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The Morphogenesis of Transposition of the Great Vessels By ROBERT P. GRANT, M.D. Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 mechanical effects of the spiraling flow of blood through the bent primitive cardiac tube. Transposition could be due, then, to an abnormality in the spiral course of blood flow, and this, in turn, perhaps a result of a disturbanee in the bendinlg of the cardiac tube. The hemodynamic theory has received considerable impetus in recent years as a result of the experiments of Goerttler2 and the observations of deVries anid Saunders.' However, while hemodynamic factors may be the energy source responsible for the anomaly, such a theory does not identify the growth abnormality that takes place. Furthermore, as we shall see, the architectural changes in transposition are much more constant and systematic from case to case than one would expect from the vagaries of blood flow alone. Goerttler realized this and pointed out that hemodynamic forces may be only a participating factor and that other growthgoverning mechanisms must also play a part. A quite different approach was taken bv Spitzer in 19234 in developing a phylogenetic theory of transposition. Following the lead of Keith, Hochstetter and others, he recapitulated normal heart development in terms of heart forms to be found earlier in the animal kingdom, and from such phylogenetic data developed a system of segmental rotations in the heart tube, alternate paths of septation, and changing hemodynamic requirements to explain normal heart development. WShile his work can be only briefly described here* he noted certain resemblances between the heart with transposition and the reptile heart. In the reptile (notably the crocodile) three great vessels arise from the ventricles, two from the right ventricle (a right aorta and a pulmonarv artery), and one from the left ven- IN THE COURSE of a study of the embryology of the flow pathways in the human heart,1 it became apparent that there might be a simpler way of looking at the morphogenesis of transposition of the great vessels thani the current torsion-detorsioni theory. To evaluate the validity of the new explanation a comparison was made between the architectural changes found in hearts with proved transposition and the changes to be predicted from this and other theories of its morphogenesis. While there ha-ve been numerous descriptive accounts of the heart in transposition, none has approached it in a systemiatic, semi-quantitative way, with use of objective criteria for case selection. The results are described in the presenit paper. While they agree in all regards with the proposed theory, cardiac development is subtle and many aspects of even normal heart development are poorly understood. It would perhaps be wiser to consider the proposed theory as a "way of looking at transposition" rather than being itself an adequate explanation of its morphogenesis. Previous Theories In effect, transposition is a reversal of the coiling of the venous and arterial flow paths responsible for the double circulation. Therefore it is not surprising that notions of the mechanism of development of transposition would be derived from theories of how the normal crossover of the two circulations is brought about. One of the oldest theories suggests that the normal coilinig in the bulbar and truneal regions is a response to the Work done at the Pathologisches Institut of the Ulniveirsity of Goettiingen, Western Germany (Prof. J. Linizbach), during the tenure of a Fellowsship frXom The Commoniwealth Funid. For more comprehensive review of this and other theories of transposition see references 5, 6, and 7. Present address: Office for International Research, National Institutes of Health, Bethesda 14, Maryland. Circulation, Volume XXVI, November 1962 819 820) Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 triele (a left aorta). He postulated that in transposition there is a torsion of the bulboventricular septum, abnlormal in man but a r:ecapitulationi of an earlier animal fornm. As a result, the left aorta bgecomes obliterated, the reptilian right aorta regains pateney, and the puilnmonary artery is brought into alignuiei:t with the left ventriele. In this way transposition (aand several other anomalies) were explained by Spitzer in terms of homuoloogies with normal architectural findings in itiore primitive aniilmal foris. In Spitzer 's day the idea that congenital anomalies were instanees of species-reversal (the ''throwvback ') was still popular in the lay miind, although biologists had discredited it. Today the ilotioi is in even less repute, and it is niot thought to play a significant role in teratology or mutation.8 Furthermore, Spitzer leaned heavily upon teleology in his explanationis, as if one part of the heart might somuehow "'know," what the funetional re(Juiremients of another part of the heart might be at sonme later day or in some later evolutionary state. Finally, while phylogeny provides fascinating glimnpses into the intricate m1etwork o-f evolutioni (the notion that evolutioIn is a "'chain'' of interlocking links is no lonoger tenable) it can shed light onlv iiidirectly, if at all, on problemns in teratology. But Spitzer's notion that there was a series of inidependeint torsiolnal events at different parts of the primuitive heart tube stimulated further w-ork along this line. Rokitansky had long before suggested that imisplacement of the two truncal ridges was alone an inade(uilate explanation for the nmorphogeinesis of transposition and he felt that there imust be torsion of some other part of the ventricular septal systenm as well. In 1935 Pernkopf and Wirtinger9 carefully studied the torsional events that appear to take place in the heart durinog niormal developmnent and postulated a torsional abnormality for transposition. They (coieluded that torsions of as much as 180 degrees might take place at eacli of three levels and at different phases of growth ini the heart tube and developed an exceedingly GRANT complex system of torsions and detorsions at different levels at different times which, they believed, brought the simple heart tube into its complex adult form. Such a formulation offered a ready explanation for transposition and other syndromes with iniversion or apparent misplacement of cardiac components. Pernkopf and Wirtinger developed their data from the study of wax models of humna-ln fetal hearts at different ages, usinog the various bulbar and truncal ridges as landmarks for the recognizing of torsions. They believed there were four truncal and two bulbar ridges in man. Abnormal torsions could bring about various alignments of the ridges prior to their fusion, resuitinig in deformities such as transposition. Subsequent work on the morphogenesis of transposition has been mainly to mnodify the schema of Pernkopf and Wirtinger. lev and Saphirt° and De la Cruz and co-workers'-1 thought that there must also be faulty absorption of the bulbo-ventricular flange (a myoblastic mass between the bulbus cordis and the left ventricular base) in transposition. It has since been showni, however, that bulbar resorption is more apparent than real in normal cardiac development. Shaner12 and Barthel6 have combimmed certain of Pernkopf and Wirtinger's torsions with hemnodynamiec considerations to explain transposition. Doerr13 and Goerttlerl4 have restudied the torsions and brought more precision and simnplifieation to the timinig amid location of these events. In the final analysis, cardiac development is mainly a product of differenees in rate anid direction of cellular multiplication, as modified by hemodynamic and other factors. iTorsions" and "detorsions" are but seeondary manifestations of growth anid always raise the question " what is twisting what ? For example, ani apparent torsion in one segment might be due to a hemodynamic surge in that segment or in an adjacent segmnent; it nmight be due to asymetrieally increased growth rate in the segment alid not truly a torsioni at all, or to a displacememut Crculation, Volunte XXVI, Nov'ember 1962 821 TRANSPOSITION OF GREAT VESSELS of the segment resulting from growth in some other segment. In short, a schema of "torsions" and " detorsions" does not identify the sites of growth abnormality and hence can never provide a definitive theory of morphogenesis. Goerttler14' 15 has attempted to identify the sites of growth potency at different regions and different stages of development of the cardiac tube by doing differential mitotic figoure counts, and has recently extended this work to experimnentally produced congenital cardiac anoma.lies. It is in approaches such as this that the most useful and valid explanation of normal and abnormal heart development will be found. Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 The Embryogenesis of the Ventricular Outflow Regions of the Heart in Man In a general sense two principles of cardiac tissue growth account for the evolution of the human heart from a single, gently coiled, peristaltic tube at the end of the third week of fetal life into the complex, four-chambered, multi-valved, trabeculated organ at the end of the fifth fetal week: (1) the tendency for inward, lumen-invading growth of the tissue at certain regions of the primitive cardiac tube, and (2) the dramatically different growth rate and growth history of the tissue at different parts of the tube. These two principles underlie normal cardiac development and they also account for many cardiac anomalies. Tha.t disturbances of the invasive growth capacity of cardiac tissue result in congenital anomalies is well recognized. Examples of arrest of this process are seen in persistent truncus arteriosus and in A-V communis; and perhaps mitral, tricuspid, aortic, and pulmonary atresias are examples of excess or displacement of this mechanism. On the other hand, the role of disturbances of differential growth in the genesis of cardiac anomalies is less easily visualized. To understand this factor one must have a elear picture of the spatial relationships of the adult heart, the product of the differential growth, and this is particularly true for an understanding of transposition. Circulation, Volume XXVI, November 1962 Figure 1 Diagram illustrating that flow is unidirectional in the right ventricle, bidirectiona,l in the left ventricle. The two