orifices in TOF is related with aortopulmonary rotation, as abnormal coronary arteries were more frequent when the aorta was more dextroposed. Figure 7 summarizes the position of the coronary orifices in our study according to the type of heart defect and in control hearts. Our initial hypothesis, according to the findings of Theveniau-Ruissy et al. (2008) on mouse embryos, was that the position of the coronary orifices may be determined by the spatial position of a ‘subpulmonary coronary-refractory myocardial domain’. This domain would be repulsive for the developing epicardial coronary arteries, which would have to circle around this repulsive domain to reach their respective aortic sinus. Experimental studies on mouse embryos have demonstrated that the normal positioning of the great arteries is achieved by a counterclockwise rotation of the myocardium at the base of the outflow tract, itself contributed by the anterior part of the second heart field (Bajolle et al. 2006), and by a ‘push’ of the pulmonary orifice in a rightward and anterior direction (Scherptong et al. 2012). The study of transgene 96-16, a marker of myocardium at the base of the pulmonary trunk, in Splotch mutant mouse embryos that display CAT and DORV, suggests that the abnormal position of the great arteries results from a premature arrest of, or a failure to initiate, outflow tract rotation (Bajolle et al. 2006) Outflow tract defects may then result from an abnormal rotation, which involves second heart field, in addition to abnormal septation, which involves neural crest cells (Waldo et al. 2005a,b).

Figure 7.

The position of the coronary orifices on the aortic/truncal circumference varies according to the degree of rotation of the outflow tract. In green, RCO; in black, LCO. CAT, common arterial trunk; DORV, double-outlet right ventricle with subaortic ventricular septal defect; TOF, tetralogy of Fallot; TOF-PA, tetralogy of Fallot with pulmonary atresia.

Therefore, we may suppose that in TOF, TOF-PA and DORV, the posterior displacement of the LCO and the anterior displacement of the RCO while the α angle remains constant might be related with an abnormal/incomplete rotation/growth of the subpulmonary myocardial coronary-refractory domain, associated with abnormal guidance of the septation at the junction between the subpulmonary and subaortic domain. In our study, the anterior displacement of the RCO was more important in DORV than in TOF and TOF-PA, which may indicate that the rotation is less achieved in DORV than in TOF and TOF-PA. This would agree with the results of previous human anatomical studies suggesting that the rotation is arrested at different developmental stages according to the type of outflow tract defect (Bostrom & Hutchins, 1988; Lomonico et al. 1988). These findings are also consistent with the anatomical study of Chiu et al. (2000), concluding that the coronary arterial pattern depends on the spatial relationship between the great vessels.

In CAT, we found that the α angle was much wider than in other outflow tract defects, due to a greater posterior displacement of the LCO, while the RCO is not displaced. CAT is characterized by a common ventriculo-arterial junction with a common arterial valve, due to failure of fusion of the outflow tract endocardial cushions, associated with a common distal intrapericardial channel (Van Praagh & Van Praagh, 1965). In CAT, the septation that would divide the CAT into aorta and pulmonary artery is missing, whereas in TOFs and DORV this septation is present but misplaced (Kirby, 2008). Consequently, the truncal circumference could be considered the addition of the ‘aortic’ and ‘pulmonary’ circumferences (Gittenberger-de Groot et al. 2002). In Splotch mutant mice hearts with CAT the transgene 96-16 is expressed in the left-hand part of the myocardium at the base of the single outflow vessel, whereas in normal heart its expression is located ventrally at the base of the pulmonary trunk (Bajolle et al. 2006). If we hypothesize that in human CAT the ‘coronary-refractory subpulmonary myocardial domain’ remains present under the ‘pulmonary part’ of the common trunk, this may explain the relative position of the two coronary orifices and the enlargement of the α angle. As shown in Fig. 8, the posterior displacement of the LCO might be due to the need for the left coronary artery to get around this hypothetical domain to reach the coronary permissive domain on the truncal circumference. In our series of CAT, we had no heart specimen with a single coronary orifice. However, in the study of Crupi et al. (1977), seven of eight single coronary orifices in hearts with CAT were located posteriorly and to the left, and only one anteriorly and to the left, which reinforces our hypothesis.

Figure 8.

The position of the coronary orifices in mice Tbx1+/−, in mice Tbx1−/− and in CAT in human. The hypothetical location of the myocardial subpulmonary domain is represented in blue. Ao, aorta; CAT, common arterial trunk; LCO, left coronary orifice; PT, pulmonary trunk; RCO, right coronary orifice.

