Anderson, RH

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Cardiology in the Younghttp://journals.cambridge.org/CTYAdditional services for Cardiology in the Young:Email alerts: Click hereSubscriptions: Click hereCommercial reprints: Click hereTerms of use : Click hereAtrial structure in the presence of visceral heterotaxyRobert H. AndersonCardiology in the Young / Volume 10 / Issue 04 / July 2000, pp 299 ­ 302DOI: 10.1017/S1047951100009598, Published online: 19 August 2008Link to this article: http://journals.cambridge.org/abstract_S1047951100009598How to cite this article:Robert H. Anderson (2000). Atrial structure in the presence of visceral heterotaxy. Cardiology in the Young,10, pp 299­302 doi:10.1017/S1047951100009598Request Permissions : Click hereDownloaded from http://journals.cambridge.org/CTY, IP address: 144.82.107.39 on 23 Aug 2012Cardiol Young 2000; 10: 299-302© Greenwich Medical Media Ltd.ISSN 1047-9511Editorial CommentAtrial structure in the presence of visceral heterotaxyRobert H. AndersonCardiac Unit, Institute of Child Health, University College, London, UKTHE STRUCTURE OF THE HEART IN THE SETTINGof so-called visceral heterotaxy remains apotentially controversial subject. Althoughthe existence of an isomeric arrangement of thelungs and bronchial tree in patients with "splenicsyndromes" was long since established,1 there arestill acknowledged experts who deny that the heartitself shows any evidence of isomerism.2 The studypublished in this issue of the Journal3 goes a longway to clarifying the bones of contention,confirming not only that the appendages them-selves are unequivocally isomeric, but that thevenous components of the atrial chambers are simi-larly arranged to reflect the presence of eitherbilateral right sidedness or left sidedness. The studyshows the value of analysing congenitallymalformed atrial chambers in terms of theirappendages and venous components, but empha-sises the need also to recognise the body of the atrialsegment, from which the appendages and theseptum grow during embryological development.It is this segment which persists in the formed heartas the vestibules of the atrioventricular junctions,but in addition forms a significant portion of thedefinitive morphologically left atrium. In this note,I will review briefly the background to thesemorphological and developmental issues.Morphological analysis of visceral heterotaxyIt is now well recognised that the normal arrange-ment of the body is one of asymmetry, with theright side being morphologically distinct from theleft, as we discussed in our recent review publishedin the Journal.4 Thus, in addition to the usualCorrespondence to. Professor Robert H. Anderson, Cardiac Unit, Institute of ChildHealth, University College London, 30 Guildford Street, London WC1N 1 EH, UK,Tel: (020) 7905 2322; Fax: (020) 7905 2324.Accepted for publication 3 May 2000arrangement of the organs within the body, and therare mirror-imaged variant, often called "situsinversus", there is a commoner abnormal pattern inwhich the abdominal organs are "jumbled up". It isthis third group, with visceral heterotaxy, whichcreates problems not only in terms of diagnosis butalso in description. All the disputes, nonetheless,are clarified by application of the "Morphologicalmethod".This principle of anatomic analysis was first usedby Van Praagh and his colleagues5 as a justifiablecriticism of our initial approach to the "univentric-ular heart".6 At that time, we had promulgated theconcept that, so as to make logical the descriptionof "single ventricle" in hearts with two ventricularchambers of dissimilar size and component make-up, we should disqualify chambers from ventricularstatus when they lacked their inlet components.Van Praagh et al.5 highlighted the conceptual defi-ciencies produced when one variable feature wasitself defined in terms of another feature which wasalso variable. Instead, they argued, anatomicalstructures should be defined according to theirintrinsic morphology, using their most constantcomponent for the purposes of definition when thestructures themselves were congenitallymalformed. As a direct extension of this morpho-logical method, it follows that, ideally, one systemof organs should not be identified, or named, on thebasis of abnormalities in another system. In fact,use of this method clarifies all of the apparentcontroversies which surround the subject of visceralheterotaxy.It is agreed that the arrangement of the organsin this setting is far