ventricles are often regarded simply as two more or less similar pumps acting in parallel and in physical apposition to one another. This is of course an oversimplification. The two ventricles are quite different both in st-ructure and the dynamics of function. For example, while in the right ventricle flow is unidirectional, in the left ventricle it is bidirectional. That is, while in the right ventricle blood enters at one orifice and leaves at another, in the left ventricle blood enters and leaves from the same orifice (fig. 1). That the left ventricle has but a single orifice is shown in figure 2. Functionally, there is a thin fibrous membrane stretched across the orifice of the left ventricle. Blood flows in on one side of this membrane and out on the other side. The membrane is, of course, the anterior leaflet of the mitral valve, attached to the left ventricular wall at the two tubercles that indent the orifice. This difference between the two veentrieles 822 822 rignre 2 hut i/it I't lt tl r etticile, shlto r structures', th ttricle, the attici. end thgfr right the httre Weit u Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 foi', inl anothier at cirnbryolog-ie gpreat tlic' hevart ill trans'pos'ition: of r'ight the tissuie. bulbms the prrimitive anITd r-ide Vent otfiter hand, fibrous, two orifices of the~ le,ft leaflet mitral tlie the of t'irshioiis A-V aiso issue( -valve) ('anIIal itito a1 Th'lins, while the amidl 1rait r1al a, iniflowl ue1t :ii1d regard iin Since teinii oni lidis beenl sept:il oi'igin11311 intro0 r-ighit ventri'iiulair was of the blll vlr shown to lIe 'r-taiii m surface of the (l igi(' imitended useful, is ini the 1i( utscle e r-i ando pr-esenit pa,,per- ut tile usa,,ge glt this, t lti Hle, mist,aken. the wvithio still. is \Virtiniger. Years te,rcnlI and e iiului1o naur d cu il-s, 'Plus- deffinitiont is used 11)v ian'n Br-itish 11Fll p1l'cse'It author, bllei(vcs t hitfilnition, an" and Europe, pdo11 AAV tire Outflowv parts ofr coinpl)onieuts. Pernikopf Keithi gave describe to the im,,ss of Arithutr Sir- d eiet itio nt has miuscle and the. and thie frour fihwohlas"ti -Nlli(l1 continental Spitzir algo Jiiust -its to uisage, of ig (the aniterior' derived tlie trieu sp id aortai the lj t nuiigs for. label sep)arati11gr flicUsPid 'The cristan supo axveutriculi'iis s tile the dividing for' i'ighrt Oni is is which the of arteriosus. tissue ventricle r-esponsible dlerived the between_ the truneus the i'alleil is r-egioni the t-uLbe by luetweell is t cordis, cardiac outflow ventAricle )Tvn i'r'ista friont aird( separated a-re, munscula-ture The twvo orifices of the right thii outflow arce separ-ated inflowN t-ire t-he of a11(1 of basi,c is a-relite('ture the inflow of the left ventricle ('011irect ive tin' vessels tt an-d veiit-i'icie wihile muisculature Orifices e al of whichl is war. significanice 11r1(lcrstalldirlg' or'ifhi'os fi or rmoved. looke-d can tiss singl t itt tissue -111 (iuuiPMo t thte seil i( ls v entricicl, and ait. iss a""d \Aii'ica,mu the o the r-iginal uisage (4RAN'I ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~l~ 1hIe rigitd ventricle din (dop) frorii (0 se'tv regions of the J)riitiitie hiear-t tube, the. inflow anid outflow parts of thfe ci vctIclc1 Ie dilevelop from twlo wvidely- sellara.,ted reg)-ions, o f the primitive cardiac tube.. AnL1d fiere is11 one of tile baffling problemts ini limrititii i'ar'diac. dlevNelopi-nent ho-w does. the aortca, whIiehi airise,S f'romn so dlistal. a. part of the tube, eontire to c('I1( mij ini exclusive anid intimrate ati a-cirwinn wvithi the left ven-tric.le, whichl develop)s fr-ont' the mnost proximal fpart of tire tiile ? Tire anlswer lies in the remarkable differ-ence M.i grwhhistorr of fib roplastice cardi,ac tis,~siwi as compa red withi Irlyol)la-st ie ('8 rd ia t issii1e. Thte tissuie that invafdes anlid divides the irun-eus arter-iosuis inito aorta ahl(l jnrhrnoiiira i airtery, and the tissue. that in-vades an-d divides the A V canial into the miitral 11(1. ii,trsicusid orifices are both l)alrt of a conitinulouls fibroplastic tra('t that -inies tile inner concave sin face of the Pr1initfive cardiac- lube. It ha(,s been shownri hr careful measuremnentf at (01(11 stagye of fetal growthi that whien this- ti~'4ssue hias completed its Iinluen-in-vadingo g-rowtih il the, truncus anid the A-V canial, di-vidinig ewaii otito twvo chiannels,7 it ceases fuirthier' (xi)ailsive g-rowth.' Clessation ta.kes place. in tlhu fifthl Week, of fetal life, When. t-Ire hen,it is onlyr a few nirillbniieters ini size. Growth of tire hleart after- this date is almost enttirely due to in-creases ini the niroblastie tissut'. As, shown iii the dliawiirg a-t thie t-o1) of figuire 3, the lie of the coile.d hcar't tube. ini the thioralx is suchli that the fibroplast ic tra-itlies betwi.eeni the aortie l)art of th-e trunctis 811(1 thec miitral part of the A-V canial. Trhis mieanis that in. the niormal heart the ao-rtie, anid miitral rings are separated by tissue, thaif (e(~ases expansive growth early in fetal life, whien. the, distancie between thei two parts of the hieart tube is Ibit a. fract-4ion of a. Itlillinictrr. While otfl(cr parts of the hecart go tr-emen(~douisl.y tlloutsai.ds.fol(d-in tirie cilsuiit iomithis anid years, this (listaiwerld'1'l11111s et,,,sir tiallv the sarit' as it. vas ini the fifthi fe~ilI wee(.k. '[it the dlitlr'IIeil'( iil growlV0 I hst Or of various iparts ot tIre hearti i'xrlairis -why, the(, aorta, derived frionti one end( of tIre heart Circulation, Volume XXVI, Nortmbcr 196C2 823 TRANSPOSITION OF GREAT VESSELS I/ Truncu VI A-V COM I A- NORMAL //ll- 1T A 1 N Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 8- TRANSPOSIrION 4_X o~~ 1, 71 \\ I/ Figure 3 Schematization of the role of the fibroplastic continuum in the development of the heart. Top, the fibroplastic continuum at its earliest stage, when the heart is a single coiled tube. Center, norrmal sequences; bottom, suggested sequences in transposition. Shaded area represents the fibroplastic tract, and, at later stages, the fibrous ventricular skeleton. The last schema in each row shows the relationship of the four orifices to the ventricular skeleton in the fully developed heart, as viewed from the ventricular base. tube, ends up in intimate continuity with the mitral ring, derived from the other enid of the heart tube. While fibroplastic tissue separates the aortic and mitral rings, myoblastic tissue separates the tricuspid and pulmonic rings. Myoblastic tissue continues expansive growth throughout the growth history of the heart, long after fibroplastic regions have ceased divisive growth. This explains why the two orifices of the right ventricle are separated. by a wide span of tissue (the crista supraventricularis), while the two orifices of the left venitriele are separated by barely a millimeter of tissue (the width of the anterior mitral leaflet). AWith regard to other relationships among the ventricular orifices, as can be seen from the "normal" schemata in figure 3, fibroplastic tissue lies between the tricuspid and Circulation, Volume XXVI, November 1962 aortic and mitral rings in early fetal stages. Because of the short growth history of fibroplastic tissue, the three orifices end up in immediate fibrous continuity with one another, no farther apart at their points of junction in the adult heart than they were in the fifth fetal week. By the same token, the aortic and pulmonary rings are also separated by fibroplastic tissue (the fused truncal ridges), and, as a result, in the adult heart the two rings are in direct fibrous continuity with one another. The difference between the two ventricles in their outflow architecture is important for an understanding of transposition. For example, it leads to a very simple, but axiomatic and virtually infallible principle for the recognition of this anomaly: if the vessel having the characteristics of the pulmonary artery is in direct fibrous continuity with the ~824 GRANT Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 anterior leaflet of the mitral valve while the aorta is not, transpositioii is present, regardless of whatever other deformities are seen. On the other hand, if this condition is not fulfilled, no matter what characteristics the great vessels have, inecluding which chamuber they seem to be facing (or from whieh. thev are proved on catheterization to be mainlv draininig), transposition is not present. For another example, various degrees of partial'" and ''in-comolplete'' transposition have been deseribed in the past. If bv these termns is meant the condition where each great vessel is partially arising from each ventricle, fronm the above diseussioni it should be evident that there is no conceivable way in which septationi of the truncus caln be complete, each great vessel in fibrous continuity with the anterior mitral leaflet, yet both ridged by bulbar mnusculature. More commonlv the ternms are meant to describe a condition where complete reversal of the great vessels has taken place, but some lesser degree of torsioln of this part of the heart is present. Such intermediate deforrnities would result in various degrees of tors.ional abnormality of the vemitricular base, and, as will be shown shortly, there is no evidence that intermediate degrees of torsion take place. Therefore there appears to be neither an embryologic nor an anatomic basis for 'partial'" or ''inconiplete'" transposition as currently defined. The Morphogenesis of Transposition of the Great Vessels As shown in the lower drawings of figure 3, if the fibroplastic tract on the eon.cave surface of the primitive cardiac tube were shifted slightly leftward, so that it lay between the pulmonary part of the truneus and the mitral part of the A-V canal, transposition would result. The early cessation of fibroplastic growth would cause the pulnionary ring to end up in fibrous continuity with the anterior mitral leaflet. The aortic ring would have as its only fibrous attachment a tendon tol the pulmoniarv artery (vestige of the fusion of the trune al ridges). Elsewhere it would be surrounided by bulbar niyoblastic tissue and therefore would end up as the outflow orifice of the right ventriele, riding amiteriorly to and parallel with the pulmonary arterv the classic features of transpositioni. In figure 3, the last drawing of each series shows the spatial relationships aimong the four orifices of the lnormual heart (above) and of the heart with transpositioin (below) as determinied by actual dissections to be described shortlv. When this relationship is compared with that shown in the next to last drawing of each series, it caan be seen that the orifices have essentially the relationships predicted for them in this theory. The appearance of the fibroplastic. tract w-hen viewed from the interior of the heart is showln in figure 4, adapted from muore detailed drawings published previously.' Froni this view, the fibroplastic tract is the ridge of tissue froni the two A-V cushionis to the truncal ridges. The portion of the tract between the ventral. cushion and the truncus has been called the "'right bulbar ridge," and considered one of a pair of bulbar ridges, anialogous to the two truncal ridges. Suchl a designation is misleading, however, because the so-called "left bulbar ridge"' is meyoblastic tissue, whereas the ridge lnow under consideration is fibroplastie. The two types of tissue have quite different emubryologie destinies and susceptibilities. Furthermore, in giving the bulbar portion a "inamne" sight may be lost of the fact that it is but a part of a fibroplastie con-itinLuum that in.cludes the A-V cushions an-d the truncal ridges.