Tetralogy of Fallot: A Morphometric
ANTON
E. BECKER,
MD,
FACC
MIKE CONNOR, MB, ChB ROBERT H. ANDERSON, MD*
Amsterdam, The Netherlands
From the Department of Pathology, Wilhelmina Gasthuis, University of Amsterdam, Amsterdam, The Netherlands. Manuscript accepted July 17, 1974. M. R. C. Travelling Fellow United Kingdom. Present address: Brompton Hospital, London, England. Address for reprints: Anton E. Becker, MD, Department of Pathology, Wilhelmina Gasthuis, University of Amsterdam, Amsterdam, The Netherlands.
March 1975
Study
Fourteen examples of tetralogy of Fallot were studied by morphometric and geometric methods, and the findings compared with results from 10 normal hearts. The data show that in Fallot’s tetralogy the conal septum is deviated anteriorly. The infundibulum, although narrow, is similar to, or of greater length than, that of the normal heart. This finding is not in agreement with recent observations suggesting that the anomaly represents lack of growth of the pulmonary conus. Our results further demonstrate that the aorta is dextroposed in Fallot’s tetralogy and that in the majority of cases absorption of the right extremity of the conoventricular flange has led to aortic-tricuspid fibrous continuity. The overall findings indicate that conal rotation has occurred in addition to anterior deviation. The data are interpreted as supporting a hypothesis of “lack of conal inversion” and conal malseptation as the morphogenetic mechanisms in tetralogy of Fallot.
The embryogenesis of the underlying malformations of tetralogy of Fallot is still much debated. The “classic” concept of this anomaly was propounded by Von Rokitanskyl in 1875. He suggested that malseptation of the truncus at the expense of the pulmonary artery produced the tetralogy since the anteriorly deviated conal septum would no longer be able to contribute to the formation of the ventricular septum. This concept was subsequently supported by Abbott,2 De La Cruz and his co-workers3,4 and Van Mierop and Wiglesworth.5 It was challenged by Van Praagh et a1.6 in 1970, who considered that the pulmonary infundibulum in Fallot’s tetralogy was “too short, too narrow and too shallow.” They stated that this feature and others in tetralogy could best be explained on the basis of underdevelopment of the subpulmonary infundibulum. However, in a morphometric and geometric study demonstrating that the pulmonary infundibulum was of normal length in Fallot’s tetralogy, Goor et a1.7 suggested that the condition was typified by dextroposition of the aorta, counterclockwise rotation of the conus and anterior deviation of the conal septum. In view of this uncertainty regarding morphogenesis, we investigated cases of tetralogy of Fallot using geometric and morphometric techniques and compared our results with similar measurements of normal hearts. In addition, we paid particular attention to the structures surrounding the ventricular septal defect, since some recent investigators8,g have described an “intracristal” defect in some cases of tetralogy.
Material
l
492
and Geometric
and Methods
Definition of Terms A clear definition of terms is necessary since confusion exists regarding the terminology of conal structures. This is particularly evident with relation to We therefore present a definition of the term “crista supraventricularis.”
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FIGURE 1. Morphometric measurements. A, diagram showing the measurements made in specimens of tetralogy of Fallot. The letters a to g indicate the dimensions recorded as described in the text. B, photograph of a specimen of a normal heart after bisection in the sagittal plane. Note how the specimen approximates the situation in Fallot’s tetralogy and how directly comparable measurements can be taken. Ao = aorta; CFB = central fibrous body: CS = conal septum: Inf = infundibulum; PA = pulmo-
nary artery; RA = rlght atrium; RV = right ventricle; VSD = ventricular septal defect.
terms in which we believe the controversial aspects are minimized. Conal septum: This structure is the embryonic septum between the aortic and pulmonary conuses. As thus defined, it may occupy different positions in normal and abnormal specimens. In the normal heart it can be considered to possess two segments. The first segment lies between the aortic and pulmonary valves and forms part of the interventricular septum, blocking the sinistro-anterior portion of the primary bulboventricular foramen. The second segment stretches from this septal component to the parietal wall of the right ventricle and forms an integral part of the crista supraventricularis. In hearts with tetralogy of Fallot, the entire proximal edge of the septum is considered to span the cavity of the
Superior aspect
FIGURE2.
Geometric
measurements.
right ventricle as a supraventricular structure. In these hearts, therefore, the septum possesses a free edge and septal and parietal insertions. Conoventricular flange: This structure is considered to represent the inner curvature of the heart tube after bulboventricular looping. lo21l It is the small segment of ventricular musculature that, after the looping process, intervenes between the atria1 and bulbar (or conal) segments of the heart tube. In a recent embryologic study’l it was termed the bulboatrioventricular ledge to indicate that it was originally composed of components from all three cardiac segments. During the normal development of the heart, the middle portion of the flange is absorbed to allow the aortic outflow tract to contact the left ventricle. This process, first described by Pernkopf and Wirtingerls and subse-
D
Inferior aspect
X
A, diagram of the superior
aspect of the heart after removal of the atrial chambers and the great arteries. diagram of measurements and angles taken on inferior surface of the mv = mitral valve; pa = pulmonary artery; rv = right ventricle; tv = tricuspid valve.
The lines constructed and angles measured are indicated. B, similar heart. ao = aorta; inf = infundibulum; See text for letter abbreviations.
