The surgical anatomy of hearts with isomeric atrial appendages—implications for surgical management

Abstract

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OBJECTIVES

The most severe combinations of cardiac malformations exist in individuals having jumbled-up thoracic and abdominal organs. These patients make up 2 distinct syndromes. As yet, the consensus is lacking on how best to describe the subsets. The subsets are frequently grouped together in terms of ‘heterotaxy’. The surgical approaches to the subsets, however, are markedly different. We reviewed our experiences with regard to the anatomy as observed in the autopsy room, by the analysis of computed tomographic studies, and in the operating room, to assess whether the lesions might be segregated on the basis of isomerism of the atrial appendages.

METHODS AND RESULTS

A review of our findings from the examination of specimens from several archives, along with investigation of a large cohort of patients being prepared for surgical treatment, showed that individuals can uniformly be segregated into subgroups on the basis of isomeric arrangement of the atrial appendages. In all instances, this was made possible by using the criterion of the extent of the pectinate muscles within the appendages as judged relative to the atrial vestibules. Segregation on this basis, which correlated excellently with the bronchial arrangement, sets the scene for an appropriate description of the remainder of the heart, providing the cardiac surgeon with all the inferences required for appropriate surgical intervention.

CONCLUSIONS

When assessing individuals having the features of so-called ‘heterotaxy’, it is possible to segregate the groups into subsets of individuals having either isomeric right or left atrial appendages. This approach provides the framework for the assessment of appropriate surgical management.

INTRODUCTION

Although the cardiac surgeon does not specifically operate on the atrial appendages themselves, it is a well-recognized fact, that hearts in which the appendages are isomeric rather than lateralized harbour some of the most complex combinations of lesions to be found in the setting of congenital cardiac disease. It is a well-recognized fact, nonetheless, that hearts with isomeric atrial appendages harbour some of the most complex combinations of lesions to be found when the heart itself is congenitally malformed. It is equally well-recognized that, within the overall group of hearts, there are 2 specific subsets. As yet, however, there is no consensus as to how these subsets should be differentiated. Some experts, for example, held that isomerism, now acknowledged as a potential discriminating feature [1], was no more than a useful mnemonic [2]. Conventional wisdom, at that time, was that the overall arrangement of the organs in this setting was ambiguous, with the subsets segregated on the basis of splenic anatomy [3]. Just as with the atrial appendages, it is equally true that the cardiac surgeon does not operate on the spleen, although this is not to discount the potential significance of the splenic lesions in diminishing the immunological state of the patients [4]. It has subsequently become evident, thanks to the experiments made by molecular biologists, that isomerism within the heart is a real thing, but that the isomeric features are to be found only in the arrangement of the atrial appendages [1]. Despite this, the influence of the isomeric features can be recognized within the overall make-up of the heart and is paralleled closely by the arrangement of the lungs and bronchuses [5]. Although changes are also to be found in the abdominal organs, these are much less harmonious with the cardiac features. They do not illustrate the direct features of isomerism as observed in the lungs, bronchuses and the atrial appendages [6, 7].

In terms of the cardiac features, the case has been made that the 2 subsets of hearts making up the overall group, still commonly described in terms of heterotaxy, are better differentiated on the basis of the presence of either isomeric left or isomeric right atrial appendages [8]. In this regard, it was shown some time ago that the appendages themselves could readily be distinguished according to the extent of the pectinate muscles they contain when judged relative to the vestibules of the atrioventricular junctions [6]. Further controversies had raged as to whether these features could be distinguished during life, particularly when using cross-sectional echocardiography. The emergence of techniques that permit the creation of three-dimensional datasets has diminished these criticisms, the more so since these techniques also show well the arrangement of the bronchial tree, which is known to correlate in excellent fashion with the arrangement of the atrial appendages [5]. In the current era, therefore, the cardiac surgeon should be forewarned of the presence of isomeric atrial appendages in the patients coming forward for operative repair. Knowledge of the likely associations of these findings is then likely to be of great significance when considering the procedures to be undertaken, which have long been recognized to have much better outcomes in those with isomeric left as opposed to isomeric right appendages [9, 10]. In this review, we have used our previous experiences to assess the significance of the features of the different intracardiac lesions to be found in patients with isomeric right as opposed to isomeric left atrial appendages. We have then assessed the potential implications of these features for those contemplating the surgical interventions likely to be undertaken in these settings. We have also compared the accuracy of demonstrating, using multidetector computed tomography, the features as observed in autopsied specimens.

