Simplifying the understanding of congenital malformations of the heart

International Journal of Cardiology, 0 1991 Elsevier Science Publishers ADONIS 016752739100169Q

CARD10

32 (1991) 131-142 B.V. 0167-5273/91/$03.50

131

01310

Anniversary Review

Simplifying the understanding of congenital malformations of the heart Robert H. Anderson Department of Paediatrics. National Heart and Lung Institute, London, U.K. (Received

2 April 1991; accepted

Introduction In the ten years that have passed since the European Journal of Cardiology became International, it seems to me, from my grossly biased position as one of the European editors of the Journal, and as a continuing researcher in the field, that our understanding of the diagnosis and description of congenital cardiac malformations has increased markedly. It also seems to me, again recognizing my obvious biases, that several, if not many, of these advances have been described in our pages. There can be no question but that much of the improved understanding stems from the increasing sophistication of diagnostic techniques, most notably cross-sectional echocardiography, which now brings detailed knowledge of all aspects of cardiac anatomy to the fingertips (or transducer tip) of the clinician, even in the tiny hearts of the fetus during its early gestation [l]. At the same time, our understanding of the structure of the heart has been furthered over this same period by detailed investigations of autopsied hearts, some obtained from embryos and fetuses. In this article, therefore, I will discuss advances in the field of cardiac morphology over the past decade, recognising that other aspects of the pathology and anatomy of congenital cardiac malformations will probably be covered in still other of our commissioned anniversary reviews. The aspects I will discuss relate firstly to semantic problems which still block unambiguous descriptions of many lesions. Second, I will address problems which continue to emerge

10 April

1991)

in the process of segmental analysis of complex lesions, referring again to the problems of nomenclature which still exist. Finally, I will review recent advances which have taken cardiac embryology away from armchair speculation and restored it to its rightful role as a scientific discipline. Previous hindrances

in understanding

It must be said that many adult cardiologists still consider congenital cardiac malformations difficult to understand. For this reason they, perhaps, shy away from taking interest in a field that, in future, will become increasingly significant in their practice. A great deal of the fault for this justified impression of complexity can be laid at the feet of many of those who write about the description and diagnosis of these lesions. Indeed, many seem to go out of their way to introduce complexity into a relatively simple arena. Such introduction of complexity is not confined only to those who write about congenital malformations. Thus, I have found a tendency amongst other editors to resist potential moves towards simplification, such as replacing classical descriptions in Latin or Greek with vernacular terms, and removal of alphanumeric classifications. In a recent paper I published in the British Heart Journal, the editor insisted I use the term “superior vena cava”, believing that the readers would not understand the meaning of “superior caval vein”. This may be so, but I find it difficult to accept. One of the steps that my co-European

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editor and I have taken to simplify overall descriptions has been to use English words and English plurals in the pages of the International Journal. At first sight, it seems strange to see “atriums” rather than “atria”, but the English form grows on you remarkably quickly! We must admit that “atriums” (and infundibulumsl were chosen as extreme examples in our move towards simplification, but increasingly we see forms such as “symposiums” appearing in the non-scientific press, and there is now no problem in pluralising an arterial duct as “arterial ducts”. How many are aware that the plural of “ductus” is “ductus”? And what is the adjectival form of “vena cava”? Is it vena caval flow, or venous caval flow? I am sure that use of English as opposed to grecolatinate forms will improve both style and comprehension. It is also my firm belief that the use of English terms, such as common arterial trunk or atria1 arrangement, rather than their classical equivalents (truncus arteriosus communis and atria1 situs) removes much of the perceived difficulty and mystery that previously surrounded congenital malformations. Indeed, use of the vernacular terms is common in the German, French and Italian languages and even in Adult Cardiology. Who quibbles about heart failure?

