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Pathogenesis of transposition complexes
Pathogenesis
of Transposition Transposition
III.
True
LODEWYK
H. S. VAN MIEROP, M.o.t and FREDERICK \I’. \L’I(;I,ESWORTH, M.D. Montreal.
T
of the Great
MATERIAL One hundred and six specimens exhibiting some form of true transposition complex were studied (Table I). In 85 the position of the ventricles was normal; in 21 there was ventricular inversion. Most of the hearts were from the collection of the Department of Pathology of The Montreal Children’s Hospital; the others were from the collection of the Subdepartment of Thoracic Surgery, Albany Medical Center, Albany, N. Y. TRANSPOSITION OF GREAT VESSELS WITHOUT INVERSION OF VENTRICLES In this condition the aorta arises anteriorly from the right ventricle; the pulmonary artery, posteriorly from the left ventricle, and the two vessels run parallel to each other (Fig. 1) The foramen ovale is always anatomically patent; the ductus arteriosus may be narrow or closed. The morphology of the heart itself is strikingly normal in about one third of the cases, although the base of the aorta is situated slightly more to the right than the root of pulmonary artery in a normal heart. The fact that the hearts in uncomplicated transposition of the great vessels look so much
Canada
* From the Department of Anatomy, McGill University, and the Departmrnt of Hospital and McGill University, Montreal, Quebec, Canada. t Present address: Albany Medical Colleqc of Union University, Albany. N. Y. 1961
Vessels*
alike suggests that the developmental error responsible is the same. Since the morphology of the ventricles and atrioventricular valves is quite normal, it is reasonable to assume that the bulboventricular loop developed normally. For the same reason it is likely that division of the conus cordis takes place in a normal fashion. Thus the error probably takes place in the truncus reBoth the truncus and intercalated gion. valve swellings develop as local elaborations of the continuous layer of young cardiac mesenchyme beneath the endocardium of the They are, therefore. not truncus arteriosus. completely separated from each other. Normally, as has been described in Part I, the truncus swellings appear earlier, grow faster and become much larger than the intercalated valve swellings. The dextrosuperior truncus swelling becomes continuous with the dextroposterior conus swelling and the sinistroinferior truncus joins the sinistroanterior conus swelling (Fig. 2 A,B,C). We propose the hypothesis that the developmental error of the truncus responsible for true transposition of the great vessels is the result of a reversal of the roles played by the truncus swellings and of the intercalated valve swellings. It must be emphasized that the intercalated valve swellings, contrary to descriptions given by previous workers, develop at about the samr level as the truncus swellings. If the intercalated valve swellings appear earlier than the truncus swellings and become the major structures in the truncus, then these swellings will execute the division of the truncus. Thus the pulmonary intercalated valve swelling forms the “sinistrosuperior truncus swelling” and becomes continuous with the sinistroanterior
HE ANOMALIESto be discussed in the present paper are characterized by a reverse anteroposterior relation of the aorta and pulmonary artery, i.e., the aorta arises anteriorly, the pulmonary artery (or its remnant) posteriorly and parallel to the aorta. The pathogenesis of these anomalies, which we consider true transposition complexes, is entirely different from that of the defects discussed in Part II, in which the aorta was generally the posterior vessel.’ Two main categories may be distinguished: those without and those with inversion of the ventricles.
