Clarifying the anatomy of tetralogy of Fallot with S-shaped ascending aorta

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Abstract Background
We recently encountered several cases of tetralogy of Fallot with an abnormally oriented S-shaped ascending aorta.In this retrospective study, we sought to clarify morphology of this unusual underrecognized variant.

Methods and results
Databases were reviewed to identify all patients with tetralogy of Fallot having an S-shaped ascending aorta.Computed tomographic angiography was used for the assessment of cardiac morphology.Out of the 21 patients, 18 (86%) had a right aortic arch, 2 (9%) had a left aortic arch, and the remaining patient (5%) had a double aortic arch.Patients with a right aortic arch, compared to age and sex-matched patients with a right aortic arch but normally oriented ascending aorta, had lesser aortic override (29.3±14% vs 54.8±13.2%;p = 0.0001) and a wider ascending aorta (25.2±6.9 vs 18.0±3.2mm; p = 0.0003).The S-shaped ascending aorta was located posteriorly, with a higher sterno-aortic distance (25.5±7.7 vs 9.9±4.5 mm; p = 0.0001).The ascending aorta was longer (4.12±1.7 vs 3.07±0.82,p = 0.03) but with similar tortuosity index (1.22±0.19vs 1.15±0.17,p = 0.23).Of the cases with right aortic arch and S-shaped ascending aorta, 16 (89%) had extrinsic compression of the right pulmonary artery (p = 0.0001), while 7 (39%) had crossed pulmonary arteries (p = 0.008), with no such ndings among those with normally oriented ascending aorta.

Conclusion
Tetralogy of Fallot with an S-shaped ascending aorta is a variant with lesser aortic override and a more posteriorly located ascending aorta.Compression of the right pulmonary artery and crossed pulmonary arteries is frequent in the presence of a right-sided aortic arch.

What is already known?
Tetralogy of Fallot (TOF) has characteristic cardiac morphology with variation mostly limited to the pulmonary vasculature.As reported in a case of TOF with a right aortic arch, an unusually tortuous ascending aorta can cause extrinsic compression of the right pulmonary artery necessitating LeCompte maneuver during surgical repair.

What does this study add?
The study provides a detailed account of an unusual yet under-recognized morphological variant of TOF with an S-shaped tortuous ascending aorta.Besides lesser aortic override and more posteriorly located ascending aorta, when present in the setting of a right aortic arch, such patients with TOF have a higher occurrence of compression of the right pulmonary artery and crossed pulmonary arteries.

Introduction
Tetralogy of Fallot is one of the most common congenital heart diseases causing arterial desaturation.Its phenotypic feature is anterocephalad deviation of the outlet septum coupled with abnormal septoparietal trabeculations, thus producing a malaligned ventricular septal defect and right ventricular out ow tract obstruction.(1-3) While the dimensions of the pulmonary arteries are the main determinant for surgical repair, other morphological factors also alter the surgical technique and outcomes.Besides its phenotypic features, there is a wide spectrum of associated morphological abnormalities (1)(2)(3)(4)(5).Some of these may be benign variations, whereas others have signi cant implications for surgical management.While echocardiography remains the main diagnostic imaging modality, other imaging modalities, such as computed tomographic angiography, catheter angiography, or magnetic resonance imaging, are often performed for preoperative assessment (5).Computed tomographic angiography in particular, owing to its high spatial resolution, provides excellent visualization of both the cardiac and extracardiac anatomy (6-9).Some time ago, we reported a patient whose right pulmonary artery was unusually compressed by a tortuous aorta.In this patient, the left pulmonary artery was not arising from the pulmonary trunk but instead was supplied by a restrictive patent arterial duct (10).Unlike other cases with a right aortic arch, despite its usual origin from the heart, the ascending aorta was tortuous, with its proximal part lying unusually leftward and posteriorly.The child successfully underwent surgical repair with a transannular patch and reimplantation of the left pulmonary artery.Aortic transection and the Lecompte maneuver were deemed necessary to relieve extrinsic compression of the right pulmonary artery (10)(11)(12).Since then, we have encountered several additional cases with abnormally oriented and tortuous ascending aorta, the majority having extrinsic compression of the mid-segment of the right pulmonary artery.(13) A detailed review of the literature indicated a paucity of information about this particular variant.In this retrospective study, therefore, we sought to clarify the morphology of this unusual variant of tetralogy of Fallot with S-shaped ascending aorta, using computed tomographic angiography as the main imaging modality.