THE DISTINCTION BETWEEN HEARTS HAVING ISOMERIC RIGHT AS OPPOSED TO ISOMERIC LEFT ATRIAL APPENDAGES

It was shown 40 years ago that, in the greater majority of congenitally malformed hearts, it was possible, on the basis of their shapes, to distinguish the morphologically right from the morphologically left atrial appendage [11]. At the time, those who continued to prefer to separate so-called ‘heterotaxy’ into the subsets of asplenia and polysplenia, arguing that the overall atrial arrangement was ambiguous in this setting, pointed out that the shape of the appendages could be altered by abnormal haemodynamics [2]. From the stance of the cardiac surgeon, it was also true that the initial shape could be altered by subsequent intracardiac operative procedures. The validity of the criticism regarding the use of shape as an arbiter was subsequently confirmed in an investigation of large group of autopsied hearts collected together on the basis of ‘visceral heterotaxy’ [6]. The same investigation did show that the hearts could be segregated into subsets of isomeric right or isomeric left appendages when taking note of the extent of the pectinate muscles. This investigation, confirmed by the findings of another large investigation [7], also showed the excellent correlation that existed between the morphology of the appendages, when using the criterion of the extent of the pectinate muscles, and the bronchial arrangement (Fig. 1).

It still remains a fact that cases occur in which there is disharmony between the arrangement of the atrial appendages and the bronchial morphology, with still further disharmony between the arrangement of the thoracic and abdominal organs [12]. Such disharmony does not invalidate using the morphology of the atrial appendages as the starting point for subsequent analysis of the intracardiac anatomy. It is the atrial arrangement that provides a better guide to the anticipated intracardiac findings [1]. The surgeon requiring to perform any intraoperative procedure is likely to enter through the right-sided atrial chamber. When using the extent of the pectinate muscles, along with the observed shape, it should always be possible for the surgeon to differentiate between morphologically right and morphologically left-sided appendages. When combining this information with the knowledge now available from the preoperative investigations, therefore, the surgeon should now be able to proceed with confidence in terms of whether the procedure is to be undertaken in the setting or right or left isomerism.

THE ANTICIPATED INTRACARDIAC FEATURES OF RIGHT ISOMERISM

The surgeon approaching the individual with isomeric right atrial appendages will note the broad triangular nature of the right-sided appendage, which will be separated by an extensive terminal groove from the venous atrial component on that side (Fig. 2C). In most instances, this will be the venous component draining the systemic veins, but in a proportion of individuals, all 4 pulmonary veins will be found returning to the roof of the right-sided atrium [13]. In these unusual settings, along with those where the pulmonary veins drain in midline fashion to the atrial roof (Fig. 2B), the finding of a terminal groove separating the pectinated appendage from the venous component, along with the pectinate muscles encircling the right-sided vestibule, and extending to the cardiac crux, will confirm that the right-sided appendage is morphologically right. Examination of the other atrial chamber will then confirm the presence of isomeric right atrial appendages, since the pectinate muscles will reach the cardiac crux on both sides (Fig. 2A). It is the presence of pectinate muscles extending to the crux of the heart on both sides that is the essence of isomeric right atrial appendages (Fig. 2). This feature is best seen when there is a common atrioventricular junction, itself an anticipated finding in the setting of right isomerism. Since there are always morphologically right appendages bilaterally in this setting, it follows that the pulmonary venous connections will always be anatomically anomalous, although the veins can connect to one or other of the atrial chambers. In around half of the hearts with right isomerism, in fact, there will be a cardiac totally anomalous pulmonary venous connection. Most usually this is through the midline confluence, which itself connects to the atrial roof between the right-sided and left-sided appendages (Figs 2B and 3A). In a minority of individuals, however, the veins can connect to the roof of either the right-sided chamber (Fig. 3B) or the left-sided atrial chamber, both having a morphologically right appendage (Fig. 4).