Sequential segmental analysis The principles of segmental analysis were introduced independently by Van Praagh and his colleagues [2-41 and de la Cruz and her associates [5,6] as long ago as the mid 1960’s. It was, however, the so-called “European School”, of which I was (and still am) a part, that refined the value of this system [7-91, not without attracting considerable vituperation on the part of one of the originators [lO,l l]! In our proposed modifications, we pointed out that, over and above the essential description of the atrial, ventricular, and arterial segments themselves, the key to diagnosis was to distinguish between their interconnexions and the relationships of these components to each other [12]. When the system was first used, it was often difficult to determine, in the clinical setting, the details of the interconnexions between the segments, particularly the morphology

of the valves which guarded the segmental junctions. The diagnosis often had to be modified in the light of findings at surgery or autopsy. The advent of cross-sectional echocardiography changed all that. It was no longer necessary, for example, to try and infer from relationships of the arterial trunks the way that they were connected to the ventricular mass, nor to predict atrioventricular connexions from the architecture of the ventricles. Problems still persisted, however, in describing some hearts, particularly when the atriums were connected to only one ventricle. It was in this setting that semantics still posed a major problem. It had become clear to the European school that there was a marked similarity, in terms of ventricular morphology, between the anterior ventricular chamber of classical tricuspid atresia and the so-called “outlet chamber” of single ventricle, particularly when the ventriculo-arterial connexions were the same (Fig. 11. When initially writing on this topic, we made the fundamental mistake of assuming that, since everyone at that time seemed happy to accept the notion that a heart could be a “single ventricle” despite the fact that it possessed two ventricles (Fig. 21, one dominant and the other rudimentary [3,13,14], this nonsensical logic would be equally acceptable when applied to tricuspid atresia (Fig. 3). So it proved for many practitioners. But not for all [15]. On the basis of our observations, we chose to espouse the system of the “univentricular heart”, attempting to achieve a logical artifice by distinguishing between ventricles and non-ventricles. This was done so as to avoid making too radical a change in terminology. Our avoidance of radical changes, and artificial conventions concerning ventricles, still left us with some difficulties, particularly in hearts with overriding atrioventricular valves. Thus, in those hearts with overriding valves, at an arbitrary point, determined by the perceived commitment of an overriding valvar orifice, a virtually identical chamber would cease to be a ventricle and become a non-ventricle or vice versa [161. The nonsense of such an approach was forcibly debated at a meeting of the British Paediatric Cardiology Group held in Birmingham in the early 1980’s. In the

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is, indeed, the case that description of these hearts has been greatly simplified by recognition of all chambers within the ventricular mass as ventricles, irrespective of their size, component make-up, topology, or position. Despite the unequivocal logic of this approach, all are by no means convinced. There are still some apparent “experts”, publishing in most reputable journals, who are still ignoring morphological facts by describing “single ventricles” when there are two ventricles, one big and the other small 1191. The same authority, having edited an entire book on the topic [20] is still able to compound his morphological blindness by stating that classical tricuspid atresia is produced by an imperforate atrioventricular valve rather than by absence of the atrioventricular connexion usually guarded by the morphologically tricuspid valve [19]. One had thought that the morphological nature of absence of one connexion had been conclusively demonstrated [21]. It is certainly demonstrated repeatedly in the clinical setting by echocardiographic studies [22-241, both transthoracic and transoesophageal, and further demonstrated by magnetic resonance images 1251. The absent connexion is

Fig. 1. These figures show the anterior ventricular chamber in (lower) a heart with double inlet left ventricle and (upper) a heart with tricuspid atresia. Both hearts have concordant ventriculo-arterial connexions. In gross terms, the anterior chambers are virtually identical, both possessing apical trabecular and outlet components but lacking any inlet component. If one is a ventricle, then so is the other.

discussions held subsequent to this meeting, it became clear that the flaw in our logic had been our initial acceptance that hearts with double inlet ventricle should be described as “single ventricle” when, without question, they possessed two chambers within the ventricular mass. On the basis of our subsequent discussions, therefore, we proposed that, rather than the ventricle being single in this situation, it was the atrioventricular connexion which was univentricular. It seemed that the recognition of the univentricular atrioventricular connexion [17,181 would cut the Gordian knot of the “Single Ventricle Trap” [lo]. It

udimentary Jnk

iD

*Left FA&l v&e

r

int left ventricle Fig. 2. This long axis section shows a heart with double inlet left ventricle with discordant ventriculo-arterial connexions. There are clearly two ventricles present, one of left morphology which is dominant and a rudimentary and incomplete right ventricle.