AUGUST
Complexes
231
Pathology,
The
Montwal
Childrrn’s
Van
234
Mierop
and Wiglesworth TABLF.i
True Transposition Principal
Embryologic Error
Inverted (mirror image) development of truncus swellings
Complexes
Anomaly Transposition ventricular
No. of Cases
of great vessels without inversion
85
Isolated anomaly With ventricular septal dcfcct and minor other anomalies With major associated anomalies Inversion of the bulboventI-icular loop
34 19 32
Transposition of the great vessels with ventricular inversion (“corrected” transposition)
21 Total
conus swelling. Similarly, the aortic intercalated valve swelling develops into a “dextroinferior truncus swelling,” continuous with the The dextrodorsal conus swelling (Fig. 2 D,E,F). true truncus swellings then merely act as the intercalated valve swellings. The aorticopulmonary septum and the conus septum develop normally. The final result is that the aorta arises anteriorly from the right ventricle and the pulmonary artery from the left ventricle posteriorly, i.e., there is transposition of the great vessels. Associated Anomalies: In 22 per cent of our cases of transposition without inversion of the ventricles, the only other major anomaly was a ventricular septal defect located in the area Associated minor of the membranous septum. In another anomalies were common (Table I). 38 per cent there were associated gross defects such as atresia of an atrioventricular valve and/or an arterial valve, double outlet right ventricle, common ventricle, endocardial cushion defect or major venous anomalies. The remaining 40 per cent showed no (major) associated anomalies. TRANSPOSITION OF GREAT VESSELS WITH INVERSION OF VENTRICLES
This anomaly, commonly referred to as “corrected transposition” and until recently considered rare, is being seen with increasing frequency.? n3 In its simplest form the aorta arises to the left and anteriorly from the leftand the pulmonary artery sided ventricle, posteriorly and to the right from the rightsided ventricle. Morphologically the rightsided ventricle resembles a normal left ventricle
106
and has a mitral valve, with an anterior and a posterior papillary muscle, each composed of two components, and the pattern of trabeculation is similar to that seen in the normal left ventricle. The left-sided ventricle resembles a right ventricle and contains a crista supraventricularis, a trabecula septomarginalis and a tricuspid valve. The atria are normal in structure and position (Fig. 3). This anomaly has been called “corrected” transposition, indicating that functionally the transposition has been corrected by a conThus comitant inversion of the ventricles. the pulmonary artery carries venous blood and the aorta, arterial blood. Lochte” believed that inversion of the bulboventricular loop together with the usual type of transposition was the cause of corrected Hence, he assumed the simultransposition. taneous occurrence of two unrelated anomalies. Geipel,5 opposing this view, held that the cardiac loop forms normally, but that secondarily the entire (undivided) truncus, because of abnormal rotation (“drehung”) to the left, is shifted to the left ventricle. The right ventricle remains the right ventricle, and the left ventricle reAfter division of the truncus mains on the left. the posterior portion, as in normal development, is then transferred to the opposite ventricle. It is this transfer which, according to Geipel, determines the position of the atrioventricular valves. The arguments on which Geipel based his concepts have since been proved invalid, and Lochte’s views have been accepted by most authors. On the basis of our own studies, however, we have come to the conclusion that corrected THE
AMERICAN
JOURNAL
OP
CARDIOLOGY
Pathogenesis
of Transposition
A
Complexes.
235
III B
FIG. 1. Tran.$mition of the great vessels without ventricular inversion. A, section
through the ventricles and great arteries. The heart has been positioned so that the plane of sectioning lies frontally. B, projectional diagram of the base of the heart. RA and LA indicate position of the right and left atrium.
transposition, i.e., in\,ersion of the ventricles associated with transposition of the great vessels, is indeed due to a single embryologic error: inversion of the bulboventricular loop. Previously the associated transposition presented something of a problem in explaining the anomaly, and a second developmental Actually, error was usually presumed present. inversion of the cardiac loop with normal partitioning of the trunco-aortic sac will of necessity lead to transposition of the great vessels, as already pointed out by Walmsley6 and by de la Cruz et al.’ If the truncus swellings de\,elop normally in relation to the (inverted) bulboventricular loop, their position relative to the truncoaortic sac will be identical to that of the swellings which divide the truncus in transposition without \-entricular inversion. The final result therefore is transposition of the great arteries (Fig. 2 G,H,I). To bring the arteries into their normal positions relati1.e to each other and to the (in\,erted) \:entricles, a second anomaly would be necessary-. The truncus swellings would have to develop in a manner similar (but here in mirror image) to that which occurs in transposition without inversion. To our knowledge no such case has been reported to date. The case of Ratner and Abbott* is probably- an example of a peculiar combina-
tion of anomalies, in which both atria are morphologically right atria. We have seen 6 such cases of atria1 isomerism usually occurring in cases of congenital asplenia. Associated Anomalies: Transposition of the great vessels with inversion of the ventricles is almost always combined with major associated anomalies. Abnormalities of the atrioventricular valves are common, particularly of the left, morphologically tricuspid valve. Insufficiency and Ebstein’s anomaly are among the more common and important defects seen. :1-l:! The relative frequency of the latter in cases of corrected transposition is interesting, since the same lesion occurring in an otherwise normal heart is extremely rare. Ventricular septal defect, pulmonary stenosis, double outlet right ventricle, single ventricle, atresia of an atrioventricular or arterial valve and endocardial cushion defect may be present. It is important to realize that the so-called “corrected” transposition is merely one form of transposition of the great vessels with inversion of the ventricles. Rotational anomalies are not uncommon. Ten of 21 cases in our series showed a rotational anomaly : In 5 cases there was dextrorotation in situs solitus, in the other 5 there was levorotation in situs inversus. We have never seen a rotational anomaly of the heart without
236
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Mierop
and
Wiglesworth
*‘.