* The conitinuity is important because the *Kramer" has preseuted evidenee that there is i1o cointiniuity betweeni the bulbar ridges auid the truineal ridges. This is certainly true of the left bulhar ridge, for it is miiyoblastie tissue while the truneal ridges are fibroplastic. It may also be true that there is nio continiuity between the right bulbar ridge (the oine we are concerned with here) and the truncal ridge in the literal senee of the word "ridge"' as an elevation- of tissue, hut there is no question of their continuity as fibroplastic tissues. It is in this cytologic senise that the wxord 'ccontinului-?'? is used here. Circulation, Volumne XXVI, November 1962 825 TRANSPOSITION OF GREAT VESSELS A - NORMAL 8- TRANSPOSITION Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 Figure 4 Internal view; of heart developmtent, schenmati, ed. Above, the normal heart; below transposition. Left, before closure of the I-V canal. TVhereas normally bulbar closure takes place in a plane perpendicuzlar to the plane of the septum, in transposition closure takes place in a plane parallel wvith the sep,tum. The fibroplastic continuum extends from the two cushions into the truncal septum. Middle, after closure of the I-V canal and development of the fibrous skeleton. The crista supraventricularis is indicated by1i the dot-dash line. The hea,rt is drawn wvith exactly the same flow relationships as on the left, but as if all ventricular musculature were transparent in order to showu the lie of the four rings. The fibrous continuum has become the aortic-pulmonary ligament; it only partially encircles the left ventricular outlet in transposition. The cushions are shown unfused to assist in orientaton but should, at this stage, be fused. Right, the septal surface of the right ventricle. The shaded area is the region where the free wall of the right ventricle attaches. The parietal and septal components of the bulbar musculature, the septal (Lancisi's) papillary muscle, and the trabecutla septomarginalis are shown. m.s.-nmembranaceous septum, showing its atrial and ventricular parts. entire tract will later consolidate to become the aortic-pulmonary ligament, a fibrous structure extending from the membranaceous septum (vestige of A-V cushion fusion) to the tendon joining the aortic and pulmonic rings (vestige of truncal ridge fusion). In the adult heart, the aortic-pulmonary ligament forms the aortic anniulus and provides a major insertion for both bulbar and left ventricular musculature.19 Abnormalities in its lie or development will be aecompanied by significant abnormalities of right and left ventricular musculature. This will be reCirculation, Volume XXVI, November 1962 turned to later, for it helps to explain some of the ventricular abnormalities often associated with transposition. In view of the abnormial location of the orifices postulated by this theory and diagrammed in figures 3 and 4, a number of deformities of ventricular architecture can be expected to occur in transposition, if the theory is correct. The remainder of the present conmiunication will be mostly devoted to studying the extent to which these deformities are actually present in hearts with transposition, and the implications thereof. 826RRANTI 826 Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 What growth or mnolding process could be responsible for a shift in the effective lie of the fibroplastic tract? The present study sheds no light on this question. Ildeed, it is altogether possible that the abnormal alignment is secondary to growth or structural changes elsewhere in the heart. It might also be asked if the shift in fibroplastie alignment is not just another way of looking at the torsion of the bulbo-ventricular septum postullated by Pernkopf and Wirtinger, bringing the right bulbar ridge into alignment with a different truncal ridge. However, this is not the ease. In the proposed theory, the aorta and the pulmonary artery are normally elaborated from the truneus, and the aorta is simply, in effect, pushed anteriorly bv the strong fibrous atachment between the mitral and pulmonary rings. The "torsion" theorv would have the truncus divided in an abnormal plane. As a result the coronary ostia should have different locations in the two theories. As will be shown, in the vast majority of eases of transposition the coronary ostia have precisely the locations postulated for them in the proposed theory, while their location has been difficult to explain in the classical theory. Also, there is no explanation in the classica-l theory for the narrowing of the crista supraventricularis found in all eases of transposition. whereas it is readilv explained in the proposed theory. Other differenees between the torsion-detorsion theory and the proposed theory will be pointed out later. But perhaps a more important difference between the classical and the proposed theory has to do with the question, which theory better provides tools for further progress in the field? The classical theory does not recognize the fibrous continuity between the pulmonary artery and the mitral valve as an inxvariable embryologic consequence of tranisposition, aiid it provides no criteria for recognizing at autopsy or experimentally the emibryologic defect upon whieh the theory is based. As ai result. a host of differenit types of ventricular septal defects with varying degrees of apparent '"overridingo" by one or the other great vessel becomes "transposition. On the other hand, while it may in time be shown that the proposed theory is not a major factor in the norphogenesis of transposition, the criterionl for recognizing transposition whieh is derivedI from this theory (the fibrous continuity 1b)e tweeli mitral and pulhuonic rings) will conItinue to be sound, reliable, and useful for the differentiating of transposition front other conotruncal anomalies. It mnust niot be overlooked that the propos.ed tlheorv (like the classical theorv) represents a vast generalization of complex embryologic events. For example, the fibroplastic parts of the primary heart tube are treated as a coiitinLumi. But truncal ridge fusion considerably precedes closure of the A-V ancd I-V canals. And the connective tissue between the aortic anid pulmonary rings is meature. fibroelastic tissue at a time whel, at the other end of the continuum. the A-V eushions still are immnnature, loosely reticulated tissue, and the A-V valves and chordae tendineac are seareely differentiated cytologically from the immature myoblastic tissue of the ventricular walls. So the so-called fibroplastie continuuim has its own differential growth. It is a continuum perhaps onlv in a spatial sense that all parts are destined to become fibrous tissue, but it may not be a continuum cytoclhemically and it certainlv is not teni- Porally. Material Amongc the hearts showing congenital malformations in the Pathology Institute of the University of Goettingen were 29 with transposition as defined above. Five of these had some degree of situs inversus and dextroversion. Since transposition in this syndrome poses special problems,.8 they are not ineluded in the present study. Among the remaining 17 cases, six showed no other functioially important abnormalitv of the ventricles specifically, they had no ventricular septal defect. The remnaininig 1I had associated ventricular septal defects; four of these had in addition tricuspid atresia, two pulintoic atresia, onie mitral atresia, and onie the A-V coinmunis deformity. There were no cases of corrected transposition i:n the series. All Circulation, Volume XXVI, November 1962 I T1RANS'OS 10N G'R E AT A'E SSE 1 S 8s2 - a, ) ./ I V(3I1 (Dmar\ V , m \TA t Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 m \111, -." -, Figure 5 lit of a noli hart 'The rer trietar s(10elt0?l ox leit) imar}ii h art w-ith h- ansjinsiiaii ( igh-t) a iaflhate trn li inr and, the gyreat v ieed (fitoti the 'entrietlar b)tisf. A )ve, tbrth esserls trailniseetd (at their roots. Belov, cpicnrdial,Ott(at (( con ecr tive tissue hiiri been t the removed doawn to the musuliatrlir aln the ftibrois rings. ihi ahimt ltrea( mitral valqv7e hris been rem red. Yote theaft the aovitaf joins. n1ia-seiilaItarc ait thle ba(Ise of its sinuse1(. Bl/ark threar eaii be seen tiiris1/icthe liearrs weev( siitiiredl bacl: to their three-dinmensioalna shape. H iearts sti. died M {ere fromii sunb'ects Awho Ilat dlied at less thian 2 years of ag-e. Electrooardio grams +were available for all but one case. Architectural Changes in Transposition Jinr its simp)lest aniatomic definitioi, traits. pos;ition- sliouild be the condition in wihielh thi aorta arises whlere normally tlhe pulmonar?N arte..ry is foutnld, anxd the pulmonary artter? alises wlhere. ntormnally the aorta is founiid lVider these circunmstances there would be 180 -de( ree rot-ationi of the great vessels al thleir poinlts of originl. 'Inl figu-re, 50 is sh1owvl tlie, ventrieular base of a niormtal heart anr ateart wvitlh tranusposition. Above, the atri; have beeni remioved; below tlwe eonmeetive: tissuLe structures (iitcludig tihe anlteroi iit ral leaflet) hia-ve also been remioved. 