The position of the RCO in CAT appears to be similar to that in normal heart, while one would have expected it to be positioned more ventrally than in other outflow tract defects. Actually, when Theveniau-Ruissy et al. (2008) analyzed the coronary pattern in Tbx1-null mice, they found that both RCOs and LCOs connected predominantly with the right/ventral aortic/truncal sinus, proximal coronary arteries coursing across the normally coronary-free ventral region of the outflow tract. This very peculiar pattern could be explained by a severe reduction of the subpulmonary myocardium, because these Tbx1-null mutants have dramatically reduced proliferation of the outflow progenitors in the secondary heart field (Theveniau-Ruissy et al. 2008). Indeed, a residual and malpositioned subpulmonary myocardial domain was identified at the dorsal/left side of the single vessel. Kirby (2008) suggested that the diagnosis of CAT in this mouse model could be revised for the diagnosis of unrecognized TOF-PA. In our series, we found only one ventrally positioned orifice in CAT: the RCO, the LCO in this specimen being left and posterior (Fig. 4). Our findings in human specimens suggest on the contrary that the truncal circumference has a dual identity, aortic coronary-permissive and pulmonary coronary-refractory. Finally, the differences in coronary arterial phenotype between Tbx1-null mouse model and human CAT indicate that the cardiac phenotype of animal mutants with a single vessel emanating from the heart should be clearly defined using specific markers of subpulmonary and subaortic myocardium rather than named CAT, TOF-PA or even aortic atresia with large pulmonary artery and conoventricular type ventricular septal defect (Kirby, 2008).

Anatomy of the coronary orifices

In CAT, the incidence of anomalies of coronary orifices is very high, varying from 50% to 70% in the different series (Bogers et al. 1993; Van Praagh & Van Praagh, 1965; Crupi et al. 1977; Anderson et al. 1978; Shrivastava & Edwards, 1977; Suzuki et al. 1989; De la Cruz et al. 1990; Chiu et al. 2002). The higher incidence of coronary orifices abnormalities in our study (87%) may be due to a bias in recruiting, as several hearts in our collection were referred for autopsy because of pre- or postoperative ischemic events or sudden death. We did not find any relation between the number of truncal valve leaflets, location of the commissures and connection of the coronary orifices. The LCO, more posterior in CAT, was found more frequently abnormal in shape, size and location relative to the sinotubular junction and the commissures than the RCO (Tables 1 and 2). This has also been extensively described and might be interpreted as a consequence of the necessary elongated course of the epicardial left coronary artery before it enters the aortic/truncal wall. Indeed, after passing over the coronary-refractory myocardial domain, the coronary artery enters the trunk at the nearest point of its epicardial course, independently of the anatomy of the sinuses or the leaflets. The mechanisms that lead to the final connection of the coronary arteries to the aorta are controversial, and certainly include a number of cellular and molecular regulations that are still unresolved. Still, the majority of the anomalies of the coronary orifices that we found correspond to radial misplacement on the truncal circumference, as it is observed in the majority of the misconnections to the aorta in isolated coronary artery malformations (Virmani et al. 1984; Basso et al. 2000). Surprisingly, in TOFs and DORV, we found a high incidence of abnormal connection of the coronary orifices above the sinotubular junction: TOFs, 3/44 and DORV, 1/11, with vertical intramural course of the first segment of the coronary artery. This abnormal longitudinal placement of the coronary orifice in these defects is more difficult to understand using the hypothetic role of the myocardial subpulmonary domain.

Concluding remarks

The position and configuration of the coronary artery orifices are often abnormal in CAT and other outflow tract defects. However, these anomalies are different according to the type of defect involved. In TOF, TOF-PA and DORV, the degree of displacement of the coronary orifices depends on the lack of rotation of the outflow tract. This could be due to the change of location of the subpulmonary domain, which does not achieve its final anterior position. The α angle is constant in all outflow tract defects but CAT, which can potentially be explained by the dual aortic and pulmonary identity of the common vessel. Along the same line, the abnormal configuration of the coronary orifices, more frequent in CAT than in other outflow tract defects, could be related with this dual identity leading to a misplacement of the subpulmonary coronary-refractory myocardial domain during heart development.

Our results also suggest that the cardiac phenotypes found in animal models should be carefully interpreted when compared with those found in humans.

Acknowledgements

We thank Robert G. Kelly, Stéphane Zaffran and Robert H. Anderson for stimulating discussions. This work was supported by the Agence Nationale de la Recherche (ANR-07-MRAR-003).

Conflict of interest

None declared.

Author contributions

LH and FB both conceived and realized the anatomical study, and drafted the manuscript. AC conducted the statistical analysis of data. DL and PP participated in the interpretation of results. DB participated in drafting the manuscript and critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Ancillary