The channel between the confluence and the atrial cavities then possesses the capacity to become stenotic, a feature of surgical significance. Since both atrial appendages are morphologically right, it is also the rule to find terminal grooves and terminal crests on both sides (Fig. 2). This is also frequently associated with the presence bilaterally of superior caval veins, which connect directly with the atrial roofs (Fig. 4B). It is a universal finding for the coronary sinus to be absent when both appendages are morphologically right. In the past, the finding of the 2 caval veins connecting with the atrial roof has been interpreted on the basis of ‘unroofing’ of the coronary sinus. This is incorrect. The coronary sinus has never been formed in this setting. Because of its absence, the coronary veins drain directly into the atrial cavities, usually at the level of the vestibules, but on occasion at a distance from the atrioventricular junction. The abnormal coronary venous drainage is another feature of potential surgical significance [14].

In the majority of instances, the presence of the isomeric atrial appendages will result in abnormal patterns of venous return, particularly since it is frequent to find the presence bilaterally of hepatic veins. It is most unusual, however, to find interruption of the inferior caval vein when there is right isomerism. As we will see, this finding is highly suggestive of left isomerism. In some individuals with isomeric right appendages, nonetheless, all of the pulmonary veins can drain to either the right-sided chamber (Figs 3B and 4C) or the left-sided atrial chamber, when all the systemic veins connect to the other atrial chamber. Such findings, which produce quasi-usual or quasi-mirror-imaged venous drainage, do not detract from the fact that the atrial arrangement remains that of right isomerism. It is the morphology of the atrial appendages, rather than the patterns of venous drainage, which determines the atrial arrangement.

This feature becomes increasingly important when describing the arrangement of the remainder of the heart. When both atrial chambers connect with the ventricular mass in the setting of right isomerism, this is typically through a common atrioventricular junction. The atrial septum, furthermore, is frequently represented by no more than a myocardial strand. It is then frequent for the common junction itself to be connected exclusively to one or other ventricle, with double inlet right ventricle through a common atrioventricular valve being a frequent finding. In many instances, each of the atrial chambers is connected to its own ventricle across the common junction. We used to describe such biventricular atrioventricular connections as being ‘ambiguous’. We now recognize that, in reality, they are mixed. This is because, when each atrium with an isomeric right appendage is connected to its own ventricle, half of the heart will be concordantly connected, while the other half will be discordantly connected. The biventricular atrioventricular connections, therefore, are mixed (Fig. 5).

Although usually found with a common atrioventricular valve, the mixed connections can also be through separate mitral and tricuspid valves. So as fully to describe this arrangement, it is then necessary also to account for the topological arrangement of the ventricular mass, which can be right handed or left handed (Fig. 5). Individuals having this arrangement in the setting of left-handed ventricular topology should not then be considered to have congenitally corrected transposition, even if there is quasi-usual venous return and discordant ventriculo-arterial connections. The atrial morphology will still be that of right isomerism. This means there will be absence of the coronary sinus, bilateral sinus nodes, and totally anomalous pulmonary venous connection, even if the drainage of the pulmonary veins is to the left-sided atrial chamber. In the setting of the common atrioventricular valve, it is also frequent in this setting to have duplicated atrioventricular nodes, producing the so-called Monckeberg sling [15].