Methods
Following approval from the institutional ethics committee, we searched our databases from January 2012 to October 2023 to identify all patients with tetralogy of Fallot and abnormally oriented ascending aorta.The demographic details were obtained from medical records.All patients had had echocardiographic evaluation by a pediatric cardiologist, and computed tomographic evaluation by a cardiac radiologist.In select cases, cardiac catheterization studies had also been performed by a pediatric cardiologist.Computed tomographic studies were analyzed using a Syngovia workstation (Siemens Healthcare, Germany).All the imaging data were retrospectively analyzed independently by a pediatric cardiologist and a cardiac radiologist.The differences were resolved by consensus, obtaining inputs from other pediatric cardiologists and cardiac radiologists.Besides the identi ed cases, we also analyzed computed tomographic angiograms of age and sex-matched patients having tetralogy of Fallot with normally oriented ascending aorta.Since the majority of patients with abnormally oriented ascending aorta had a right aortic arch, the comparison was made only for those with a right aortic arch.For each case, we included one age and sex-matched control.After evaluating the segmental cardiac anatomy, we analyzed all the morphological variables in a prede ned fashion, placing special emphasis on the spatial relationship of the arterial valves, the orientation of great arteries, the arrangement of the right and left pulmonary arteries, and the sidedness of the aortic arch.We also noted the presence of crossing of the pulmonary arteries, the origin and course of coronary arteries, and any anomalies of the aortic arch.The analysis of the aortic root and aorta was performed after obtaining the true short axis of the aortic root using the double oblique technique.( 14) After a multiplanar assessment, all measurements were made in two orthogonal planes.The analysis was supplemented by volume rendering and virtual dissection (9).
The sterno-aortic and sterno-vertebral distances were measured to de ne the relative position of the ascending aorta in the mediastinum.The distance between the ascending aorta and sternum was taken midway between the sinutubular junction and the origin of the rst branch of the aorta (Fig. 1A).The length of the ascending aorta was assessed by measuring its length in the centreline, as well as the shortest length between the sinutubular junction and the rst brachiocephalic artery.We then calculated the tortuosity index, de ned as the ratio between the centreline distance and the shortest length of ascending aorta (Fig. 1B).(15)

Statistical analysis
Categorical data were represented by percentages or frequencies.They were compared using Fisher's exact test.Continuous variables were summarized as median with range, or mean with standard deviations, and were compared using an independent two-tailed t-test.A p-value of < 0.05 was considered statistically signi cant.All statistical analyses were performed using IBM SPSS V.23 software.

Results
We identi ed 21 patients with abnormally oriented ascending aorta.The age of the patients ranged from 2 months to 21 years.Their oxygen saturation ranged from 65 to 85%.All had normal sequential segmental anatomy.In all patients, there was a solitary large malaligned ventricular septal defect and an obstructed right ventricular out ow tract (Figs. 2 and 3; Videos 1-3).All except one patient had brous continuity between the lea ets of the aortic and mitral valves.
Video 1. Echocardiogram in subcostal view shows a malaligned ventricular septal defect characteristic of tetralogy of Fallot but with less than 50% aortic override and a posteriorly located tortuous ascending aorta.Video 2. A catheter angiogram in the left anterior oblique view with cranial angulation shows a malaligned ventricular septal defect characteristic of tetralogy of Fallot but with less than 50% aortic override and a posteriorly located tortuous ascending aorta.Video 3. A catheter angiogram in the anteroposterior view shows a malaligned ventricular septal defect characteristic of tetralogy of Fallot but with less than 50% aortic override and a posteriorly located tortuous ascending aorta.

Ventricular out ows, aortic override, arterial valves and arterial trunks
In all cases, the ventricular out ow tracts were normally oriented, with aortic override ranging from 10 to 45%.The override was signi cantly less in cases with a right-sided aortic arch compared to controls having a normal orientation of the ascending aorta (29.3±14% vs 54.8±13.2%,p 0.0001) (Table 1; Figs. 2   and 3; Videos 1-3).
One patient had pulmonary atresia.In the remaining 20 patients with pulmonary stenosis, the pulmonary valve was superior to the aortic valve, being to the left and anterior of the aortic valve in 17 patients (88%).In 1 (5%) patient, the arterial valves were side by side, with the aortic valve lying to the right of the pulmonary valve.In the other 2 (10%) patients, the pulmonary valve was located right and anterior to the aortic valve.In most patients, we noted that the subpulmonary out ow tract was poorly visualized on transthoracic echocardiography.