malformed hearts. This imbalance having, apparently, been corrected by shifting the emphasis from the univentricular nature of the heart to that of the atrioventricular connexion, his immediate response was that we no longer needed the latter term. It seemed to me, however, that division of all congenitally malformed hearts into those with either biventricular and univentricular atrioventricular connexions was both clean and clear-cut (17,181. It has soon emerged that this is not the case [26,27]. Hearts exist in which one atrioventricular connexion is absent, or there is a common atrioventricular valve exclusively connected to one atrium, in which the only atrioventricular valve present is connected to two ventricles, and often shared equally between them (Fig. 4). This arrangement is often described as “double outlet atrium” [28-301. In terms of the atrioventricular connexions, the arrangement is biventricular but uniatrial. When found with absence of one atrioventricular connexion, it cannot be placed in the univentricular category [17,18]. Thus, I was clearly wrong when I argued that all hearts could be placed conveniently and accurately into the categories of univentricular or biventricular atrioventricular connexions! The auestion remains. therefore, as to whether we Fig. 3. This long axis section shows a heart with tricuspid atresia (due to absence of the right atrioventricular connexion) with concordant ventriculo-arterial connexions. This heart also possesses a dominant left and a rudimentary right ventricle. Neither this heart, nor the one shown in Fig. 2, can logically be described as a “single” ventricle.

represented by the adipose tissue of the atrioventricular groove interposed between the floor of the blind-ending atrium and the ventricular mass. We had thought all now acknowledged this obvious anatomic fact. But apparently not [19]. You can take a horse to water.. . . Experience in the latter part of the 1980’s, however, has further revealed semantic problems remaining with the univentricular atrioventricular connexion itself. My co-European editor has always taken great delight in pointing out that the “Univentricular Heart” did far more for my career structure than my efforts to clarify the subject did for the understanding of congenitally

Uniatrial connection

8 Ive Biventdular

connection

Fig. 4. This diagram shows the arrangement produced by a straddling and overriding atrioventricular valve when one atrioventricular connexion is absent. The connexion produced is biventricular but uniatrial. It does not fit into either of our existing biventricular or univentricular categories for the atrioventricular junction, calling into question our existing approach.

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still need these two categories! It is certainly the case that complex hearts of this type cannot be described adequately in short titles, however catchy they may be. This remains the problem with terms like “tricuspid atresia” itself. As we discussed recently in our pages [27], everyone knows (or thinks they know) what is meant by “tricuspid atresia”. But we had debated previously the differences that can emerge between the understanding of the term by the embryologist, the morphologist, and the clinician [26]. The embryologist may be able to demonstrate morphological evidence that, during development, a connexion may have existed between an atrium and a rudimentary ventricle [31]. Subsequent to birth, and without the aid of histological investigation, this microscopic evidence is not seen by the clinician or the morphologist, who describes the arrangement appropriately as gross absence of the atrioventricular connexion [26]. Further problems then exist for the clinician because although, with cross-sectional echocardiography, it is possible to distinguish absence of an atrioventricular connexion from an imperforate atrioventricular valve, both produce the same haemodynamic effect (Fig. 5). Furthermore, in terms of the haemodynamic arrangement and its clinical consequences, exactly the same arrangement exists when the right atrium is blind-ending irrespective of whether the left atrium is connected to a morphologically left ventricle, a morphologically right ventricle, or a solitary and indeterminate ventricle. Should all of these examples (Fig. 6) be described as tricuspid atresia? For the clinician, a case can be made in favour of this proposition. For the morphologist, the example in which the left atrium is connected discordantly to a dominant right ventricle almost certainly represents mitral atresia since, had the right-sided atrioventricular connexion developed properly in this setting, it would almost certainly have been guarded by a mitral valve. Indeed, when the right valve is imperforate and the atrioventricular connexions are discordant, the imperforate valve can be shown to be of mitral morphology (Fig. 6). And what of the situation with a solitary and indeterminate ventricle? Who knows what would have been the morphology of the missing valve in

Absent AV Connexion

lmperforate Right AV \ialve Fig. 5. This diagram shows the fundamental difference in morphology when tricuspid atresia is produced (lower) by absence of the right atrioventricular connexion and (upper) by an imperforate valvar membrane in a heart with concordant atrioventricular connexions.