F
FIG. 2. Division of the truncus arteriosus. A, B, C, normal heart. D, E, F, transposition of the great vessels without ventricular inversion. G, H, I, transposition of the great vessels with ventricular inversion (“corrected” transposition). THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Pathogenesis
of Transposition
Complexes.
III
237
FIG. 3. Transposition of the grrat vessels with inversion of the ventricles. A, section through the ventricles and ascending aorta. B, prqjectional diagram of the base of the heart.
of the ventricles. In normal development of the heart where the cardiac loop bends to the right, the apex of the heart eventually lies on the left side. In corrected transposition, where the loop is inverted, normal evolution of the apical portion should bring the apex on the right side. Therefore, as pointed out previously by de la Cruz et al.,’ the rotational anomaly in corrected transposition represents the normal condition, and its occurrence in transposition with inversion of the \-entriclcs is not at all surprising. inversion
REVIEW
.WD CRITICISM OF CERTAIN CURRENT
CLASSIFICATIONS OF TRANSPOSITION COMPLEXES
Geipe15 proposed eight possible types of transposition comp1f.x. Four were uncorrected functionally; the other four were corrected. In all eight types the aorta is located anteriorly the pulmonary artery, posteriorly. MijnckebergI adopted Geipel’s classification but rearranged it. The types Al-4 were uncorrected, types Bl-4 were corrected. Harris and FarberI gave diagrams of the eight possible variants, and Cardelli6 rearranged the sequence of the diagrams to fit Geipel’s classification as adapted by MBnckeberg. Cardell’s illustrations have since been adopted by others. His type Al illustrates complete transposition; A2 is the same in situs inversus totalis. Type AUGUST
1963
B3 is corrected transposition; B4 is again the Types A3 and 4 and same in situs inversus. Bl and 2 have in common that the aorta arises anteriorly from a chamber which is morphologically a left ventricle, ancl a pulmonar) artery which originates posteriorly from a morphologic right ventricle (so-called “anaIt becomes immediately tomical correction”). apparent that these four types cannot be exYet 4 cases of type A3,“-lg six explained. amples of type B1’X~20-2* and two examples of type B2?5,?6 have been reported to date. Apparently no example of type A4 has been Lochted believed that errors in observaseen. tion led to erroneous interpretation of the specithem inexplicable mens. Geipe15 considered variations of nature. Actually the reason for They their inexplicability is rather simple: do not and cannot exist at all: they are pmhryologic im@xsihiliti~s. An anteriorly located aorta originating from a morphologic left ventricle would place the crista supraventricularis in that ventricle. This is not possible, since the crista, which is derived from the conus septum, belongs to the morphoAn anterior great artery, logic right ventricle. whether it be the aorta or the pulmonary artery, always arises from a morphologic right ventricle or part of a right ventricle (as in tricuspid atresia and rudimentary outflow chamber). The number of leaflets of an atrioventricular
238
Van
Mierop
valve is no indication of its true nature since variations are common. Much more reliable is the structure of the ventricle and papillary muscles.27 A review of the reported examples of types A3, Bl and B2 showed that none of these could be accepted as such with certainty : Type A3. Lochte” remarks of the cases of Walshelg and Stalz” that no description of the ventricles or illustrations were given. MGnckeberg’” states that in Thtremin’s Case 37 the aorta arose anteriorly from the conus pulmonalis and that the pulmonary artery originated from the left ventricle like a normal The tricuspid valve is said to have aorta. had two leaflets and the mitral three. No description is given of the ventricles or papillary muscles. Grunmacht3 calls his case corType Bl. rected transposition. The tricuspid and mitral valves are said to be on the right and left side, respectively, but this is not in accord with the illustrations, which clearly show a mitral on the right and a tricuspid on the left. Thtremin’s Case 4718 is described by Lochte,4 who points out that structurally the ventricles were inverted although the atrioventricular valves are said to have had the normal number of cusps. Lewis and Abbott’sz” case appears from the illustration to be a straightforward corrected transposition. It is said that the atrioventricular valves were normally arranged? but no description or illustrations were given. There Doerr’s?* case is difficult to analyze. was a common ventricle, and both atrioventricular valves are said to have had three leaflets; however, the papillary muscles on both sides resembled those found in a left ventricle. We would like to point out here that in many cases of common ventricle both atrioventricular valves resemble mitral valves structurally. The description of the heart reported by Carns et a1.,21 though interpreted by Abbott, Their Figure 4 is singularly difficult to follow. suggests that the right ventricle and right atrioventricular valve were morphologically a left ventricle and a mitral valve, respectively. The nature of the atrioventricular valves in Brown’szO case is merely indicated by the designations tricuspid and mitral valve; no further description is given of the ventricles. The illustrations consist of rather simple line drawings. Ty,be B2. Gutwasser’P case had the crista