Additional abnormal features should always then be expected at the ventriculo-arterial junctions. It is very unusual to find concordant ventriculo-arterial connections. Most usually the connection is that of double outlet right ventricle, or else there is transposition, transposition in this setting being defined as discordant ventriculo-arterial connections. It is also usual to find either obstruction or atresia of the outflow tract of the morphologically right ventricle. It is very rare to find a common arterial trunk. It is also unusual to find the arrangement of tetralogy of Fallot, although it can occur. In most instances, if there is pulmonary atresia, then the pulmonary arteries themselves are fed through an arterial duct, which can be right or left sided. On occasion, the pulmonary arteries must be anticipated to be discontinuous. There will then usually be bilateral arterial ducts. The aortic arch, along with the cardiac apex, can be right sided or left sided. These features do not serve to distinguish between the 2 subsets of so-called heterotaxy. It is the morphology of the atrial appendages that provides the best means of discriminating the subsets.

THE ANTICIPATED INTRACARDIAC FEATURES OF LEFT ISOMERISM

As with the other subset of hearts found in the setting of so-called heterotaxy, the distinguishing feature for the cardiac surgeon of left isomerism is the morphology of the right-sided atrial appendage. This is the more significant in the setting of left isomerism, since the finding of a long and tubular atrial appendage, if seen in the operating room, is indicative of either left isomerism or mirror-imaged atrial arrangement. Access to the preoperative images should now permit differentiation between these options, most obviously because, in almost all cases, the bronchial arrangement will be harmonious with the arrangement of the atrial appendages (Fig. 6). On occasion, it may be difficult, even in the autopsy room, to distinguish the left atrial appendage simply on its shape. It is the extent of the pectinate muscles relative to the right-sided atrioventricular junction that will serve as the distinguishing feature. There is always a smooth vestibule between the margin of the appendage and the cardiac crux when the appendage is of left morphology (Fig. 7).

The features of left bronchial morphology should now be readily apparent from clinical imaging (Fig. 8). In the setting of left isomerism, the left-sided appendage will also obviously be of left morphology (Fig. 7A). It is not surprising, since both atriums have a morphologically left appendage, that the pulmonary venous connections, in contrast to the arrangement in right isomerism, are almost always morphologically normal. Symmetrical drainage, with 2 pulmonary veins connecting to an atrium on each side, is a frequent finding (Fig. 6B). Should all pulmonary veins be connected to one or other of the atrial cavities, then it is again frequent to find quasi-usual (Fig. 7B) or quasi-mirror-imaged venous drainage. As with right isomerism, this should not be interpreted as evidence of a usual or mirror-imaged atrial arrangement. It is the morphology of the atrial appendages that is the defining feature (Fig. 7).

In the setting of left isomerism, although the pulmonary veins are usually normally connected, even if bilaterally symmetrical, it is the rule to find anomalies in the systemic venoatrial connections. The most usual finding is interruption of the inferior caval vein, with continuation through the azygous venous system. The connection can then be to either a right-sided superior caval vein or a left-sided superior caval vein. This feature is easy to identify using clinical imaging (Fig. 8). The finding of interruption of the inferior caval vein should always arouse the suspicion of left isomerism, but it can be found with usual atrial arrangement, even when there are multiple spleens and left bronchial isomerism [16]. In the latter setting, the intracardiac anatomy is usually normal, providing further evidence that the arrangement of the appendages provides the best guide to intracardiac anatomy. As with right isomerism, it is frequent in left isomerism to find bilateral superior caval veins. Unlike the situation in right isomerism, where each caval vein connects to the atrial roof alongside a terminal crest, the veins in left isomerism connect in the form of a coronary sinus. Thus, drainage of one or other vein through a coronary sinus is a frequent finding. The other caval vein in this setting then shows various degrees of ‘unroofing’. When the coronary sinus is present, it also receives the venous drainage from the heart. In a minority of cases, the coronary sinus can be absent, usually with a common atrium and absence of any atrial septation. The coronary veins then connect to the atrial chambers directly, as is uniformly the case in the setting of right isomerism.