this circumstance had it developed! As we discussed in our recent editorial [27], our preference in this setting is to avoid nominative terms such as “tricuspid” or “mitral” atresia, and instead to describe in detail the underlying anatomy, using terms such as “usual atria1 arrangement with absence of the right-sided atrioventricular connexion, the left-sided atrium being connected to a dominant right ventricle with an incomplete and rudimentary left ventricle in posterior and rightsided position”. This is unlikely to satisfy the practitioner who looks for a label for each heart. The terms tricuspid and mitral atresia are not going to disappear from the cardiological thesaurus. Those who use only these terms, however, must be aware that they can conceal a multitude of sins [19]! In arguing that we were unhappy with the term “tricuspid atresia”, Rao was far from the mark. It was inappropriate use of “single ventricle” that produced, and continues to pro-

LA to Left

Abmnt

Alrlovontricular

Ve”trlcle

LA tO Rbht

Connexion

Ventricle

LA to Solitary

Ventricle

Fig. 6. This diagram shows some of the possible segmental combinations producing atresia of the right-sided atrioventricular junction in hearts with either (upper) absence of the atrioventricular connexion or (lower) an imperforate right atrioventricular valve. Not all of the atretic valves are of tricuspid morphology, or would have been, had they been formed during development. This variability, only some of which is illustrated here, shows the problems existing in usage only of the terms “tricuspid” or “mitral” atresia to describe these variants.

the atria1 and ventricular septal structures. It was the absence of the septal components which was, classically, believed to produce the typical septal deficiency of the malformation [34]. In the past decade, several morphological studies have demonstrated the dangers inherent in interpreting this anatomy on the basis of presumed embryology. Thus, it has been shown [35] that the left atrioventricular valve in the hearts under discussion (Fig. 7) bears no resemblance to the normal mitral valve (Fig. 8) over and above its residence within the left ventricle. The valves in “endocardial cushion defects” cannot be described properly in terms of mitral and tricuspid valves with cleft leaflets. Instead, the right and left valves in

duce, insuperable difficulties in description of hearts in which the atriums are connected to only one ventricle. It is “single ventricle” which should be expunged from usage, except when describing those rare hearts with a truly solitary ventricle. Relationship

of morphology and cardiac development

The other area which has contributed in no small way to difficulties in understanding the morphology of congenital lesions has been the habit of describing important features on the basis of the presumed embryological development. The exemplar of this approach is the socalled “endocardial cushion defect”. Established concepts for the understanding of this lesion [32,33] had been based on the presumption that clefts exist in the leaflets of the mitral and tricuspid valves. These, in turn, were held to be the consequence of failure of fusion of the primordiurns presumed responsible for formation of not only the valvar leaflets, but also components of

Fig. 7. This view of the left atrioventricular valve from the apex of the left ventricle in a heart with an atrioventricular septal defect, the ventricle having been opened in clam-like fashion, shows the trifoliate arrangement of the valve, with the so-called “cleft” (in fact, the commissure between the left ventricular components of the two bridging leaflets) pointing at the ventricular septum.

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turn _.

% W-aortic

&flow _t

Fig. 8. This short axis section of a normal heart. viewed from beneath. shows how the subaortic outflow tract separates the mitral valve from the septum. There is no comparison, in terms of gross morphology, between this valve and the left valve shown in Fig. 7 over and above their residence within the left ventricle.

the malformed hearts are part of a unique common valve. This valve, and the other stigmas of the lesions, exist because of failure of formation of the atrioventricular septal structures found in the normal heart [36]. Because of this, it has been suggested that they are best described as atrioventricular septal defects [37]. Once approached in this way, the typical morphological features are appreciated in their own right, and readily identified by either cross-sectional echocardiographic [38] or magnetic resonance imaging [39]. It is then equally noteworthy to appreciate that some of these morphological stigmas were recognized in the mid-nineteenth century. As pointed out by Ebels [40], Peacock described in exemplary fashion the basically intact nature of the atria1 septum along with the trifoliate nature of the left atrioventricular valve [41]. “Classical” concepts of embryology, therefore, were a positive hindrance in the full understanding of the surgical anatomy of hearts with deficient atrioventricular septation. But this should be seen as a criticism of the interpretations of the embryologists themselves rather than the science of embryology. As was described in the pages of our Journal [42], direct evidence has never been advanced to substantiate

cushions contribute materially to the substance of the valvar leaflets. Indeed, it has been shown that the leaflets are formed by delamination of the superficial layers of ventricular myocardium and invagination of the tissues of the atrioventricular groove [42]. The concept of delamination, however, has a long pedigree [43], while Van Mierop, on whose concepts Netter based his drawings showing the cushions contributing markedly to the formation of leaflets and septal structures, subsequently stated that the major function of the cushions was to “glue” together the centre of the heart. At any event, Wenink and Zevallos [44], following up the elegant studies on development of the normal mitral valve [42,43], discovered and described two human embryos showing deficient atrioventricular septation, with the valves being

Fig. 9. This long axis section through a normal heart shows the sleeve of free standing infundibular musculature which supports the leaflets of the pulmonary valve. The “outlet septum”, as such, has no individual identity within the normal heart.