Ascending aortic length, orientation, and tortuosity
In all patients, the ascending aorta was tortuous, producing an S-shaped orientation when viewed from the head end (Figs. 1 and 4 and Video 4).The tortuosity was less pronounced among patients with leftsided and double aortic arches.Compared to controls, those with right-sided aortic arch had longer ascending aorta (41.2±17.0mm vs 30.7±8.2 mm, p 0.025), although the tortuosity index, as well as the shortest distance between the sinutubular junction and the rst aortic branch, were not different (Table 1).
Video 4. Virtual dissection follow-through obtained by modi ed volume rendering of a computed tomographic dataset shows details of the intracardiac anatomy, arterial trunks, and pulmonary arteries.

Right ventricular out ow tract and pulmonary arteries
The right ventricular out ow tract was obstructed in all patients.It was atretic in one patient, with all the remainder having subpulmonary stenosis.The length of the pulmonary trunk was not different from the controls (Table 1).Of the 18 cases with right aortic arch, 16 (89%) had compression of the mid-segment of the right pulmonary artery.No such compression was found in the remaining 5 (28%) patients.Of these patients, 2 had a right arch, 2 a left arch, and the remaining a double arch.In those with compression of the right pulmonary artery, it involved the mid-segment near the right bronchus.The compression in the anteroposterior direction gave the right pulmonary artery an oval shape (Figs.2C and 5 and Video 5).In addition, 3 (21%) of our patients, and 1 control, also had stenosis or atresia of the ori ce of the left pulmonary artery.In 7 of our 18 (39%) cases with right arch, the pulmonary arteries were crossed, a feature not found either in the controls or in the patients with left or double aortic arch (Figs.2C and 5C).
Video 5. Multiplanar reformatting of computed tomographic dataset showing extrinsic compression of the right pulmonary artery by dilated and tortuous ascending aorta.

Branching of aortic arch
The aortic arch was right-sided in 18 (86%) patients, being left-sided in 2 (9%), and double in the other (5%).In all except 3 patients, the branching pattern of the brachiocephalic vessels was as expected for the side of the aortic arch.The patient with a double aortic arch had the left common carotid and left subclavian arteries arising from the left arch, while the comparable right-sided vessels arose from the right arch.Another patient with a right-sided aortic arch had isolation of the left subclavian artery, while 1 patient had an aberrant retroesophageal left subclavian artery.

Coronary arteries
The coronary arteries arose in a normal fashion in all but one patient.In the outstanding patient, who had a right-sided aortic arch, the left circum ex coronary artery arose from the right coronary artery taking a retro-aortic course.