1: eat?. he sleen thiat in traiisposition thi.ere itot Ca 180-de'gree c nelnoe ini the positioln o flie great -vessels at liest onily a 9O-degre lifferi-eitee ftrot their ioriital locations. ( irctslation0W, Volume XX VI, November 1962 For the reuttainigr eases of trallsl)oSitioll, ani.other metlhod for stulyigt tfli lie of tltie orifiies was used, oLe wihieh dlil niot require s;o itrueh tlisseetion anti was imiore aeeurttce. 'Tlee niiethod was a:Ilso used for the situdy oft a nLumber of control hearts amnoug which Were several other types of congenital anotmaliecs. IF me surgical wire ws carefully thre-,aded through the circumference of each of the four orifices, and the free enii of the wir -, approp)riately bent. to enable identifyiutig the orifi(e. -\Viv of a (lifferennt gauge was usetd to tutlinie mit be otlher' vetitrie ular structureswnwhhieh of iitterest. After wiring roe ntgcnogrcuits were made of eachi lheart ini tw-o viewXrNs at right gles to each otlher. The ceniter of' e'acll orifice was establishied on eacDh filmi. miid bv simple geometry the angles betweelle the folur orifices were caleulated in thre-tlintcttsional space. Figure 6 sliows a typic-al roetitoviiogratNI. A normal ltear t, a heart witl3 ti ratit- (I~ ~ ~ ~ ~ ~ ~ ~ ~ ~'I' ~ CRAN 828 S28 NORMAL TRANSPOSITION 1 2- 345 6 7 Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 Figure 7 ti/itr i fillt- otlrchitcftctft in tlifosi*1/f/jobltos oof / )t iott/itof i tflit or t 1)0i/1o0. Abovet, fit fli 1t!*e)fseSl:^.7'hc auffic7 bet/ rre9v!) the)XJ{^)( o!' the oufloulx iJhiq (z1, Me mcdM9eIe I.r is *.1, the eutrij rlvi c'tot iisiiit ctu)i t, mlittit Figure 6 i t t(I for ' isi 1ioifj the lie of tfe ev fm tie fle f nwo filu?is {f-Ifobn fr/'Cidil' trifi(icts. Otliyi oif ?'it;lft aoltIts to etoch otter is8 sliowin. Fine wire onutitivues eoch o) ?ifice, wifth tItiicicr wire itlongy fli j)tosteriior snlci. Above, ao lieort if illi onItrtor nor ial heiart fromt /roinSpotisi/ion; 11nddle, inftif ; below, lheort ni/fh tetralogy of Fitilot ith "oicrriding" byj the ot<orto. Xr- o/y one on a a w positioi, aind a heart wvithi tetralogy of Fallot wvith ` overridino' (lextroposition) of the aorta arce slhownl It can be seenl that the allngular relatioishli) among, tlhe four orifiees in the heart withi tranisposition is identieal withi that siowxx ini thIle phiotograplh in. figure and1(1 the dr8awing fini figure 3, anti is (quiite differenit from thOat ini thle norma.l lheart. On the othier hand, in the hieartt witih teAtralogy of Fallot witlh ''overiri(liig, the orifices ha,tve positionis thiat (rew the Smile as in th( n1orimal rphe simplest wvay to of onti hieiart. onftflot i0i9J it ite fihet )itost cf rfliti oti tflu otbiorniol tiitoni ce from flit the poitif ohc.e thfi fri(unfpiti inu-i p/ioiediit to deseribe the (Hif- fer-enee ini alignmenit of thle orifiees is a1s follows: in the heart witlh iiornoal venlitieular skeleton a str-aight linie ean be drawni thirough thle eniters of the pulinonie, aortie, anid triciuspid rings; ini the, heart with traitsthr'ough thle )osition, the straightlinie a runs Below, fthe tie of tfleotoflon orifice of the tight 1to1f4 rictt Tliat onylt cfoaee the pltone of tfle ontf/toI orifice otdl flthr plne of fhe tricuspid tilnt wa(IS ,otiistti?urd. 1, Ment iraonticrous StJ)tfulu; ,2, tricuspid ring; .3, matn tophe' seporofing ptrittot anti septot conttponents of buif)ir mvneuslttuifre; septiti,.'6, / to'bctaa sep ft)tomi'giniiis, t lodtt (rtfor enters of the ao fie, puinfiionie, aniid mitral rillngs. ''Overriding'' l)y the aorta seih as is seen iat tetralocy of Fallot has often been eonsid'yt> p'' of transposition. As hias been red a 't piointed oit prev imusly, this is niot correet.'9 The venttiieulcar skeh1't ni is fluPfltil ill these eases, as l)roved In this roeiitgenogcrami, and(1 have' norniallv ' thle a ortie and pulilioiii rings loeated rigins with respect to thIe other orlifiees. Ih ''overriding,'' the aorta ''faces'' the right ventvie Ie becautse o0f tle( particular I( (ea tioIl of the ventricular septal defeet as w ill be disenssed later. WVithi biht a singyle exeepttion, all 17 eases Circulation, Volume XA VI, November J962 TRANSPOSITION OF GREAT VESSELS Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 of transposition showed essentially the same degree of deformity of the ventricular base as shown in figure 5. There was not more than 15-degrees variation in aortic-pulmonic angle among these eases, which is within the range of error of the method. If there is such an entity as "incomplete" or "partial"' transposition due to lesser degrees of rotatioln of the orifices, it must be rare indeed. The single case among the 17 that did not fit into this pattern was a case of transposition with "single ventricle" deformity, tricuspid atresia, and incorporation of tricuspid valvular elements into the mitral ring. Here there was a 180-degree rotation of the aorta and pulmonary artery from their normal positions. The reason for the greater deformity can be ascribed to the complete absence of both right and left ventricular septal musculatures. As a result only a thin rim of bulbar musculature separated the transposed aortic ring from the mitral ring, permitting it to lie beside the pulmonary artery (but to its left) instead of anteriorly to it. The deformity in transposition is as if the aortic orifice had simply been "pushed" anteriorly by the crowding of the pulmonic ring toward the mitral ring. This is precisely the mechanism proposed by the present theory. It will be noted that the aorta comes to have a position where nornmally musculature of the crista supraventricularis lies. Interestingly enough, this is also the location of the right aorta in the crocodile, as Spitzer pointed out. He was aware that there was not a 180-degree reversal of position of the orifices of the two great vessels in transposition. Pernkopf and Wirtinger postulated a 180-degree rotation, although many of their figures show no more than 90 degrees. Subsequent authors have often recognized that the rotation is less than 180 degrees. Such an abnormality in the ventricular skeleton should be accompanied by predictable changes in ventricular architecture. In all cases studied this has proved to be the case. For example, the plane occupied by the outflow orifice of the right ventricle should be Circulation, Volume XXVI, November 1962 82'3 more nearly in the samne plane as that occupied by the tricuspid ring than in the normal heart. By the same token, the plane occupied by the outflow orifice of the left ventricle should be more nearly perpendicular to the long axis of the left ventricle than in the normal heart. These two alterations are diagrammed in figure 7, and were present in all cases. Another predictable deformity, presenit in all cases, was the narrowing of the crista supraventricularis. In the normal heart, the shape of the septal surface of the right ventriele is roughly triangular, with the posterior cusp of the pulmonic valve at the apex of the triangle (lower left drawing of fig. 7). Normally, the distance from the diaphragmatic border of this triangle to the membranaceous septum (spanning the tricuspi(d orifice) is relatively equal to the distance from the membranaceous septumn to the pulmonic valve (spanning the width of the crista supraventricularis). The ratio between the two distances is roughly one. In the infant heart and the heart with right ventricular failure (and consequent dilatation of the tricuspid ring) the tricuspid measurement is greater than the crista supraventricularis measurement, and the ratio is increased. Interestingly enough the ratio is also increased in marked left ventricular hypertrophy.* But *There are perhaps sound enmbryologic reasons for this. The two ventricles are in physical continuity with each other in both their inflow anid outflow regions along the initerventricular septum. The inflow part of the septum (the width of the tricuspid orifice is a measurement of the inflowv region of the right ventricle) is developed by the downward growth of the two ventricles, so there is a rich anastomotic m-iuscular syncytium between the two ventricles in this region. On the other hand, the outflow part of the septum (the width of the crista supraventricularis is a nmeasurement of the outflow region of the right ventricle) develops later and is due to the bulbus cordis f olding over the base of the left ventricle. The anastomotic muscular syncytium is much less abundant in this region. Therefore hypertrophy of left ventricular muscle is less readily communicated to tbis regioni of the right ventricle than to its inflowsr musculature. S30 Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 in these coniditionis the ratio is rarely miore than 2 :1, and they are easily recognized on other grounds. Among the eases of tranispositioIn studied, the crista supraventricularis measuremenlt was never more thaii a third of the tricuspid measurement. This narrowing of the crista can be seen fromn the drawings in figure 7 anld the photographs of hearts in other figures. The narrowing of the crista supraveintricularis was studied in greater detail in the six h-tearts with transposition with no ventricular septal defect in order to determin-ie whether any specific bulbar muscular components were absent to account for the narrowinig. While the hearts were too small for extensive disseetioln, all niormal hulbar comlponenits (as described in referenee 19) were present in these lhearts but they were thinner than normial anid there was marked overlapping of the more proximial coinponents by the more distal components. Indeed, the trabecula septomarginalis was often nearly hidden from view bv the overlapping bulbar musculature. The right ventricular septal surface was altered in still other ways bv the narrowinrg of the crista supraventricularis. Normally. the posterior cusp of the pulhoniie valve is plumb with the right ventricular septal surface. The imiedian raphe at the base of this cusp (a landmark between the parietal antd septal bundles) is in the midline of the septal surface. In transposition., with the right ventricular outflow orifice drawin nearer the trieuspid ring, the right ventricular septal surface is, in effect, rolled anteriorly. The median raphe is nio longer median and comes to lie along the left side of the septal surface, with the so-called septal bundle ofteni becominig part of the free wall of the right