13x

delaminated from the abnormal ventricular mass, itself resulting from failure of fusion of the cushions. When the embryology is properly investigated, therefore, it accounts appropriately for the anatomy as it is observed. This has also been shown to be the case for development of the outflow tracts of the heart. Much important experimental work has been done recently regarding septation of the ventricular outlets and the arterial trunks [45--481. These sophisticated investigations cannot properly be interpreted, particularly in malformed hearts, until we have an equally solid appreciation of the normal anatomy of these regions and the nature of the structures responsible for normal septation. My own understanding of the normal anatomy in this respect has undergone marked revision. As described in another review in the

Journal [49], we - and others [50] - had believed that the entire posterior wall of the subpulmonary infundibulum formed a septum between the ventricular outflow tracts (the outlet septum). We had based our categorisation of ventricular septal defects on this premise [51]. Subsequent dissections of the normal heart showed that our concept was incorrect. These dissections showed that the entire subpulmonary infundibulum was a free-standing sleeve of ventricular myocardium (Fig. 9). A defect could simply not exist in this location in a normally structured heart. It so happened that, coincidentally, the Leiden group had been investigating the development of this part of the heart using serially sectioned human embryos. In this way, Bartelings and Gittenberger de Groot 1521also demonstrated the insignificant extent of the outlet septum in the normal heart,

Fig. 10. This section through a human fetus prior to expansion of the atrioventricular junction, has been processed to demonstrate reaction to an antibody prepared against the nodose ganglion of the chick. The antibody demarcates the junction of the inlet (starred) and outlet components of the ventricular loop. The positive tissue comprises a ring. the upper (circled) and lower (boxed) components being seen in this section. Reproduced by kind permission of Drs Andy Wessels, Wout Lamers and Antoon Moorman. University of Amsterdam, and Prof. Szabolcs Viragh, University of Budapest.

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and similarly pointed to the importance of the development of the free-standing subpulmonary infundibulum. Since then, they have interpreted their findings in terms of normal development to explain the variations in anatomy in four malformations of the ventricular outlets - namely tetralogy of Fallot, common arterial trunk, complete transposition and double outlet right ventricle. These provocative and stimulating reviews, highlighting many previous deficiencies, are to be published in the next two issues of our Journal [53,54]. As might have been expected, therefore, when both anatomical and embryological studies are carefully conducted by those who have detailed knowledge of both the structure and development of malformed hearts, the correlations between the techniques are very close. It would be amazing if they were not. It is only when categorizations of anatomy are predicated on less than certain notions of development that problems arise. The embryological studies themselves, nonetheless, will prove of much greater value in the clinical context if described using terms that are readily compatible with those used by morphologists and pathologists, ensuring, of course, that this approach is applied only as far as it is scientifically justified [55]. Newer embryological studies are then likely to necessitate major rethinking, since they describe observed facts, as opposed to the previous approaches which inferred embryological processes from interpretation of the structure of malformed hearts. Thus, I had argued, based on my understanding of anatomy and embryology at the time, that the developing inlet component of the morphologically right ventricle was derived from the inlet component of the primary heart tube - the part proximal to the primary ventricular foramen [561. A very recent study performed by the Amsterdam group of anatomists [57] has cast the gravest doubts on this hypothesis. Using an antibody developed against the nodose ganglion of the chick, they have demonstrated a discrete ring of myocardial tissue which separates the inlet and outlet components of the developing ventricular loop (Fig. 10). With subsequent development and septation of the heart, the remnants of this ring of myocardial tissue, which also forms

the atrioventricular conduction axis, are found encircling the right atrioventricular junction, the entirety of the right ventricle being distal to the ring (Fig. 11). The anatomists from Amsterdam discussed these important findings both with me and with the group from Leiden. We are still debating some of the finer points. To me, at any rate, it seems that the findings of Wessels et al. [57] constitute very strong evidence that the inlet