and Wiglesworth supraventricularis on the right side, as is to be expected in corrected transposition in situs inversus totalis. No description is given of the ventricles, and the right and left valves are merely said to have been bicuspid and tricuspid. In Fingerhuth’P case the atrioventricular valves are not described ; however, Geipe15 states that the pictured left atrioventricular valve looks as though it consists of three leaflets. In this case there was also a common ventricle, which often, as already stated above, makes analysis of the atrioventricular valves difficult. It is interesting to note that of the 25 cases of corrected transposition reported by Cardell16 in 1956, 8 (30y0) were classified as belonging to types Bl and B2. Since then many more cases of corrected transposition have been seen, and well over a hundred cases have been described in the literature. Yet all of these were of types B3 or B4. We are, therefore, convinced that in reality only two types of transposition of the great vessels exist: one without and one with inversion of the ventricles. Each of these may occur in mirror image in cases of total situs inversus of the viscera. SUMMARY
AND
CONCLUSION
Morphologically the atria and ventricles are strikingly normal in uncomplicated cases of transposition of the great vessels without inversion of the ventricles. We believe that the anomaly could be due to a single embryologic error, namely-, the inverted development of the truncus swellings. The dextrosuperior truncus swelling is situated sinistrosuperiorly ; the sinistroinferior truncus swelling develops dextroinferiorly. This anomaly, in combination with normal division of the truncoaortic sac, leads to transposition of the great vessels. The remainder of the heart develops normally. Major anomalies, other than the ventricular septal defect, were present in only 32 of our 85 cases. Transposition of the great vessels with inversion of the ventricles, corrected transposition being one type, is due to an inverted formation of the cardiac loop. Normal development of the truncus swellings relative to the bulboventricular loop, and normal division of the trunco-aortic sac, must lead to transposition of the great vessels, since the position of the truncus swellings in relation to the trunco-aortic sac is identical to that seen in transposition without ventricular inversion. THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Pathogenesis
of Transposition
REFERENCES 1. VAN MIEROP, L. II. S. and WIGLESWORTH, F. W.
2.
3.
4.
5.
6. 7.
8. 9.
10.
11.
12.
Pathogenesis of transposition complexes. II. Anomalies due to faulty transfer of the posterior great vessel to the left ventricle. Am. J. Cardiol., 12: 226,1963. ANDERSON, R. G., LILLEHEI, C. W. and LESTER, R. G. Corrected transposition of the great vessels of the heart, a review of 17 cases. Pediatrics, 20: 626,1957. SCHIEBLER,G. L. et al. Congenital corrected transposition of the great vessels: a study of 33 cases. Pediafrics, 27: 851, 1961. LOCHTE. Ein Fall van Situs viscerum irregularis, nebst einem Beitrag zur Lehre van der Transposition der arteriellen grossen Gefasstamme des Herzens. &itr.@th. Anat., 24: 187, 1898. GEIPEL, P. Weitere Beitrage zum Situs transversus und zur Lehre van den Transposition der grossen Gefasse der Herzens. Arch. Kinderh., 35: 112 and 222,1903. WALMSLEY T. Transposition of the ventricles and the arterial stems. J. Anat., 65: 528, 1930-31. DE LA CRUZ, M. C. et al. An embryologic explanation for the corrected transposition of the great vessels: additional description of the main anatomic features of this malformation and its varieties. Am. Heart J., 57: 104, 1959. RATNER, B., and ABBOTT, M. E. Rare cardiac anomaly. Am. J. Dis. Child., 22: 508, 1921. BECU, I,. M., SWAN, H. J. C., DUSHANE,J. W. and EDWARDS,J. E. Cardiac clinics. CXLIV. Ebstein malformation of the left atrioventricular valve in corrected transposition of the great vessels with ventricular septal defect. Proc. Staff. Meet. Mayo Clin., 30: 483, 1955. EDWARDS, J. E. Differential diagnosis of mitral stenosis ; a clinicopathologic review of simulating conditions. Lab. Invest., 3: 89, 1954. HELMHOLZ, H. F., DAUGHERTY, G. W. and EDWARnS, J. E. Cardiac clinics. CXLV. Con“mitral” genital insufficiency in association with corrected transposition of the great vessels: report of probable clinical case and review of 6 cases studied pathologically. PTOC. Staff Meet. Mayo Clin., 31: 82, 1956. MALERS, E., BJBRK, V. O., CULLHED,J. and LODIN, H. Transposition functionally totally corrected
AUGUST 1963
Complexes.