ventricle, as showni in the upper drawing of figure 7. Incidentally, the shift in the position of the median raphe is fuirther evidence that it is not a line of closure of the bulbar part of the I-V canal, as lhas sometimes been suggested in the past. Any theory of transpositionl must explain the lie of the coroimary ostia. According to G3RA(\RANT the present theory the two ostia should be found in the two aortic sinuses which lie on: each side of the tendon connlectinog the aorta and pulnmonary artery, as diagraimned in figuire 3. It is necessary to define their location-s in teriis of the tendon joininig the twvo great vessels because this tendonl identifies the plane of fusioin of the two trunieal ridges dividing the truncus arteriosus. In the presen-t theory it is assuimed that truncal septationi proceeds normially? in which case the ostia should have the same relationiship to the tenidon as they have in the niormal lheart (also shown in figure 3). On the other hand, in the torsion-detorsion theory, muost authors have postulated that two otheu truineal ridges f use to divide the truncus; therefore the coronary ostia should have an altered relationiship to the tendon. In all but one of the 17 cases in this series, the coronary ostia were as predicted by the present theory. In the one case, both ostia arose fromn a single aortic sinius, the one that is adjacent and posterior to the tendon. But, it muay be protested, if we accept this interpretation for the lie of the coronary ostia, they will have exchanged with each other the region of the heart they each irrigate. To meake this clear, let the reader imagine himself at the center of the aortic orifice, facinig the aortic wall where the tendon to the pulmonary artery attaches. By this theory of transpositioni th e ostium to his left, which iii the normal heart leads into the left eoroniary artery, now is mainly irrigating the right ventricle. The ostium to his right, which niornmally led iilto the right coronary artery. im transpositioni is mainly irrigating the left veentriele. One cami only point out that little is kniown about the determinanits of the lie orf the coronary arteries beyond their ostia. Nearly certainly, genetic and other encoding factors will play a less and less important role the farther one moves down the corollary arteries fromn the ostia, and local factors will. beconme more imnportant determ-inants. It mnav well be that c-oronary arteries temid to be elaborated, as are experimental collateral arteries. Circulation, Volume XXVI, November I962 8I1S Tl{ANSlt0SITION 01F (G REAT AVESSELS 831S j I | 11 l 0 /, <1 -1t -0-0---5I 'I .-.,.-.-- Figure 8 Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 i. 'l7e heart has a ( 1)isplacetnent oj the left venutluor rg if;ktio.i large veitricular septal defecit. the incision. prtends front. the right ventricle, across the septum ovller the (defect into the left ventricle, Nhowing the ri'ight ventricle commlinunicating thr ough the defect iuto the outflow tr at a! the leftfen tricle. The inembrnanaceous septum ties inmoediately behind the chorda extecuding from tlhe smnlall septal (Lancisi's) papillary minuscle to thte ctiterior tricuspid leaflet. Note thle distance fronm this point to the left rentricular outflow cusps ( punttonici. AYointltty th letuft rentri -icaur outflovw Cusps (aortic) cross the membranaceous septtt in at tbout the stme point vithere the tricuspid ring crosses it. 7, Aorta; 2, outflow trail of tfhe igight centriule; 3, tricuspid orifice; 4, posterior leaf of the tricuspid valve; 5. pulmoit rl arterY;: 6, rig/it att riot part of inemb ranoceous septuin ; 7, septal papil/lo n isnciisle. from t-he vasecular soliree thiat is niearest the tissue to Ie irrigated. In aniy ease, this is whiat is suggoested as taking place in transpo- clh<aniges iii thlie mnciubranaceous seJ)tum were inoted whliel ar-e of initerest: (1) While the portion of the meumbranaceons septum that sitioin. Thie IIost intere,sting(- anid perlhaps the most ilpl)ortalit chiangoes are those related to the inebnranaceous septium an1d the aortic-pulmiionary Ihganmect. Tlie imembranaceous septumii is difficult to describe aniatomically. Tt faces a-ll fouir chamanbers; it formis part of the marg in of three orifices anid. is continuous withl thliree valxve sv stems; and it provides insertioni for botlh rioght anld left venitricuilar imnsenlatuire and also for both right anid left infunlilibular mnuiseulature. Thus defects almnost anywhere in the heart will tend to hav-e somne effTet on-i this structuire. ('uriousi>x e!noughl th.ere hias never been (a detailed stuidy of its norimial architecIture, and( we know little about its enbryoloy(v l)yevonI thie faet that it-, is on1e of tthe products of the A-V ctuslionis. I)oerr18 hlas.; emphasized its crucial, fuleral position for cardiac ilor)hogceiesis. In the hearts with tranisposition, two se/-)rate's the left ventriele fromr Circulation, Volume XXVI, November 1962 the right atriumin tra1sllniui. atc,d well, in all but three cases of transjposition, the por'tion separatincr the righlt anid left ventricles transillum-linated irreg-ularlv, if alt all. u'lie opacification proved to be due to a layer of left ventrieular muscle overlyhino the left suirfa(cie of the mnembrana(oluS sepAtui. One can1 only guess that perlumps this mneans thliere is a displacemnenit M ferio rly of left ventriuenl ar musculature, wihdich normally inserts on the aortic-pulmoniarv teindoni. This was the first evidenice that there wvas ani albormality of left ventricular niuiseiilature in. transposition. (2) The portioni of the inembranaecous septumn separating the right atrium front the left ventricle was usuallyv inecreasedl ii surface area in; the eases of transp)osition. This is best seeni by comparingZ wivhere on its ri(ht side the tricuspid ring crosses it, wvith wlhere on its left side the aortie culsps cross it. Normally, the tricuspid ring 832 GRANT 234 - 120--- Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 7-- Figure 9 Architecture of the right ventricular outflowu region. On the left, the left ventricular components are shown; on1 the right, the bulbar components that overlie and are continuous with the left ventricular components are shown. Top, drawings of the heart as viewed from the rentricular base. Center, the same heart is viewed from the ap,ex. Bottom, the right ventricular outflow tract in the large bulbar septal defect and "overpresence of riding." (a.o., aortic orifice; m.o., mitral orifice; scle (the bulbospiral bundle); I, left ventricular 2, ao rtic-pulmona ry liga m ent; 3, membrranaceous septum; 4, lateral tubercle of the left entricle; , pullmonic ring; 6, tendon from aorta to pulmothe part of the membranaceous niaary artery; septum that separates the right atrium from the left ventricle; 8, tricuspid ring; 9, crista supra,ventricularis; 10, median rap,he separating parietal from septal bulbar muscle bundles; 11, lower m>a}rgirn of trabecn la septoma rginalis; 12. modcvatoir band. a mu 7, erosses the miiem:lbranaceous septum almost directlv opposite the lie of the aortic cusps. In transposition, however, the pulmonary cusps often lie far distally from the lie of the tricuspid ring, as shown in figure 8 (and diagramnied in figure 7). The explanation for this is not known, but it is as if the fibroplastic continuu:n, which holds the pulmonaryriinog to the mitral ring in transposition, had been strenuously opposed at some date after the completion of these structures and stretching of the pulmonary attachmnent had taken place. AVith regard to the aortic-pulmonary ligamaent, normally this structure is at the line of attachment of the aorta to the left ventricle, encircling the outflow lip of the left ventricle from one tuberele to the other and therefore anatoinists call it the aortic annulus. It is continuous with the membranaceous septum and also gives rise to the tendon connecting the aortic and pulmonie rings (fig. 9). From the enmbryologic point of view, it appears to identify the line of closure of the bulbar part of the I-V canal and therefore is a principal expression in the adult heart of the fibroplastic continuum which extends from the A-V canal to the truncus. From the point of view of heart function, it not only provides the main insertionl for the musculature of the left ventricular outflow tract (principally the bulbo-spiral group) but also for the musculature of the crista supraventricularis and for certain of the intrinsic muscle components of the right ventricular outflow tract. In the presence of transposition this ligamerit is shortened (corresponding with the narrowing of the crista supraventricularis) and only partially encircles the outflow orifice of the left ventriele, as shown in figure 4. The shortening is apparently due to the fact that, wixith the pulmnonary ring drawn closer to the mitral ring, the plane of division of the truneus comes to lie much nearer the tricuspid ring than in the normal heart. It is difficult to see how this deformity could have been predicted from the torsion-detorsion theorv of transposition, yet it is perhaps the most important deformity of the ventricles in this syndrome, for it results in certain deficits of left ventricular nmuscle in transposition. These deficits can be seen in the external shape of the left ventricle and may be responsible for the ventricular septal defects often associated wvith transposition. Circulation, Volume XXVI, November 19~2 TRANSPOSITION OF GREAT VESSELS Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 The alteration in left ventricular shape is shown in figures 3 and 5. When the heart is viewed from its base, normally there is a prominent "shoulder" of left ventricular muscle immediately beneath the left margin of the right ventricle. In transposition this prominence is no longer seen, and the musculature of right and left ventricles forms a smooth left border. The "shoulder" is made up of muscle that inserts on the aortic-pulmonary ligament. Regarding ventricular septal defects in transposition, 11 of the 16 cases had septal defects in the outflow tract of the right ventricle. One had, in addition, the A-V communis deformity. In all but two cases the septal defect was distal to the trabecula septomarginalis. (In the case with the A-V communis deformity, the trabecula septomarginalis separated the bulbar from the communis defect.) Of special interest