Fig. 11. This section through a human embryo at a stage subsequent to expansion of the atrioventricular junctions shows the eventual site of the ring of tissue which reacted to the antibody to nodose ganglion, and which delimited the junction of the inlet and outlet components of the ventricular loop. As can be seen, the lower part of the ring (boxed) remains on the crest of the ventricular septum, while the upper margins (ringed) occupy the atria1 extent of the right atrioventricular junction. This is highly suggestive that the entire right ventricle is derived from the distal (outlet) component of the initial ventricular loop (see Fig. 12). Figure reproduced by kind permission of Drs Andy Wessels. Wout Lamers and Antoon Moorman, University of Amsterdam, and Prof. Szabolcs Viragh, University of Budapest.

I40

component of the right ventricle is derived not from the proximal component of the developing ventricular loop, as I had originally thought [56], but from the component distal to the primary foramen (the outlet component). Significantly, study of the sections with the Amsterdam group showed us that the ring of tissue reacting positively to the antibody to nodose ganglion was already occupying an atrioventricular position within the inner heart curvature, even when the atrioventricular junction is connected virtually exclusively to the proximal part of the ventricular loop (Fig. 10). The essential step in development of the inlet of the right ventricle, therefore, is simply one of expansion of the developing right atrioventricular junction over the primary ventric-

a) developmental

ventricular

tissue

ary ring L entire conduction b) developmental

a) definitive

axis b) delinitiva

Fig. 12. These figures demonstrate the different possibilities concerning the derivation of the inlet component of the right ventricle. According to the recent work from the team from Amsterdam, the inlet is derived from the distal component of the ventricular loop, meaning that the ventricular septum is formed in its entirety from the primary septum (lower panels). Initially. 1 had suggested [56] that the inlet component was derived from the proximal component of the loop, and that the inlet septum had a different origin from the apical trabecular (primary) septum (upper panels). The concept proposed by the Amsterdam group (lower panels) is almost certainly the correct one.

ular septum. This view of development provides a much simpler appreciation of formation of the ventricular septum, it no longer being necessary to postulate separate formation of inlet and apical trabecular components [56] (Fig. 12). New studies, such as those from the Leiden and Amsterdam groups [42,43,52-54.571, therefore, do permit us to obtain a much more accurate appreciation of the morphological mechanisms involved in cardiac development. When combined with exquisite scanning electron microscopical studies, with appropriate fixation of the heart [58], we should soon be in position to chart precisely the various steps involved in processes which remain controversial, such as transfer of the aorta to the developing left ventricle and the atrioventricular junction to the developing right ventricle. Combining this knowledge with techniques of molecular biology [45-49,59-611 should then take us closer to unravelling the true morphogenesis of congenital malformations of the heart. It is our hope that the International Journal will take as important a role in promulgating these advances over the next decade as we hope it has played during its first decade. References Allan LD. Chita SK. Sharland GK, Fagg NLK. Anderson RH. Crawford DC. The accuracy of fetal echocardiography in the diagnosis of congenital heart disease. Int .I Cardiol 1989;25:279-288. Van Praagh R. Ongley PA, Swan HJC. Anatomic types of single or common ventricle in man: morphologic and geometric aspects of sixty necropsied cases. Am J Cardiol 1964; 13:367-386. Van Praagh R, Van Praagh S. Vlad P. Keith JD. Anatomic types of congenital dextrocardia. Diagnostic and embryologic implications. Am J Cardiol 1964:13:510-531, Van Praagh R. The segmental approach to diagnosis in congenital heart disease. In: Bergsma D. ed. Birth Defects Original Article Series. Volume VIII, No. 5. The National Foundation: March of Dimes. Baltimore, Williams and Wilkins. 1972;4-23. De la Cruz MV, Berrazueta JR. Arteaga M, Attie F. Soni .I. Rules for diagnosis of arterioventricular discordances and spatial identification of ventricles. Br Heart J 1Y76;38:341-354. De la Cruz MV. Nadal-Ginard B. Rules for the diagnosis of visceral situs. truncoconal morphologies and ventricular inversions. Am Heart J 1972;84:19-32. Shinebourne EA. Macartney FJ, Anderson RH. Sequen-

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