from normal. Indeed, in the pastthe unusual arrangements were often considered tobe, and described as, "ambiguus". When eachsystem is described in its own right, however, allaspects of potential ambiguity are removed.7Analysis of large numbers of patients show thatthere are two subsets within the overall grouping of300 Cardiology in the Young July 2000visceral heterotaxy. In the abdomens of thesepatients, the most characteristic feature is eitherabsence of the spleen or the presence of multiplespleens. Within the thorax, in contrast, it is almostalways an isomeric arrangement of the lungs andbronchial tree that dominates the picture. In theheart, when the cardiac structures are analysedwithin the precepts of the morphological method,then there is unequivocal evidence of isomerism ofthe atrial appendages.8 Usually, the presence ofisomerism of the morphologically right atrialappendages is accompanied by right pulmonaryand bronchial isomerism, and by absence of thespleen. Similarly, isomeric left atrial appendages aremost usually found when the lungs and bronchuseson both sides are similarly of left morphology, andthere are multiple spleens within the abdomen. Butthis is not always the case. Should there be discrep-ancies in the positions of the organs, then eachsystem should be described separately and specifi-cally. Within the heart, it is the isomeric arrange-ment of the atrial appendages, judged on the extentof the pectinate muscles relative to the atrioven-tricular junctions, which is the best discriminatingfeature when assessed in the setting of largenumbers of hearts, with the venoatrial connectionsrevealing marked variability.8 As the careful studyfrom Korea3 now shows us, however, there arepatterns to be found in the arrangement of thevenous connections which reflect the presence ofeither bilateral right or left sidedness. The mostobvious feature of the normal morphologically leftatrium is the connection to it of the four pulmonaryveins. But, following the rules of the morphologicalmethod, we are not permitted to use the pulmonaryveins as the final arbiter of which chamber ismorphologically left, since the chamber is readilyrecognised on the basis of its own intrinsicmorphology even when the pulmonary veinsconnect to an extracardiac site, as in hearts withtotally anomalous pulmonary venous connection(Fig. 1). Analysis of the left atrium in such heartsdemonstrates the significance of the smooth-walledbody of the left atrium, which gives rise to the char-acteristic appendage, supports the vestibule of themitral valve, and is separated by the septum fromthe morphologically right atrium. In similarfashion, whilst the connections of the caval veins,particularly the inferior caval vein, are obviousguides to the existence of the morphologically rightatrium, they cannot be used specifically to definethat chamber. Indeed, the morphologically rightatrium is indistinguishable from the normalchamber in those persons who have usual atrialarrangement and interruption of the inferior cavalvein, with return of the blood from the abdomenFigure 1.This heart had totally anomalous pulmonary venous connection, withthe venous confluence initially draining infradiaphragmatically. Ascan be seen, the left atrium is recognised as such on the basis of thestructure of its appendage. In addition to the vestibule and the septum,nonetheless, the atrium possesses a substantial smooth-walled bodyeven in the absence of its pulmonary venous component.through the azygos venous system. As indicated,therefore, when following the morphologicalmethod, it is the atrial appendages that must beused to define the identity of the atrial chambers.For total clarity of description in the setting ofvisceral heterotaxy, nonetheless, it is essential tospecify all the venoatrial connections. As theaccompanying study shows,3 there are patternswhich can then be anticipated in the setting ofisomerism. When both appendages are of rightmorphology, then the venous components of theatrial segment similarly show the patterns of bilat-eral right sidedness, with preservation of an exten-sive smooth-walled systemic venous component onboth sides, with universal failure during develop-ment of conversion of the morphologically left sinushorn into the coronary sinus. There is either totalVol. 