The atrial septum is typically much better formed in left as opposed to right isomerism. Oftentimes, there is a common atrioventricular junction, guarded by either a common atrioventricular valve or separate right and left atrioventricular valves. With isomeric left atrial appendages, this arrangement is typically seen with biventricular and mixed atrioventricular connections. It is much more frequent, when there is left isomerism, to find concordant ventriculo-arterial connections. This can produce the arrangement, when there is left-handed ventricular topology, of the seemingly paradoxical situation of ‘isolated ventricular discordance’. In reality, the situation is the consequence of either quasi-usual venoatrial connections and mixed atrioventricular connections with left-handed ventricular topology, or quasi-mirror-imaged venoatrial connections and right-handed ventricular topology. The concordant arterial trunks in these arrangements will be seen to leave the ventricular mass in a spiralling fashion. Examples with different atrioventricular and ventriculo-arterial connections do occur. It is much more frequent with left isomerism to find the patterns producing relatively normal circulations. If the obstruction is found within the ventricular outflow tracts, it is usually the left ventricle that is involved. Hence, it is also frequent to find aortic coarctation, or interruption when the outflow obstruction is extreme. Because of the isomeric left atrial appendages, the sinus node is always abnormal. If present, it is typically displaced towards the atrioventricular junctions and is hypoplastic [15]. It is also much more frequent to find complete atrioventricular dissociation when there are isomeric left atrial appendages, often in foetal life, although this can also be found with right isomerism.

DISCUSSION

It has long been recognized that 2 discrete subsets of cardiac lesions are to be found in the setting of so-called ‘heterotaxy’. The differences between the sets are as great as the differences between chalk and cheese. There has been much discussion on how best to describe and account for the differences [2, 3, 6, 7]. When the final decision regarding the difference was reached in the autopsy room, it was reasonable to distinguish between cases having multiple spleens as opposed to those with the absence of the spleen [3]. Careful comparison of the arrangement between the different systems now reveals that the splenic arrangement is frequently discordant with the pattern of the thoracic organs, including the heart [6, 7]. The arrangement of the bronchial tree provides a much better guide to an atrial arrangement [17]. Discrepancies do still occur between bronchial and atrial arrangement, even if such disharmony is much rarer than found with the abdominal organs. The obvious answer to these dilemmas is to determine atrial arrangement on the basis of the features of the heart itself. This has been considered difficult to achieve using cross-sectional echocardiography. Now, with the advances made in the resolution of multidetector computed tomography, and the ability to reconstruct the three-dimensional datasets, it is an easy matter not only to recognize the features of the atrial appendages but also to correlate the cardiac findings with the arrangements of the thoracic and abdominal organs (Figs 4 and 8). The markedly different features of right, as opposed to left isomerism, will then obviously pose different surgical challenges. This means that detailed knowledge of the existence of isomeric atrial appendages, and the likely coexisting cardiac anomalies, is of paramount importance prior to surgical intervention.

Recognition of bilateral morphologically right atrial appendages, for example, enables the surgeon to predict the precise location of sinus nodes, which will be duplicated. Recognition of isomerism of the left appendages, in contrast, alerts the surgeon to the possibility of an abnormal location of the atrial pacemaker. E1, E2 (References (E1-E75) are available in the Supplementary Material.) Thus, in this latter setting, it is desirable to transect the superior cavoatrial junction as low as possible while performing unilateral or bilateral superior cavopulmonary connection. Precautions should also be taken when completing the Fontan circulation, ensuring as far as possible the avoidance of injury to the sinus node, or nodes, and their arteries [E3]. While performing a bidirectional superior cavopulmonary connection as staged palliation for functionally univentricular repair, a preoperative diagnosis of an enlarged azygos vein with an intact inferior caval vein should always be differentiated from that of an azygos continuation of an interrupted inferior caval vein prior to ligating the azygos channel. Azygos continuation of the inferior caval vein occurs in at least two-thirds of individuals’ left isomerism. When the inferior caval vein connects directly to the atrial chambers from below, it may connect to either the left- or right-sided atrium (Fig. 8). In left isomerism, this should be distinguished from the bilateral connection of hepatic veins, with a hepatic vein often coexisting with an inferior caval vein in those with right isomerism [E4, E5].