Discussion
Tetralogy of Fallot is immediately recognizable based on a malaligned ventricular septal defect and characteristic infundibular phenotype.Morphologic variations are well recognized.It seems, however, that the variant with an S-shaped aorta has thus far escaped attention.We have now discovered this unusual nding in 21 of our patients.The tortuous aorta is part of a relatively uniform constellation of abnormalities.Not only is the ascending aorta dilated and tortuous, but it is also located relatively posteriorly.In those with right-sided aortic arch, this results in overcrowding of vascular structures in the posterior mediastinum, producing anteroposterior compression of the mid-segment of the right pulmonary artery between the ascending aorta anteriorly, and the right bronchus and the right-sided descending aorta posteriorly.In contrast, despite similar tortuosity of the ascending aorta, compression of the right pulmonary artery was lacking in those with left-sided and double arches.The older age of patients possibly explains our nding of frequent compression of the right pulmonary artery as aortic dilation is known to be progressive and age-dependent in tetralogy of Fallot.Also, aortic dilation is inversely proportional to the ow of blood through the pulmonary arteries.Those with less pulmonary ow tend to have larger aorta and smaller right pulmonary artery, leading to an increased likelihood of compression.Recognition of the extrinsic compression as the cause of the narrowing of the right pulmonary artery is important in these patients.As in the treatment of our rst case, (10) the Lecompte maneuver, or aortopexy, may be needed to achieve sustained relief from the extrinsic compression produced by the dilated ascending aorta (16).
Crossing of the pulmonary arteries is also unusual in patients with tetralogy of Fallot (17).More than onethird of our patients with right aortic arch, nonetheless, had crossed pulmonary arteries.We speculate that the coexistence of this nding with the tortuous ascending aorta may indicate abnormal rotation of the developing proximal out ow tract and arterial trunks as the underlying mechanism producing tetralogy of Fallot with S-shaped ascending aorta.
The aortic override was much less in our patients than in their controls.This, again, is unlike the usual situation with tetralogy of Fallot.In an autopsy study, the aortic override was found to range from 31 to 100%, with most individuals having greater than 50% override.(18) In our study, all of our patients had an override of less than 45%.(18) An abnormal location of the aortic valve relative to the pulmonary valve, furthermore, was observed in only 3% of the autopsy specimens.(18) The nding of an abnormally located aortic valve in one-tenth of our cohort likely re ects the selective inclusion of patients with tortuous ascending aorta.
We were perplexed to nd such a large number of patients with a seemingly unrecognized variant of tetralogy of Fallot.While making a more detailed literature review, we found that a tortuous ascending aorta is also part of the unusual arrangement variously described as 'anatomically corrected malposition of great arteries', 'isolated infundibuloarterial inversion', or 'TOF {S,D,I}'.(19)(20)(21)(22)(23).The additional feature proposed for these cases, however, is that the arterial trunks extend in side-by-side fashion into the mediastinum, rather than spiralling as was the situation in our cases.While an unusually lesser degree of override, combined with the more posterior location of the aortic valve, gives an appearance of side-byside arterial trunks, the overall anatomy remains that of tetralogy of Fallot.Moreover, since the surgical management is similar to tetralogy of Fallot, we believe that it is better to describe details of the overall arrangement of the ventricular out ows and arterial trunks in such situations (24,25).It is arguably the use of ill-de ned terminologies, such as "infundibulo-arterial inversion", and the lack of a systematic approach, which has left the S-shaped tortuous ascending aorta as an unrecognized entity, despite its unique morphologic characteristics.One of the cases previously reported by one of us has all the features we have now encountered in our overall series.On a detailed review, we realized that the case has no speci c morphologic characteristics to justify the previously chosen label of isolated "infundibulo-arterial inversion".(13) Our ongoing experience exempli es the di culties that have previously been encountered in understanding ill-de ned variants of common cardiac malformations.Several of the previously described examples of tetralogy of Fallot with alleged "infundibulo-arterial inversion" have striking similarities to our cases.(13,16,21).Not only was the ascending aorta tortuous in some of these but the pulmonary arteries were also crossed, just as we have observed (13,16).Compression of the right pulmonary artery was not seen in the case reported by Nelson and colleagues, which had side-by-side arterial trunks, but there was extrinsic compression of the distal right bronchus (16).The authors attributed the nding to a low-lying dilated transverse arch.It is possible, nonetheless, that the mechanism could be the same as in our cases.The lack of compression of the right pulmonary artery in their case may well be related to the young age of the patient.
Based on the ndings of our study, we suggest that a nding of less than 50% aortic override, and any suggestion of tortuosity of the aorta during the echocardiographic study, should immediately raise the suspicion of an S-shaped ascending aorta.Di culty in visualizing the subpulmonary infundibulum during echocardiography could also provide a clue towards the diagnosis.This should also prompt a detailed assessment of the right pulmonary artery for any extrinsic compression.With our own increased experience, we have now been able to identify many of our patients con dently using echocardiography, although computed tomographic angiography was performed to delineate the morphologic ndings to optimize the planned surgical intervention.

Limitation
We recognize that our study is limited by its retrospective nature which did not permit adjustment of various measurements to the body surface area.There could be an association with DiGeorge syndrome, but genetic testing could not be performed.Only a few patients underwent surgery, so surgical correlation was not possible.

Conclusion
We conclude that a tortuous and S-shaped ascending aorta is a distinct morphologic variant of tetralogy of Fallot with important clinical and surgical implications.We hope our ndings might help others in the prompt detection and appropriate surgical planning of this unusual under-recognized variant.

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Table 1
Demographic and morphologic characteristics of patients with tetralogy of Fallot having right aortic arch with S-shaped or normally oriented ascending aorta