10, No. 4 Anderson: Atrial structure in the presence of visceral heterotaxy 301absence, or marked diminution in size, of thepulmonary venous contribution to the atriums.When connected to the heart, the pulmonary veinsalmost always enter the smooth-walled atrialcomponent close to the mid-line. In contrast, in thepresence of bilateral appendages of leftmorphology, there is far greater development of thepulmonary venous component, which is itself typi-cally present bilaterally, increasing the size of thesmooth-walled atrial component, but with diminu-tion in size and importance of the systemic venouscomponent, usually but not always with return ofthe inferior caval venous blood through the azygossystem. The patterns of venous connection,nonetheless, continued to show variation in thehearts examined,3 confirming that it is theappendages themselves, with their contained pecti-nate muscles, which serve as the most consistentmarker to the presence of isomerism in the atrialsegment of the heart.Developmental implicationsThe study from Korea3 is also important for thosewho continue to seek the molecular mechanismswhich underscore the development of symmetry asopposed to lateralisation within the bodily organs.The evidence is becoming increasingly moreconvincing that concepts of the five-segmentedprimary heart tube are unduly simplistic. When theheart tube is first formed, the convincing studies ofde la Cruz and her colleagues show that, in effect, itis made up of only the ventricular segments.9 Thesesegments are themselves formed in series, and giverise to the apical components of the left and rightventricles, respectively. Although it is true that"looping" of this tube to either the right or left is aninitial indication of the breaking of symmetry,10 it isequally true that formation of the ventricles in eithera right hand or left hand loop has very little to dowith subsequent isomeric development within theheart. Indeed, I am aware of only one well-docu-mented example of ventricular isomerism.11 It is theatrial segment of the developing heart which needsto be the focus of those who seek the genes whichgovern the regulation of cardiac symmetry andasymmetry. As de la Cruz and her colleagues haveshown,9 the atrial segment is younger in develop-mental terms than the ventricles. When first seen inthe developing heart, however, it has an obviousbody, into which the systemic venous tributariesinitially drain in symmetrical fashion (Fig. 2). At thestage at which the body of the atrial segment is itselfalready well established, the lungs have yet todevelop, and the atrial myocardium is continuousposteriorly with the substance of the developingRightatriumFigure 2.This transverse section is from a 4mm human embryo obtained andsectioned by Dr Leon Gerlis, and reproduced with his permission. Itshows the initial symmetry of the systemic venous tributaries, whichdrain from the outset into the body of the developing atrial segment (seeF'g- 3).mediastinum through the so-called "dorsal meso-cardium" (Fig. 3). By this stage, nonetheless, theatrial appendages have already grown out in parallelfrom the body of this initial atrial segment. And, inthe normally developing heart, each appendage canbe recognised on the basis of its own intrinsicmorphology from the first stage at which it is seen,negating suggestions that their shape reflectshaemodynamic patterning.2 This normal pattern ofdevelopment, with the body of the primary atrialsegment giving rise to the appendages and vestibulesof both definitive atriums, and also providing thescaffold for formation of the primary atrial septum,and then persisting as the body of the morphologi-cally left atrium, provides the background for under-standing the abnormal patterns described by theKorean group in hearts with isomeric appendages.3The acquisition of the systemic venous componentby the morphologically right atrium, and the appear-ance of the pulmonary vein in the dorsal meso-cardium, with subsequent incorporation into themorphologically left atrium, are very much laterevents in development.12 Such incorporations areperturbed when the atrial segment itself is formed insymmetrical rather than lateralised pattern, as302 Cardiology in the Young July 2000Terminal crestRightappendageDorsalmesocardiumiFigure 3.This further section from the Gerlis 4mm embryo, taken at a morecranial level than figure 2, shows how the body of the atrial segmentis continuous posteriorly through myocardial-mesenchymal reflectionswith the tissues of the mediastinum — the so-called dorsal meso-cardium. At this stage, neither the lung buds nor the pulmonary veinhave yet developed. Already, however, the appendages have grown outfrom either