III
239
associated with mitral insufficiency. Am. Heart J. 59: 817, 1960. 13. VA\I MIEROP. L. H. S., ALLEY, R. D., KAUSEL, H. \V. and STRANAHAN, -4. Ebstein’s malformation of the left atriaventricular valve in corrected transposition, with subpulmonary stenosis and ventricular septal defect. Am. J. Cardiol.. 8 : 270, 1961. 14. M~INCKEBERG.J. G. Die Missbildungen dcs Hernens. In: HENKE, F. and LUBARSCI~,0. Handbuch der Spcziellen Pathologischen Anatomic und Histologie, Springer.
Vol.
2,
p.
77.
Berlin,
1924.
.J.
HARRIS, J. W. and FARBER, S. Transposition of the cardiac vessels, with special reference to phylogenetic theory of Spitzer. Arch. Path., 28: 427, 1939. 16. CARDELL, B. S. Corrected transposition of the great vessels. &it. Heart J., 18: 186, 1956. 17. STOLTZ, J. A. Vice de conformation du coeur. con15.
sistant coeur;
la transposition des ventricules du trhpeu de temps apres la naissance. Arch. g&z. r&d., s7: 213,185l. 18. 19.
20. 21.
22.
23.
TH~REMIN,E. Etudes sur les affections congtnitales du coeur. Paris, 1895. Asselin et Houzeau. WALSHE, A. Fall van Cyanosis, van einer Transposition der Aorta und Pulmonar-Arterie abhangig. J. Kinderkr., 2: 305, 1844. BROWN, J. W. Congenital Heart Disease, ed. 2, p. 269. London, 1950. Staples Press. CARNS, M. L., RITCHIE, G. and MUSSER, M. J. An unusual case of congenital heart disease in a woman who lived for 44 years and 6 months. Am. Heart J., 21: 522,194l. DOERR, W. Zur Transposition der Herzschlagadern. Virchore,s Arch. path. Anat., 303: 168, 1938-39. GRUNMACH, E. uber angeborene Dextrocardie, verbunden mit Pulmonal Stenose und Septumdefckten
24. 25. 26. 27.
dam mart
des Herzens
ohne
Situs
transvrrsus.
Rerl.
klin. Wchnschr., 27: 22, 1890. LEWIS, F. T. and ABBOTT, M. E. Reversed torsion of the human heart. Anat. Rec., 9: 103, 1915. GUTWASSER,C. Inaugural Dissertation, Gottingen, 1870. Cited by Loch& and by Geipel.5 FINGERHUTH,M. Inaugural Dissertation, Zurich, 1901. LEV, M. and ROWLATT, U. F. The pathologic anatomy of mixed levocardia. Am. J. Cardiol., 8: 26, 1961.
of Transposition Transposition
III.
True
LODEWYK
H. S. VAN MIEROP, M.o.t and FREDERICK \I’. \L’I(;I,ESWORTH, M.D. Montreal.
T
of the Great
MATERIAL One hundred and six specimens exhibiting some form of true transposition complex were studied (Table I). In 85 the position of the ventricles was normal; in 21 there was ventricular inversion. Most of the hearts were from the collection of the Department of Pathology of The Montreal Children’s Hospital; the others were from the collection of the Subdepartment of Thoracic Surgery, Albany Medical Center, Albany, N. Y. TRANSPOSITION OF GREAT VESSELS WITHOUT INVERSION OF VENTRICLES In this condition the aorta arises anteriorly from the right ventricle; the pulmonary artery, posteriorly from the left ventricle, and the two vessels run parallel to each other (Fig. 1) The foramen ovale is always anatomically patent; the ductus arteriosus may be narrow or closed. The morphology of the heart itself is strikingly normal in about one third of the cases, although the base of the aorta is situated slightly more to the right than the root of pulmonary artery in a normal heart. The fact that the hearts in uncomplicated transposition of the great vessels look so much
Canada
* From the Department of Anatomy, McGill University, and the Departmrnt of Hospital and McGill University, Montreal, Quebec, Canada. t Present address: Albany Medical Colleqc of Union University, Albany. N. Y. 1961
Vessels*
alike suggests that the developmental error responsible is the same. Since the morphology of the ventricles and atrioventricular valves is quite normal, it is reasonable to assume that the bulboventricular loop developed normally. For the same reason it is likely that division of the conus cordis takes place in a normal fashion. Thus the error probably takes place in the truncus reBoth the truncus and intercalated gion. valve swellings develop as local elaborations of the continuous layer of young cardiac mesenchyme beneath the endocardium of the They are, therefore. not truncus arteriosus. completely separated from each other. Normally, as has been described in Part I, the truncus swellings appear earlier, grow faster and become much larger than the intercalated valve swellings. The dextrosuperior truncus swelling becomes continuous with the dextroposterior conus swelling and the sinistroinferior truncus joins the sinistroanterior conus swelling (Fig. 2 A,B,C). We propose the hypothesis that the developmental error of the truncus responsible for true transposition of the great vessels is the result of a reversal of the roles played by the truncus swellings and of the intercalated valve swellings. It must be emphasized that the intercalated valve swellings, contrary to descriptions given by previous workers, develop at about the samr level as the truncus swellings. If the intercalated valve swellings appear earlier than the truncus swellings and become the major structures in the truncus, then these swellings will execute the division of the truncus. Thus the pulmonary intercalated valve swelling forms the “sinistrosuperior truncus swelling” and becomes continuous with the sinistroanterior
HE ANOMALIESto be discussed in the present paper are characterized by a reverse anteroposterior relation of the aorta and pulmonary artery, i.e., the aorta arises anteriorly, the pulmonary artery (or its remnant) posteriorly and parallel to the aorta. The pathogenesis of these anomalies, which we consider true transposition complexes, is entirely different from that of the defects discussed in Part II, in which the aorta was generally the posterior vessel.’ Two main categories may be distinguished: those without and those with inversion of the ventricles.