was the fact that in four cases, when the defect was viewed from the right ventricular side, it appeared narrow and slit-like, parallel with the trabecula septomarginalis. When it was viewed from the left ventricular side, it was round and large. On careful study of the bulbar musculature in these cases, all normal bulbar muscular components were present. The defect was narrow and slit-like because normal bulbar elements overlay it. Thus, in these cases the defect appeared to be due to a deficit of left ventricular musculature in the outflow region. The bulbar musculature was normally elaborated but apparently could not fuse across the deficit of left ventricular substructure. It has been pointed out previously that iii the ventricular septal defect of tetralogy of Fallot and other syndromes unassociated with transposition, the septal defect appears to be primarily due to a failure of certain bulbar muscular components ever to develop.19 Perhaps in the ventricular septal defect of transposition we have the opposite mechanism, a septal defect due primarily to a failure of certain parts of left ventricular musculature to develop. If so, it is very likely that the left 833 ventricular muscle failure is due to an absence of adequate insertional tissue, manifested by the shortening of the aortic-pulmonary ligament. It must be pointed out that not all hearts with transposition and a veiitricular septal defect showed this " pure " left ventricular muscle defect. In at least four cases certain bulbar muscular components were also absent in the region of the septal defect. The shortening of the aortic-pulmonary tendon means that the main ligamentous structure for the support of the outflow tract of the left ventricle is defective in transposition. It is little wonder that a wide range of different degrees of "overriding" by one or the other great vessel niay be seen in transposition. They have been given a number of different names on the basis of clinical findings, (Taussig, Bing, etc.). WVhich are due to defects of the ventricular skeleton in transposition, which are simply large ventricular septal defects, and which are due to still other embryologic defects is not known. One of the more important problems now facing pathologists and clinicians alike is the sorting out of these conotruncal syndromes and developing objective anatomic criteria on a sound embryologic basis for differentiating them. The Ventricular Electrocardiogram in Transposition There were 12 cases of transposition with or without ventricular septal defects but with no complicating inflow abnormality such as mitral or tricuspid atresia or the A-V communis deformity. Eleven of the 12 had essentially identical QRS electrocardiograms: the mean QRS vector was directed rightward superiorly and more or less plumb with the frontal plane. The QRS loop (plotted from the conventional tracing) was narrow, with its major magnitude in the terminal segment. Whether the loop traveled clockwise or counterclockwise depended upon trivial differences in spatial direction of instantaneous QRS vectors (fig. 10). In all cases there was some degree of QRS prolongation for the age of the subject. Thus, the typical QRS electroCirculation, Volume XXVI, November 1962 GRANT 834 I I I I1 Figure 10 spailtiatl QRS v ector and the frontal plane Q RS loop in the typical case of transposition.0t Mean plotted on the tri-acixal reference figure. SI S283-to-S1S2r3 pattern. Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 'I1his QRS finding is quite astonishing in the liht of the anatomic findings described above. For nmanv years electrocardiographers have attributed the S1S2S3 pattern, when fouind in abnormal hearts, to hypertrophy of the crista supraventricularis,* because this is the oimly part of the ventricular heart that is "facing"' the right shoulder. (Electrocardiographic theory has always held that a giveni QRS vector tends to be perpenidicular to the veentricular wall from which it is generated; ill the patternl, the QRS vector poin-ts toward the right shoulder.) Indeed, it has oftenl bee-i called the "crista supraveintricularis pattern." Yet one of the most striking differences between- the heart with transposition and the normal heart is the remnarkable X aduction in mass amid surface area of the crista supraventricularis in transposition. Nor cloes attributing the QRS finding to right bundle-branch block solve the paradox, for it still remainis necessary to explain why the terminal forces are directed rightward amid sl1periorly instead of rightward and iniferiorly as in the usual case of right bundlebra-tich block. There are two possible ways to solve this dilemma. Perhaps the electrocardiographic theorv is incorrect which postulates that a QES v-ector is perplenldicular to the region of 515253 thla eiista supraventricularis iii its origlual miieaniiig: for the portioi of tissue that lies between the tricuspid and piilmaoic rings ai-d against which the aorta curls. Eleetrocard iognplliers have aire mtiore tused the term Circulation, Volume XXVI, November 1962 orthodox 1)odY. A secon-d possibilitv, coinsistenlt with elec- car:dioorami in transposition teinds to be the p)athologists ati(l the venitricular wall where it is generated. It must be admitted that the postulate rests entirely onl theoretical colnsiderations, phvsical and mathematical calculations of the distributioni of an electrical field arounid an open. non-biological generating surface. The author knows of no experimenits demuonistratinig thlat this principle is true specifically of QRS forces as recorded at the surface of the tuim8an i trocardiograplmie thleorv, suggests that thie miiean QRS vector ini transposition is actually the resultant of two other inajor vectors haying differenit direetions. For examnple, if there were a mean: QRS vector generated froml the left venltriele wvlhielh had the direction of mlarked left axis deviationi, and another m-eani QRS vector generated relatively simultaneously froin the right ventricle with markecl rihlt axis deviation (perhaps parallel withthe lead I axis), thIe resultant of these two v-ectors would have the S182'. (lirectioni. There are anatomiie features of transpositioii that imiake this "resultanit" explanationi of the QRS axis plausible. First, the left ventricular imiuscular abnormality of tran-spositioni is precisely in the region of distributiotn of fibers from the anterior division of the left l)ulLdle branieh. It has beemi slowmi both cliiiically and experimentally that interruption or danmage to these fibers results in left axis deviation.20 F-urther indirect supportinrg evidenece is found in the three eases of transposition which had, in addition, tricuLspid atresia. It is well recognized by electrocardiographers that tricuspid atresia is associated with left axis deviation. Whliether tIme left axis deviationl is due to hlypoplasia of the right veentricle or to a left venitricular coinduetion defect will require further study. for either is possible. To appreciate how deformned the ventricular lheart is in this syindroime, onie nuist studv it th ee-dinmensionally, as shlowni in figure 11. It canl be seen that only a sm-all part of right veintricular inusculature is presentt only the bulbar part. There is nio vestige of the part of the right ventricular mnusculature that develops from the trabeeulated region of the TIiA\SPSITIONOF (;IiEAT J)i'l.ii'>MF l1'Ieatl t7411) (thle liec XXvall in floXv 11811 foliilll(l. -Is 835 3 ESES anti tfle 118e 1 ft vecoti'jell lS 818(1 deWXalI is ('0l(idSillal>v jIO)Stlc'iOi it thleue is 110o ai-.~-isilliin illalal-~lie( men,i1raiiaeea)iis s')l11181, illd tat il-g thiaI hie're is also anl ali il0lli'iiia!,itv inl 1111 ig-lol of the1c l)athXXvay o1 tIn Iniridle ot, IN S. Ill anyv cvxcot, it is (fuite- elear I alIhere is no slihstanlt ml rigid. veiitricuflar rfigtXXvarl (QR8 vee 10' HIn these eases. As a result, cveii t1loiongl I iA IiPsl)Iitioii I s pII-s('ilt-, oiie, Wvohild eiPIlt 11)(S1 ('8515e 111 5,110W. 0111¼v Jellt 8IXI5 devicatioii elhiareter'isl ie. of triilSJIild atresia. '['hiis pIrovedl to1 11 51). AlIl thrcee showed the niarked' left axis deviatioii eii'aeaeleristie, ofI tri cuspid atrelusa XXvitliont aIX dIisceri1lille effect frmnII iiisilai111to1 1(1 JInovXd 1 Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 tr'ini'Spositionl. It, l1(011-ld(1 lIe Jilltel1 oLt' that tratisp)ositioii 1 he nlot tileI onlV (eauise of tile SIS283 pattern. it Iils senl. inl othier congoeniital- heart anomtalies (althioughf i)rol)a1)ly 11(11 tts reg-ularly), aiidi is inl aet,(uireti right ¼'vintrieular hypertrophy ywliere perhiaps it is dite to hyper,t.trophy of' thle e,rista spaitrclrs ltothproof Is, still, xvanthing). anid it is eveni seen occasiontill>v ii perfectly- normial sull)ects of any- age grouMp. Differentiating Transposition Anatomically from Other Conotruncal Anomalies There arc, anomialies that often arc (hiffielult t-o differentiate fromi- transpositionl. )nie is thie larg,e bvilhar septal. lefect witli twxo (dextroposition) IbX especialiX i-f thc- puhonioe, oriflce is ii1ark~ed ''(IXverr.iding 1 lie aorta, smllall. TPLc othier Is persisten.,t trmumnis arteriosois andi( its varia-ltls sueti as 'pseudotruncus.' s i traiisposition., In-1 thlese cond(itionls, not erista suipravciitrioIdaris ma> lIe Tiarflie roved, flhe aorta appears to he takiiig' OtIf fr-ont tlle rigt Xcitricl e,nieinbranaeeoos septumt relationshipvs are ahoornial, and tie. left yenI rien181iarmscoflatutre is, oftenl deficienlt (fig.1 21. hO ftic'i iiidIiXv a lcarge iulhlar septal d tIect cani resenible trallspositionl, it is nlece's sarv- to nmiierstaiid thie aniatomny of the righit vllitricular ouitflowv region, diag-rammied ini C'ircuhlation, Volume XXVL, Novemrber 1.962 A, p /W--l< - ..( p } Ow6 (V. -OAf Figure 11 h1(111tSis 4o'ui t1(ilt ('ot' cftmjIOrisof. oil the (lt Y'(IM0y Il ljlllth,i)lrl ritci/ld d Alit joh' InI(st/-I (1111t r/I p11(I1.t li/l Ofbiio' 00/l/ dillicit0/0/Olc iml/lf Icl Theiio'tldiii $ 11(1 t h 'l t1)( 11 7/ie /)( (tilt vcltr' 't fc 'a 2r If t is (I siltII fly OC 'lrce /i figlnee 9. \Whlill the righit veltriiuelar tIiu1seluhat ure is gro1sslv a sync>vthim. tXwo layers (If dliieetiomiat alrays (If muiscle caim lIe ita,de out1 [ii its oOtfloXv regolio. 