Although the arrangement of the inferior caval vein tends to distinguish those with left from right isomerism, this is not the case for the superior caval vein. At least half of patients with right isomerism, and up to two-thirds of those with left isomerism, have bilateral superior caval veins [E2–E8]. The coronary sinus, of course, is universally absent in right isomerism [E3–E8]. When bilateral superior caval veins are present with right isomerism, each connects to the top corner of its atrium. This makes it difficult to divert the left superior caval vein to the right-sided atrium, or the right superior caval vein because of its short length [E4, E5, E9–E13]. Diversion of left superior caval venous flow to the right superior caval vein in front of, or behind, the aorta, as proposed by Van Son and associates, is difficult to achieve in this setting as it may obstruct both the superior caval venous flows [E9–E16]. In left isomerism, in contrast, both superior caval veins are trying to be morphologically left. It is not unexpected, therefore, to find one or other draining through a coronary sinus [2, E4, E5].

It is particularly important to take note of the hepatic venous connections. As already emphasized, these also vary markedly, especially when there are isomeric left atrial appendages. These veins pass through the diaphragm, connecting directly to the atrial chambers from below. They usually connect to 1 atrium, but sometimes connect to both atriums separately, or to both sides of a common atrium [E4, E5, E17]. Such direct hepatic venous connections are present in all patients with an azygos extension of the inferior caval vein but can also occur in individuals with an inferior caval vein connecting directly to an atrial chamber. Preoperative demonstration of such venous arrangements can facilitate the construction of an intra-extraatrial Fontan pathway for redirection of the systemic venous return [E18–E26]. Rerouting of the hepatic venous system into the systemic venous pathway is essential in the setting of a previous superior cavopulmonary connection, or in the Kawashima repair for individuals with pulmonary arteriovenous malformations [E27–E34]. When performing a subtotal cavopulmonary connection with partial or total hepatic vein occlusion, it is important to investigate for an interconnecting venous channel between the inferior caval vein and the hepatic veins just below their separate entry to the heart [E35].

In those individuals with quasi-usual or quasi-mirror-imaged drainage, it can be relatively simple to achieve atrial septation without creating an obstruction. This is not necessarily the case when the venous pathways are eccentric, which is more usually the case [9, E36–E44]. The venous drainage from the heart itself is also usually grossly abnormal, particularly in absence of the coronary sinus [9, E4, E5, E36–E44]. Thus, knowledge of the precise patterns of systemic and pulmonary venous drainage is a prerequisite for a successful surgery.

In this regard, we stress again that the pulmonary venous drainage in right isomerism is always anatomically abnormal, even if returning to the heart, because of the bilateral presence of right atrial appendages. If connecting to the roof of one or other atrium, there is usually a significant distance between the right and left-sided veins (Fig. 4C). In contrast, when connecting in midline fashion through a venous confluence, there is the potential for stenosis at the venoatrial junction. The presence of pectinate muscles all around the muscular atrioventricular vestibules can also present problems in creating an unobstructed pulmonary venous pathway [E4, E5, E8, E45–E57].