AUGUST
Complexes
231
Pathology,
The
Montwal
Childrrn’s
Van
234
Mierop
and Wiglesworth TABLF.i
True Transposition Principal
Embryologic Error
Inverted (mirror image) development of truncus swellings
Complexes
Anomaly Transposition ventricular
No. of Cases
of great vessels without inversion
85
Isolated anomaly With ventricular septal dcfcct and minor other anomalies With major associated anomalies Inversion of the bulboventI-icular loop
34 19 32
Transposition of the great vessels with ventricular inversion (“corrected” transposition)
21 Total
conus swelling. Similarly, the aortic intercalated valve swelling develops into a “dextroinferior truncus swelling,” continuous with the The dextrodorsal conus swelling (Fig. 2 D,E,F). true truncus swellings then merely act as the intercalated valve swellings. The aorticopulmonary septum and the conus septum develop normally. The final result is that the aorta arises anteriorly from the right ventricle and the pulmonary artery from the left ventricle posteriorly, i.e., there is transposition of the great vessels. Associated Anomalies: In 22 per cent of our cases of transposition without inversion of the ventricles, the only other major anomaly was a ventricular septal defect located in the area Associated minor of the membranous septum. In another anomalies were common (Table I). 38 per cent there were associated gross defects such as atresia of an atrioventricular valve and/or an arterial valve, double outlet right ventricle, common ventricle, endocardial cushion defect or major venous anomalies. The remaining 40 per cent showed no (major) associated anomalies. TRANSPOSITION OF GREAT VESSELS WITH INVERSION OF VENTRICLES
This anomaly, commonly referred to as “corrected transposition” and until recently considered rare, is being seen with increasing frequency.? n3 In its simplest form the aorta arises to the left and anteriorly from the leftand the pulmonary artery sided ventricle, posteriorly and to the right from the rightsided ventricle. Morphologically the rightsided ventricle resembles a normal left ventricle
106
and has a mitral valve, with an anterior and a posterior papillary muscle, each composed of two components, and the pattern of trabeculation is similar to that seen in the normal left ventricle. The left-sided ventricle resembles a right ventricle and contains a crista supraventricularis, a trabecula septomarginalis and a tricuspid valve. The atria are normal in structure and position (Fig. 3). This anomaly has been called “corrected” transposition, indicating that functionally the transposition has been corrected by a conThus comitant inversion of the ventricles. the pulmonary artery carries venous blood and the aorta, arterial blood. Lochte” believed that inversion of the bulboventricular loop together with the usual type of transposition was the cause of corrected Hence, he assumed the simultransposition. taneous occurrence of two unrelated anomalies. Geipel,5 opposing this view, held that the cardiac loop forms normally, but that secondarily the entire (undivided) truncus, because of abnormal rotation (“drehung”) to the left, is shifted to the left ventricle. The right ventricle remains the right ventricle, and the left ventricle reAfter division of the truncus mains on the left. the posterior portion, as in normal development, is then transferred to the opposite ventricle. It is this transfer which, according to Geipel, determines the position of the atrioventricular valves. The arguments on which Geipel based his concepts have since been proved invalid, and Lochte’s views have been accepted by most authors. On the basis of our own studies, however, we have come to the conclusion that corrected THE
AMERICAN
JOURNAL
OP
CARDIOLOGY
Pathogenesis
of Transposition
A
Complexes.