'Vlie m,ore smuperficial Ia>eIT cnsists (If eoinpoiieents that ins-'ert oIii thle ImIl(imilie ring(. Thiey pass across thfe scl)- ald surface (If tlil righit ven~tricle, eithler to merg-e XX itli r-igit venltricul'ar free waIl 11(118t'ulatiuri or to hecomne a part o-f thec trah)eeilca septomoarginialis aiid thie ii()(erator Ilaild. 'j'li, deeper, thicker layer c-onsists of coIil}oliellls that inisert oni the aortie-hltiilotiary' lig-amneit, xvlere left -ventri(ucular olltfl(IX ilulseulatuiir and( erista siipravelitriclllar-is musculature also inisert. It appears that builbar sehltal dlfeets are duie to the absciiec (If certaiiiClli111jonleits iii Ilotli lavers of bulbar musculature. il 'Phll deficiencyv in thie suplerficial lax-er determinies ivhiere iii the liuilbar region the(, defect wvill lie whlile the deflictien in thie deeper laxver deternijules howv large-( till defect xwili ho. WVithi large hulbar diefects, nwarlv all of thie deepIer layer miay he ail.seilt. Fromi the e,mh.rv> illogic. poinit of viexv, t1fis meanis that the lateral ridg~e of inyoblastie tissue failed to) fuse S3(; 8GRAN'I' t/ 4 3 2- ? Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 Figure 12 lfe mc it fro cii cvit/i ptl v the i o/t s/co cm0/tf rI/ S t//it ieniocc. is tte t tilclctis tic /l att1(1/, to 1, A tcorior m t rcc n wtcf 3i , r1ttr1joscc.8n in /st. i ste' f/t citrcci (tion uo to f1t rn l cci itccflt t; se iel wed //hii h the iit ii 9, left ftacl b/undil/e cci ture; i/i //Sci t t ic i/i t/i ildi titherigh i//st Ftititn o f rig iht cetctiit //icr free ival/ l ///sculat/te ( l/(1 01/h/i. bidibitir P///scle buntdleits; 5, riIghct c ooi iorcq c//It /7/,'I; a; singlIc poic t of ijnls ,tion oft ecistic t 9)tiit ci l 'icc 1 csc I//it; 7, intsetti ni of o n Inclcu i i fn ser'tiOn o f lef t ic- o 1, , o i thfe fibroplastie, cointimcuuitm. Witlh n1o Iculbar I nuisculature ini the ouitflow regioi], the left venmitrie l ar mn use inl ature is inc apable of growingr across to mieet time aorti- pulniouiary li'ia,11nent. and the defect is- 'throuAgh and throug-h. Withi neither righlt nlor left vemi' tricular septal miusecilature mneeting, the aortic-pulmuconary ligamient, the only miusculature' inse,rti omii t1e li(gament an-d mieefting the lip of the aorta is t h-e crista sutpraventricularms. l1int this mn-useculature belon(,s strietlyN to time free Nxxall of thei rigiht vemitricle. As a result, the aorta is suispemded anteriorly, solelv bv the free wvall of tIme rigfht venitricle, aind thlis is the reason xxhy, ii '"ox erridling, the aorta apl)ears to origrinate fromn. the right ventlriele. TPhm're is nio abniormiiality of the venitricular skeleton. 'T'ine ahbrormnalitx lies in the elahora tioilm of bulbar muscuilatutre. Thlerefore thie, wxav to (ditefrenltiate it fromti transposition is to see if the ventricular skeleton is albormnal. wvitlh 'l'llis is miost sillmply (11on ly seeing whiclh outflow orifiee is continious withi the anterior itral leaflet, as poinltedI out earlier. LIn the large venitricular sept)al defect tlie mitral auid triduspld valve surfaces are often conttiniuous wvitlh eachl otlier. Such a defect is some(-t4imes explained as due to "absenee'" of thie nnl.mbranaceous septuim. But if it were truly ahsenit there would be free counnunieatlion between three, anid perhaps all. four chalibl)ers. Tt is imiiportanit to remteibler thilai anatomically the nieminbratnace-ous septum is b)ut aii inisertionial tenidon foir atrial anid veiitr-icular mi-useulature. Wlhten a given region of museulature fails to fuse wvitlh the fibroplastic con-rtinuum, it does not develol) its tendon, and that part of the mnembranaceous septuim will be absenit. In tle large ventrien lar septal defect it :is usuially the musculatiure of the trabecula septomargiincalis that failed to mtteet the fibroplastic conitinuuim. 'The tetn(loll for this musculature is the part of the, tciemlbranaceous septum separating tle two ventricles aiid separating the mnitral anid tricuspid riligs valve surfaces. But other parts of the miemiubraiaceous septum are usually present in. suclh cases, notably the part se,par atingo the right atriumn fronti the left veciitricle. Iii the heart withi tranispositiont. aiid a large ventricular septal (lefect, the mitral anid tricuspi(l valve surfaces muiay at first appear to I)e- conltinuous. Ilowvever, oni closer study of all suelh cases in the present series, there was founid a slenider banid of left ventricular musdc extenidinig to the pulmonie, ring and separatin, thee imiitral and tricuspi(d valve surfaces. Thlis is illustratetd in figure 13. This is apparently the sameIleft ventricular mnuscle, described earlier, wllich oxerlies the mcemItlrwaiaceous septumi in othier hearts with tranispositioni. ini this lheart it extended precisely to the reg-ion between the outflow cusps wlxere normiially the interventrieular part of the menibraniaceous septum lies. It is iriteresting, thlat the abn-iormal or (lisplaced band of left ventricular musculature hlas sueh growtlh primacy that it will appear even in tihe abCircutlation, Volnune XXVI, November 1962 1 VESSS ELj S TRANSPOSITION(O)F GIREAT Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 (Iltf tof tllis part otl the neiiltrlanaceous seeptum. lRegar(liig "'tructies,'" it is onilv possihie i 1as)pets that relateot here to discussx ((tlan the vejitrieular skeleton. Whlile. (eclassical is rea(lily recognized at autopsy> t ni Iies C soneitinies it is dfifficult to h)e sure that the pulmionary artery is ahsent, and oecasio)lllly thiere are oiilv three olutflow C11J)5 (resinp bliliig an aorta) instead of fotur. Buit even ini the classical ease one, muitist determttine if tin^ skeleton is otherwise nioormYlal. When the fibirons andcl imuseular struetures attaehiing to the truncal ring, are stutdied, eertain of them reflite to the aorta, others to the pulmrltoiiary arter>-, certain are left ventricular, otliers are r ighlt ventricular. r11ie plane h)etween the two group)s will indieate thie planie in xx Inelh thle dlivided if further develz trnclcus would have, oJ)lllt had taken place. Tph1el heart shown i n figure 12 is a classieal cset of lersistellt truniens arteriosus,. It ('al hie seen that thehlalf of tIew truneal ring- xvitli coronary ostia is cointiinuous Aitlh the anterior leaflet of the mitral valve. Since thie aortic part of the truneus adjoins the miiitral valve, the trtncal ring is in niormial p)ositionl in tlis ease. Faill tire of tile truneacl ri(lges to fuse is its oni> skeletal ahniormriality. However, nearly eelltainlv thiere will be eases of 'truncus?" withi tle transpositiollal deformity of the velntriclar Skeletoll, tile )ullllollic part of the truniical rillo eolltinuou's with the-}aliterior- miiitral leaflet. of septal defect with pul In eases houl.bar ittoiiarv artery atresia (often called '`pseilotrutlleus bv the ehliciian) the ventricular skele0ton is ittore (ifieult to appraise liecause pl)llnonary' valvular eleinents are abselit. One mig-ht tllillk the preseciee or aibsenee of trans- position: could h)e deterlntined in(lirectlv. That is, if the aortie rilcr is hiot conltilluous withi the aniterior imiitral leaflet, the pulmoniie rilig (Ilowever vestigial) mnust he. But this is niot neeessarilv the ease. Neufeld, Duislhane, anid Edwards2' have deseribed a groul) of eases that bear on this under the title 'Origin of Bothl G reat Vessels from tle Right VYeiCirculation, Voltmec XXVI, November 1t962 Figure 13 Ainomalos it I't ientit cidt/t ttisct e in titt t's )s'itio,t, cls)e:-up2 of'( h c (sfrtsIf -h at /<lar.ty rentr ilcW(IrS son/til0 d/iletct in itfiitt/on to finnspnosi/imn. Titv cif s nineinno njft/i t J / 0/ll.fches terit( ini' tic|dt the Jlnni' n/ 1h/i defect nf let -ncr c t es j,)t! n t c(I h , t) fi' iJ )trip n f i eft r. c f tficui/in* t On1 btecift ninocci. fith initi'tti itnd lciiitspid 'ti/ic strf ('tic ts. po)02tion',- a.1r, axo tliC ottnieitit-iial rIt/ce c itsps; nt'.p it/tm icti' it rmfin t.v'.n tr ict.ispid vl ves!, ,9.p}fat ? r'ct/e; anomtm ni mS'cc, t e sti'i nt/ (J 1 t Ic'cr iCi'u/ctr musole. tricle.'' (To bie sure. am1ong the 11 eases ie- l)olted terew are three ii- which the aortie ring was in fibrous eontiu-tity vitil the anterior nitral leaflet. ]While the A-ord 'orioill 1ny.a1, differenit mileanligs, frol ani mtahavl maae anatonic anId enllibtryologicj)oiit of view, (iie imuiist collclle tlat in. these three eases the aorta `originiated` wvith- the left venltriele LI(l nIot wi;thl thle r'ighlt/.) Nevertheless, ill thel reinlaillillg eases there is 110 dlount that neither the aor}tie( iior the pulmlonie riilg) Was il fibrous eonltiillitv w\itlh the anterior nitral le a fle t. 'liese ecases are extremely ih portamit, fol* they represent a rieviousl>' un1knoNvi tVp)e (f coiigeiiit-all lalforlaiitiiLl of the veintricular skele,ton. TI(o interpret thenti in thet light of' the emlbryolog(ic shemiea deserihnd ahove, evilulnu is illter' dleitlv thle fibroplasti(e coiti ruptetI by iiuse 1ulature tlhe fihbroplastie proeess dividing fthie truineus is 110 loniier con- 838 8",38 tttihll0tellt ot' the p11110(1 iamry art-Ierx lax lbetxweeii the ilmlie and( mi'trl.1 t i'tilSpSitOil 4, pa. ant. I Figure 14 it/ tI00110/ lit JI1)uscti/or scp)lotIlo/1o ) ]'oln isoith: ou11o It otifit 1c5 ino ttatsposit ion. -Thtre -i's a / hot(pid ttot volI c1 810f ((to tII,, Itc cittittIIl c o coo t ill 1)01IS ; 01i/itIIri of tile tOt )- otitj.)o-itttt Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 1111118.C(H xvilp hew c(In(e5 (lenit (ugtheA canal1. Since iio. par't (If thle trttiieus is iieldl to theo mitral ring- hy a tiltrotus attaelniiemit, thie left xonttriele never acquires a truliial outlet. And(l wxhein tie, truncus ffiiilly dixvides, it- siiiply- providles tie, b-tlbius xx-itb txxo otitt lets xwlhere formeriy it iicad bu-t one. T1lw imrl alle! I uhel)(s -becomne the ''douible outlet*" fo thrgh ellitr (I(e, a teo.ru WNithatu112 inijro_ arc of so1111i' for tllev explain wliy there, are iiiportaiiee, outlet" righlt veiitricle lImit oaes(f ''double huolbalfhy there xwiii never be described (cases of ''double ou-tlet'' left ventriele. It is interest-Aiti thiat the genieral. shiape of the hear is, niormiai in thiese. eases, for thiis means tiiat eitiier tuec interruptioti of tlime fibroplastic coiitniuutmtii occurred after the. heart hiad acquired mncost of' its shape., or thie fibrophastie eontini uxitii is miwithier caue or(1 riesulit of the 1)cIid In) tlue, prixutixe cardia,rc tube. -Also, tiiese ea4seIS suggoest that thev limlite(l groxvtih capacityN of thie