The frequent association of hypoplastic, atretic or discontinuous pulmonary arteries can further influence the pulmonary venous flow. Severe obstruction to pulmonary venous flow may mask the clinical importance of the pulmonary venous anomaly [E7, E8, E58]. Volume overload produced by construction of a systemic-to-pulmonary artery shunt, or superior cavopulmonary connection, in neonates with obstruction to pulmonary venous flow, particularly in those with coexisting non-compliant functionally univentricular circulations, has resulted in death [8, 9, E8, E34–E40, E52, E59, E60]. Several histopathological investigations have revealed intrinsic pulmonary venous stenosis, smaller mean indexed pulmonary venous sizes and overall decreased pulmonary venous size [E61–E64]. In the light of all these problems, it is hardly surprising that the early mortality of functionally univentricular repair, undertaken with greater frequency in those with right isomerism, even though decreasing subsequent to 1990, remains much greater than the early mortality now anticipated for those with tricuspid atresia or double inlet ventricle in the setting of lateralized atrial chambers. And, despite encouraging results in recent decades, reports for those with a functionally univentricular heart and totally anomalous pulmonary venous connection still reveal 53% mortality at initial palliation and 38% mortality at the completion of the Fontan circulation [8, 9, E7, E8, E34–E40, E52, E53].

As can be anticipated from the overall less severe combinations of lesions found when there is left isomerism, several groups have demonstrated their ability to perform a biventricular repair in up to half their cases, with operative mortalities ranging between nil and 23% [9, E35–E44]. Biventricular repair, nonetheless, often requires the construction of complex atrial and ventricular baffles. The construction of such baffles can now be facilitated by appropriate preoperative demonstration of the likely pathways for the systemic and pulmonary circulations through the heart. These complex pathways also present severe technical challenges should transplantation be chosen as the therapeutic option [E65–E75].

CONCLUSIONS

When considered in the global context, it is now possible with accuracy to distinguish between the 2 subsets of so-called ‘heterotaxy’ on the basis of isomerism of either the right atrial appendages or the left atrial appendages. Although not always in harmony with the arrangement of the other thoracic or abdominal organs, it is rare to find broncho-atrial discordance. It is the morphology of the atrial appendages that provides the best guide to intracardiac morphology. Clinical imaging is now sufficiently good that the cardiac surgeon should no longer be in doubt regarding the precise atrial arrangement when he or she enters the operating room. Even in undiagnosed cases, it should be an easy matter still to distinguish between morphologically right and left atrial appendages. These features then provide the basis for the understanding of the remaining cardiac structure. In this initial review, we have summarized the likely associations. We are in the process of analysing our own surgical results on the basis of a distinction between isomerism of right versus left atrial appendages in the population encountered at the All India Institute of Medical Sciences, New Delhi, India. We anticipate that these results will emphasize the significance of differentiating the subsets of heterotaxy on the basis of their isomeric features.

SUPPLEMENTARY MATERIAL

Supplementary material is available at EJCTS online.

HUMAN RIGHTS/ETHICAL APPROVAL STATEMENT

The authors assert that all procedures contributing to this study comply with the ethical standards of the relevant national guidelines on human experimentation and with the 1975 Declaration of Helsinki, as revised in 2008.

Funding

No funding was provided.

Conflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of the article.

Data Availability Statement

Data are available in the Supplementary Material.

Author contributions

Diane E. Spicer: Conceptualization; Data curation; Methodology; Resources; Supervision; Visualization; Writing—original draft; Writing—review & editing. Ujjwal Kumar Chowdhury: Conceptualization; Investigation; Methodology; Resources; Validation; Visualization; Writing—original draft; Writing—review & editing. Robert H. Anderson: Conceptualization; Methodology; Resources; Visualization; Writing—original draft; Writing—review & editing. Niraj Nirmal Pandey: Resources. Lakshmi Kumari Sankhyan: Resources. Niwin George: Resources. Shikha Goja: Resources. Vishwas Malik: Resources.

Reviewer information

European Journal of Cardio-Thoracic Surgery thanks Hannah Rosemary Bellsham-Revell, Yoshihiro Oshima and the other, anonymous reviewer(s) for their contribution to the peer review process of this article.

REFERENCES