235
III B
FIG. 1. Tran.$mition of the great vessels without ventricular inversion. A, section
through the ventricles and great arteries. The heart has been positioned so that the plane of sectioning lies frontally. B, projectional diagram of the base of the heart. RA and LA indicate position of the right and left atrium.
transposition, i.e., in\,ersion of the ventricles associated with transposition of the great vessels, is indeed due to a single embryologic error: inversion of the bulboventricular loop. Previously the associated transposition presented something of a problem in explaining the anomaly, and a second developmental Actually, error was usually presumed present. inversion of the cardiac loop with normal partitioning of the trunco-aortic sac will of necessity lead to transposition of the great vessels, as already pointed out by Walmsley6 and by de la Cruz et al.’ If the truncus swellings de\,elop normally in relation to the (inverted) bulboventricular loop, their position relative to the truncoaortic sac will be identical to that of the swellings which divide the truncus in transposition without \-entricular inversion. The final result therefore is transposition of the great arteries (Fig. 2 G,H,I). To bring the arteries into their normal positions relati1.e to each other and to the (in\,erted) \:entricles, a second anomaly would be necessary-. The truncus swellings would have to develop in a manner similar (but here in mirror image) to that which occurs in transposition without inversion. To our knowledge no such case has been reported to date. The case of Ratner and Abbott* is probably- an example of a peculiar combina-
tion of anomalies, in which both atria are morphologically right atria. We have seen 6 such cases of atria1 isomerism usually occurring in cases of congenital asplenia. Associated Anomalies: Transposition of the great vessels with inversion of the ventricles is almost always combined with major associated anomalies. Abnormalities of the atrioventricular valves are common, particularly of the left, morphologically tricuspid valve. Insufficiency and Ebstein’s anomaly are among the more common and important defects seen. :1-l:! The relative frequency of the latter in cases of corrected transposition is interesting, since the same lesion occurring in an otherwise normal heart is extremely rare. Ventricular septal defect, pulmonary stenosis, double outlet right ventricle, single ventricle, atresia of an atrioventricular or arterial valve and endocardial cushion defect may be present. It is important to realize that the so-called “corrected” transposition is merely one form of transposition of the great vessels with inversion of the ventricles. Rotational anomalies are not uncommon. Ten of 21 cases in our series showed a rotational anomaly : In 5 cases there was dextrorotation in situs solitus, in the other 5 there was levorotation in situs inversus. We have never seen a rotational anomaly of the heart without
236
Van
Mierop
and
Wiglesworth
*‘.
F
FIG. 2. Division of the truncus arteriosus. A, B, C, normal heart. D, E, F, transposition of the great vessels without ventricular inversion. G, H, I, transposition of the great vessels with ventricular inversion (“corrected” transposition). THE
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FIG. 3. Transposition of the grrat vessels with inversion of the ventricles. A, section through the ventricles and ascending aorta. B, prqjectional diagram of the base of the heart.
of the ventricles. In normal development of the heart where the cardiac loop bends to the right, the apex of the heart eventually lies on the left side. In corrected transposition, where the loop is inverted, normal evolution of the apical portion should bring the apex on the right side. Therefore, as pointed out previously by de la Cruz et al.,’ the rotational anomaly in corrected transposition represents the normal condition, and its occurrence in transposition with inversion of the \-entriclcs is not at all surprising. inversion
REVIEW
.WD CRITICISM OF CERTAIN CURRENT
CLASSIFICATIONS OF TRANSPOSITION COMPLEXES
Geipe15 proposed eight possible types of transposition comp1f.x. Four were uncorrected functionally; the other four were corrected. In all eight types the aorta is located anteriorly the pulmonary artery, posteriorly. MijnckebergI adopted Geipel’s classification but rearranged it. The types Al-4 were uncorrected, types Bl-4 were corrected. Harris and FarberI gave diagrams of the eight possible variants, and Cardelli6 rearranged the sequence of the diagrams to fit Geipel’s classification as adapted by MBnckeberg. Cardell’s illustrations have since been adopted by others. His type Al illustrates complete transposition; A2 is the same in situs inversus totalis. Type AUGUST
1963
B3 is corrected transposition; B4 is again the Types A3 and 4 and same in situs inversus. Bl and 2 have in common that the aorta arises anteriorly from a chamber which is morphologically a left ventricle, ancl a pulmonar) artery which originates posteriorly from a morphologic right ventricle (so-called “anaIt becomes immediately tomical correction”). apparent that these four types cannot be exYet 4 cases of type A3,“-lg six explained. amples of type B1’X~20-2* and two examples of type B2?5,?6 have been reported to date. Apparently no example of type A4 has been Lochted believed that errors in observaseen. tion led to erroneous interpretation of the specithem inexplicable mens. Geipe15 considered variations of nature. Actually the reason for They their inexplicability is rather simple: do not and cannot exist at all: they are pmhryologic im@xsihiliti~s. An anteriorly located aorta originating from a morphologic left ventricle would place the crista supraventricularis in that ventricle. This is not possible, since the crista, which is derived from the conus septum, belongs to the morphoAn anterior great artery, logic right ventricle. whether it be the aorta or the pulmonary artery, always arises from a morphologic right ventricle or part of a right ventricle (as in tricuspid atresia and rudimentary outflow chamber). The number of leaflets of an atrioventricular