side of the primary atrial segment, and are readily distin-guished on the basis of their morphology.shown by the structure of hearts with isomericappendages. This atrial segment, and the developingatrioventricular junctions,4 therefore, need to be thefocus if we are to clarify the developmental mecha-nisms leading to the formation of isomericappendages, and their subsequent influence on theremainder of the heart. The mechanisms under-scoring formation of the ventricular loop are alsoimportant, but these are more likely to form corol-lary events in the developmental cascade producingcardiac symmetry. As the Korean group have nowshown,3 this involves the entirety of the atrialsegment, albeit to greater or lesser degree.AcknowledgementI am grateful to Dr Leon Gerlis, Visiting Professorat the National Heart and Lung Institute, ImperialCollege, London, for granting me access to hispersonally prepared series of human embryos. Icontinue to be indebted to the British HeartFoundation, together with the Joseph LevyFoundation, for their ongoing support.References1. Landing BH, Lawrence TK, Payne VC, Wells TR. Bronchialanatomy in syndromes with abnormal visceral situs, abnormalspleen and congenital heart disease. Am J Cardiol 1971; 12:456-462.2. Van Praagh R, Van Praagh S. Atrial isomerism in theheterotaxy syndromes with asplenia, or polysplenia, ornormally formed spleen: an erroneous concept. Am J Cardiol1990;66: 1504-1506.3. Min J-X Kim C-Y, Oh MH, Chun YK, Suh Y-L, Kang I-S, LeeH-J, Seo J-W. The arrangement of the systemic and pulmonaryvenous components of the atrial chambers in hearts withisomeric atrial appendages. Cardiol Young 2000;10:4. Anderson RH, Webb S, Brown NA. Defective laterahsation inchildren with congenitally malformed hearts. Cardiol Young1998;8: 512-531.5. Van Praagh R, David I, Wright GB, Van Praagh S. Large RVplus small LV is not single ventricle. Circulation 1980,61:1057-1058.6. Keeton BR, Macartney FJ, Hunter S, Mortera C, Rees P,Shinebourne EA, Tynan M, Wilkinson JL, Anderson RH.Univentricular heart of right ventricular type with double orcommon inlet. Circulation 1979;59: 403-411.7. Uemura H, Ho SY, Devine WA, Anderson RH. Analysis ofvisceral heterotaxy according to splenic status, appendagemorphology, or both. Am J Cardiol 1995 ;76: 846-849.8. Uemura H, Ho SY, Devine WA, Kilpatrick LL, Anderson RH.Atrial appendages and venoatrial connections in hearts withpatients with visceral heterotaxy. Ann Thorac Surg. 1995;60:561-5699. de la Cruz MV, Sanchez-Gomez C, Palomino MA. The prim-itive cardiac regions in the straight tube heart (Stage 9-) andtheir anatomical expression in the mature heart: an experi-mental study in the chick embryo. J Anat 1989; 165:121-131.10. Yost HJ. Inhibition of proteoglycan synthesis eliminates left-right asymmetry in Xenopus laevis cardiac looping.Development 1990; 110: 865-874.11. Rinne K, Smith A, Ho SY A unique case of ventricularisomerism? Cardiol Young 200;10: 42-4512. Webb S, Brown NA, Wessels A, Anderson RH. Developmentof the murine pulmonary vein and its relationship to theembryonic venous sinus. Anat Rec 1998;250: 325-334.

Analysis of visceral heterotaxy according to splenic status, appendage morphology, or both.

Atrial appendages and venoatrial connections in hearts with patients with visceral heterotaxy. Ann Thorac Surg.

Atrial isomerism in the heterotaxy syndromes with asplenia, or polysplenia, or normally formed spleen: an erroneous concept.

Bronchial anatomy in syndromes with abnormal visceral situs, abnormal spleen and congenital heart disease.

Defective laterahsation in children with congenitally malformed hearts. Cardiol Young

Development of the murine pulmonary vein and its relationship to the embryonic venous sinus. Anat Rec

Ho SY A unique case of ventricular isomerism?

Inhibition of proteoglycan synthesis eliminates leftright asymmetry in Xenopus laevis cardiac looping. Development

Large RV plus small LV is not single ventricle.

The arrangement of the systemic and pulmonary venous components of the atrial chambers in hearts with isomeric atrial appendages. Cardiol

The primitive cardiac regions in the straight tube heart (Stage 9-) and their anatomical expression in the mature heart: an experimental study in the chick embryo.

Univentricular heart of right ventricular type with double or common inlet.

Atrial structure in the presence of visceral heterotaxy

Atrial structure in the presence of visceral heterotaxy

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