fibroplastir, contin,11uum1 is iri part i.e sl(Iishe f'or briningiito thie txwo ventricuilar- ''l'11(s(' cuibry ologile II c rings)ote xxeve ioliitoiar.x al resia ( sexerI ol Neittelds5 (1s8(5 h11( Jplloiiirliiv ste1110515 lrg 1)111 iioie 1iaid pIlliioIlIarv altrlesa i)llbatr sepilal df(let)' anld a xx'i(le 1)811(1 of 11111 ettllt treejiaiit ingIlie toil till rin1g froiti I lie ig tier ouitflow reg,ionl. Neit her I le aloitie 1ii) the Site o)f attachrlieiit ot iI lie amt r.et ie p)lMlil( m, V. o0/ itO 41/~ ~ ~ ~ ~NTI~ .TRA impjlieationis itifundihula togethier. Thlere was onie heairt iiifthe present series thlat closely resembledl tue hiearts described 1y Neufeld and ccoxvorkers amid J)crhlaps shieds furthier Ight on this inaterestingp antomaly. Ift is; siioxx'u In figntre 14, as vicxxed fr-oni thie venitricula-r 11881. In adldition to resenblihig- nlaux arlterx was evxli suggvest ivelv coiitiliiitois xxiilte turid ring'. '['ile iiittssci]atiire sepflow reami ltvd to aratinig iiflox.1( Ihe c(litirelx blhtllal. Inlseulta ire cotirsitig('I etiiiitcreiiti.tllx armltld thle base of the( txx 0) olutftlox '-I rite'l res'. Inl thlis ease, thenl. t.he separation oIf iittlox 81(1itt oflow regonIMs flinl( the of the tiihrous cmotit 111111110-AWa ititerritpt iou aeemoqfc)II IIslIIe d Iv1)x hItIlhar1 iitseI II at I Ire1 . T'I I1 ilnflldibllolltllo. o)f tIhe roligt x i iem1( lotngli JILxt.apose(1 the iii lldii(lltllmu of, the left x eti tricele hut protrtudedl hex 01mi1 the v ciiiritular ilase. Ihlie protrtusimll of the IIuLIIIl perhaps cixplaitils wihy, -ill N'eufelds eae tile 1)111 and ort ie rings apjpear dooial 111.0111cMI i(o he, .1ii the satne plcate wxitli eaeli othe.r, blitt abno-rmtally distan-it from tile plhtte of thle inflow oritiees' a criterion xxhielhi thev found usefi111 ill the el iiiieal reeoglnitill of, these It is imossible that th ef(let ortit 'x ill t--ins hear11.t is onlyv (ifferellt, ili (legree fro-ml t hat 1 l1s. s (4in eertaitil othe(r heart-swti N i notd tioii. For example, -it xxvas piit ouit that (Ifften ill traiisposit 1011 the left x nuelrotittloxx orifice lies cOulisiderably i)eyoll( ~its n1or. mia] position xxvith refer-nce to the ineiiiraiiace,ons sepItun., anid aii exampijle wxas slioxxvi in1 figure11 8. Aiid pr].otrtlsi(1 1 o the( hbUr1(011 poient heyo(111( the, hoty o)t thle left x ciii ricde xxas inirticul:irly strikingT In t1w c'ase )f tr i figure ii. (oIl ItI A III ('tisp.,)I d a trecsia shown. he that the factor a:ce.oulltilo- fo(.r this, protrIii siin iin traiish)sfit ion wxheni more proIlullled(. (lixvides the ti) )ilcmcoit iutitin and IlIn righit xT c1Iit r i(de restll'ts dotd)[le (titiet Clearly there is iiin elit' tlo he learlied about the iuor1Phogeiie1)(sis- (If CMiigeiiital card liai tnomalies. tinr,latimt,( Vootw tAttx xV'I Norfttbcr I TRANSPOSITION OF GREAT VESSELS Summary and Conclusions Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 From earlier studies of the embryology of the ventricular skeleton a new explanation of the morphogenesis of transposition of the great vessels is offered. It is simpler than earlier torsion-detorsion theories, and provides criteria for differentiating tranlsposition from other conotruncal anomalies, which previous theories do not. The theorv postulates that there is, in effect, a shift in the orientation of the fibroplastic continuum which lines the primitive heart tube, extending from the A-V canal to the truncns arteriosus. Norinally this continuum holds the aortic part of the truncus in fibrous continuity with the mitral part of the A-V canal. It is suggested that in transposition it is the pulmonic part of the truncus that is held in continuity with the mitral ring. Such a morphogenetic sequence would be accompanied by predictable abnormalities of other parts of the ventricular architecture. These would include (1) narrowing of the crista supraventricularis., (2) re-orientation of the bulbar part of the right ventricular septal surface, (3) a particular lie of the coronarv ostia, and (4) certain deformities of left ventricular musculature. Seventeen hearts writh transposition and a number of control hearts and hearts with other types of congenital conotruncal anomalies were studied. In all iiistances the deformities predicted were found to be present. The abnormality of left ventricular museulature proved to be of special interest. It is probable that the ventricular septal defect which often accompanies transposition is, in many instances, due primarily to an abnormalitv in the development of left ventricular nmuscle. This is in contrast with the septal defect seen in tetralogy of Fallot and other conditions without transposition, where the elaboration of bulbar nmusculature appears to b)e primarilv at fault. Regardinog the electrocardiogram in transposition, nearlv all cases niot coinplicated by inflowNT tract deformities showed the 8152S3 pattern with QRS interval prolongation. This Circulation, Volume XXVI, November 1962 839 pattern has in the past been attributed to bypertrophy of the crista supraventricularis. But in transposition the crista supraventricularis is always greatly reduced in mass and surface area. To resolve this paradox withinl present electrocardiographic theory, it is suggested that the mean QRS vector in tranisposition may be a resultant of two other simultaneously generated vectors. One is fromn the left ventricle, showing left axis deviationi secondary to the left ventricular musenlar abnormality of transposition; the other is from the hypertrophied, dilated right ventriele and shows marked right axis deviatiotn, The resultant of two such vectors would write the S1S2S3 pattern. The anatomic differentiatioin of tranisposition from certain other outflow tract anomalies is discussed. In particular the ventricular skeletal abnormalities are compared in (1) conventional bulbar septal defect with mnarked overriding" by the aorta, (2) persistenice of the trunieus arteriosus, (3) "pseudotruncus," anid (4) the svndrome of the "double outlet" right ventricle. Acknowledgment The author wvishes to express his great indebtedness to Prof. Jules Linzbach, Chief of the Pathology Institute of the University of Goettingen in Western Germany, for generously making the material and resources of his Institute available, for his unflagging interest in this work, for his stimulating and challenging ideas, and for his warm hospitality during the author 's stay in Goettingen. References 1. GRANT, R. P.: The embryology of the ventriicalar flow pathways in man. Circulation 25: 756, 1962. 2. GOERTTLER, K.: Hemodynamische Untersuchungen fiber die Entstehung von Missbildungen des arteriellen Herzendes. Virchow 's Arch. 328: 391, 1956. 3. DE VRIES, P. A., AND SAUNDERS, J. D. M.: Developmenit of the ventricles and spiral outflowv tract in the human heart. Contribution to Embryology No. 256, Carnegie Institute of Washington. Baltimore, 1961. 4. SPITZER, A.: tber dein Bauplan des missgebildeten Herzens. Virchow 's Arch. 243: 81, 1923. 5. HARRIS, J. S., AND FARBER, S.: Transposition of the great vessels. Arch. Path. 28: 427, 1939. GRANT 840 Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 6. BARTHEL, H.: Missbildungen des menschlichen Herzens. Stuttgart, Georg Thieme, 1960. 7. GOuL-D. S. E.: Pathology of the Heart. Springfield, Illinois, Charles C Thomas, 1960. 8. HARDIN, G.: Nature ad(l mani's fate. Newv York, Rhinehart, 1959. 9. PERN.KOPF, E., AND WIRTINGER, W.: Das Wesen der Traiisposition im Gebiete des Herzens. Virehowx 's Arch. 295: 143, 1935. 10. LEV, M'., AND SAPHIR, 0.: Transposition of the great vessels. Arch. Path. 39: 172, 1945. 1 1. DE LA CREZ, M. V., AND DA ROCHA, J. P.: An ontogenetie tlheory for the explanation of congeniital aiialformations insvolvinig the truineus and eonus. Amii. Heart J. 51: 782, 1956. 12. SHANER, R. P.: Complete anid corrected transposition of the aorta, pulmiionary artery, aind ventricles in pig embryos. Am. J. Anat. 88: 35, 1951. 13. DOERR, MT.: Die forinale Entstehuntg der wvichtigsten Missbildungen des a rteriellen Herzens. Beitr. path. Anat. 115: 1, 1955. 14. GOERTTLER, K.: -Normiale unid patlhologische Entwicklung des nienschlielneii Herzens. Stuttgart, Georg Thieme, 1958. 15. GOERTTLER, K.: Die Stoffwechseltopographie des embryonalen Huhnherzens und ihre Bedeutung fiir die Entstehung angeborener Herzen. Verhandl. deutsch. path. Gessellseh. 40: 181, 1956. 16. GROHMANN, D.: Mitotische Wachstunmsintensitit dles emhbryonalen und fetalen Hiihnehenherzens. Ztschr. f. Zellforsch. 55: 104, 1961. 17. KRAMIER, T. C.: Partitioning of the truncus and conus in the human hjeart. Aml. J. Anat. 71: 343, 1942. 18. GRANT, R. P.: Dextroversion. Circulation 18: 25, 1958. 19. GRANT, R. P., DOWNEY, P. M., AND MAMAHON, H.: Architecture of the right ventricular outflow tract in man. Circulation 24: 223, 1961. 20. GRANT, R. P.: Spatial vector electrocardiography. New York City, Blakiston Division of McGraw Hill, 1957. 2-1. NEUPELD, H. N., DUSHANTE J. W., AND EDWARDS, J. E.: Origin of both great vessels from'i the right ventricle. Circulation 24: 399, 1961. 22. WITHAM, A. C.: Double outlet right ventricle. Am. Heart J. 53: 928, 1957. Difference of Opinion I cannot fall out or contemnn a man for an errour, or conceive why a differenee in Opinion should divide an affection; for Controversies, Disputes, and Argumentations, both in Philosophy and in Divinity, if they meet with discreet and peaceable natures, do not infringe the Laws of Charity. In all disputes, so much as there is of passion, so inuch there is of nothing to the purpose; for then Reason, like a bad Hound, spends upon a false Scent, and forsakes the question first started. And this is one reason whv Controversies are never deteramined; for, though they be amnply proposed, they are scarce at all handled, they do so swell with unnecessary Digressions; and the Parenthesis on the party is often as large as the main discourse upon the subject.-SIR THOMAS BROWNE. Religio Medici. Edited by W. A. Greenhill, M.D. London, MacMillan and Co., Ltd.. 1950, P. 98. Circulation, Volume XXVI, November 1962 The Morphogenesis of Transposition of the Great Vessels ROBERT P. GRANT Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 Circulation. 1962;26:819-840 doi: 10.1161/01.CIR.26.5.819 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1962 American Heart Association, Inc. All rights reserved. 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