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valve is no indication of its true nature since variations are common. Much more reliable is the structure of the ventricle and papillary muscles.27 A review of the reported examples of types A3, Bl and B2 showed that none of these could be accepted as such with certainty : Type A3. Lochte” remarks of the cases of Walshelg and Stalz” that no description of the ventricles or illustrations were given. MGnckeberg’” states that in Thtremin’s Case 37 the aorta arose anteriorly from the conus pulmonalis and that the pulmonary artery originated from the left ventricle like a normal The tricuspid valve is said to have aorta. had two leaflets and the mitral three. No description is given of the ventricles or papillary muscles. Grunmacht3 calls his case corType Bl. rected transposition. The tricuspid and mitral valves are said to be on the right and left side, respectively, but this is not in accord with the illustrations, which clearly show a mitral on the right and a tricuspid on the left. Thtremin’s Case 4718 is described by Lochte,4 who points out that structurally the ventricles were inverted although the atrioventricular valves are said to have had the normal number of cusps. Lewis and Abbott’sz” case appears from the illustration to be a straightforward corrected transposition. It is said that the atrioventricular valves were normally arranged? but no description or illustrations were given. There Doerr’s?* case is difficult to analyze. was a common ventricle, and both atrioventricular valves are said to have had three leaflets; however, the papillary muscles on both sides resembled those found in a left ventricle. We would like to point out here that in many cases of common ventricle both atrioventricular valves resemble mitral valves structurally. The description of the heart reported by Carns et a1.,21 though interpreted by Abbott, Their Figure 4 is singularly difficult to follow. suggests that the right ventricle and right atrioventricular valve were morphologically a left ventricle and a mitral valve, respectively. The nature of the atrioventricular valves in Brown’szO case is merely indicated by the designations tricuspid and mitral valve; no further description is given of the ventricles. The illustrations consist of rather simple line drawings. Ty,be B2. Gutwasser’P case had the crista
and Wiglesworth supraventricularis on the right side, as is to be expected in corrected transposition in situs inversus totalis. No description is given of the ventricles, and the right and left valves are merely said to have been bicuspid and tricuspid. In Fingerhuth’P case the atrioventricular valves are not described ; however, Geipe15 states that the pictured left atrioventricular valve looks as though it consists of three leaflets. In this case there was also a common ventricle, which often, as already stated above, makes analysis of the atrioventricular valves difficult. It is interesting to note that of the 25 cases of corrected transposition reported by Cardell16 in 1956, 8 (30y0) were classified as belonging to types Bl and B2. Since then many more cases of corrected transposition have been seen, and well over a hundred cases have been described in the literature. Yet all of these were of types B3 or B4. We are, therefore, convinced that in reality only two types of transposition of the great vessels exist: one without and one with inversion of the ventricles. Each of these may occur in mirror image in cases of total situs inversus of the viscera. SUMMARY
AND
CONCLUSION
Morphologically the atria and ventricles are strikingly normal in uncomplicated cases of transposition of the great vessels without inversion of the ventricles. We believe that the anomaly could be due to a single embryologic error, namely-, the inverted development of the truncus swellings. The dextrosuperior truncus swelling is situated sinistrosuperiorly ; the sinistroinferior truncus swelling develops dextroinferiorly. This anomaly, in combination with normal division of the truncoaortic sac, leads to transposition of the great vessels. The remainder of the heart develops normally. Major anomalies, other than the ventricular septal defect, were present in only 32 of our 85 cases. Transposition of the great vessels with inversion of the ventricles, corrected transposition being one type, is due to an inverted formation of the cardiac loop. Normal development of the truncus swellings relative to the bulboventricular loop, and normal division of the trunco-aortic sac, must lead to transposition of the great vessels, since the position of the truncus swellings in relation to the trunco-aortic sac is identical to that seen in transposition without ventricular inversion. THE
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