Iv = left ventricle;
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TABLE I Measurements
Case no.
in 10 Normal
Hearts and 14 Hearts with Tetralogy Length Infund. (a)
Age (yr)
(mm)
Length RV (b) (mm)
of Fallot
Aortic Conus (c)
Conal Septum (d)
Pulmonary Conus (e)
Aortic Circumf. (f)
Pulm. Circumf. (g)
Angle of GA (a)
(mm)
(mm)
(mm)
(mm)
(mm)
(“)
(“)
6 8 12 6.5 18 12 10 7.5 8 16
27 33 42 25 58 42 34 30 28 58
28 35 42 25 60 48 34 22 28 56
44 57 48 58 60 53 57 46 45 67
94 95 87 96 95 101 99 93 97 96
18 44 32 51 25 50 31 75 25 23 19 21 32 67
9 31 13 33 11 14 3 39 13 15 10 12 19 33
17 40 32 38 37 32 26 28 29 32 31 38 31 37
97 94 93 94 98 93 96 93 98 95 94 100 96 93
Pulm.
= pulmonary;
Angle of IAS (c)
A. Normal Hearts 1 2 3 4 5 6 7 8 9 10
10/12 1 9/12 5 1 36 5 1 10/12 8/12 8/12 14
12 13 21 11 25 20 14 12 15 16
30 38 52 21 70 53 35 29 33 55
6 10 13 7 17 12 11 8 9 17
2 1.5 2.5 2 5 3 2.5 3 2 2.5
B. Hearts with Tetralogy of Fallot 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Circumf. ventricle.
37
9 22 15 20 12 21 9 29 14 10 10 15 23 23
12 36 21 36 19 42 34 49 20 20 28 20 23 61
= circumference;
GA = great
arteries;
7 8 7
hr 7112 6112 3112
6 7112 43 4112 3/52 3112 2112 18/12
5 17 12 20 10 20 12 22 9 7 9 10 11 15 IAS = interatria!
quent German embryologists, has been recently endorsed by several investigators.11J3J4 After this normal absorption, the right extension of this flange persists and, together with the parietal part of the conal septum, forms the normal crista supraventricularis.ll However, in malformed specimens the flange can produce aortic-atrioventridular valve discontinuity.5 Crista supraventricularis: This term will be used here only to describe a structure in the normal heart. It is considered to be the supraventricular muscle mass that separates the pulmonary and tricuspid valves.15 It is formed from two components,11J2 the right extension of the conoventricular flange as the outer component and the parietal part of the conal septum as the inner component. In some hearts, the latter component extends toward the apex of the ventricle, where it fuses with a well formed septal trabecula (see later). This septal trabecula is not considered part of the crista supraventricularis. Trabecula septomarginalis: This term is used to describe the extensive septal trabecula that extends from a position just beneath the pulmonary valve toward the ventricular apex and continues as the moderator band onto the parietal wall of the ventricle. This definition corresponds to that given by Tandler16 for a common variation of his trabecula septomarginalis. It is also in keeping with Keith’s description17 of the left sep-
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2 3 4 5 3 4 2 10 3 2 3 4 6 9
3 8 4 8 4 10 4 10 6 5 4 5 7 8 septum;
Infund.
= infundibulum;
RV = right
tal band and the description by Lev and SaphiP of the septal muscle bundle. Although the term trabecula septomarginalis is now commonly used to describe only the moderator band, it is evident from the descriptions cited that the latter structure is a continuation of the septal trabeculation. Van Mierop et al.1° used the term trabecula septomarginalis to describe both the septal band and the moderator band, and we follow their precedent. The trabecula septomarginalis is therefore considered to possess anterior and posterior limbs at its superior extent. The septal part of the conal septum is inserted between these limbs in the normal heart, and the papillary muscle of the conus arises from the posterior limb. The anterior papillary muscle arises from the trabecula septomarginalis toward the ventricular apex, and the moderator band frequently fuses with the parietal extension of the conal septum after it has crossed the ventricular cavity. An annulus is therefore formed between the conal septum, its parietal extension and the trabecula septomarginalis. Case Material Twenty-four hearts were studied, 14 specimens of tetralogy of Fallot and 10 normal hearts. To be considered an example of tetralogy, a heart was required to possess the combination of pulmonary infundibular narrowing, ventricular
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septal defect, overriding aorta and right ventricular hypertrophy in the presence of mitral-aortic fibrous continuity. Patients with Fallot’s tetralogy ranged in age from 7 hours to 43 years. The normal subjects were 8 months to 36 years old (Table I).
Morphometric Measurements The following morphometric observations were recorded in all specimens (Fig. 1): I. The infundibular length (a) was measured from the septal commissure of the pulmonary valve to the most inferior point of the conal septum. II. The length of the right ventricle (b) was recorded from the ventricular apex to the most inferior part of the conal septum. III. The proportions of the embryonic bulbus occupied by aortic (c) and pulmonary (e) outflow tracts and the thickness of the conal septum (d) were noted. In the specimens of Fallot’s tetralogy these measurements were taken on a line that passed from the most posterior part of the aortic outflow tract, beneath the conal septum to the anterior wall of the right ventricle (Fig. 1A). To produce a comparable situation in the normal hearts it was necessary to make a sagittal section through the heart that bisected the aortic outflow tract. This section then delineated the dimensions of both outflow tracts together with the thickness of the conal septum (Fig. 1B). IV. The circumferences of the aortic (f) and pulmonary (g) external orifices were measured.
Geometric Measurements These measurements were recorded after removal of the atria1 chambers and great arteries had revealed the fibrous valvular rings and a transverse cut through the ventricles had been made in the plane of the atrioventricular rings. These procedures made it possible to place a glass sheet upon the superior and inferior surfaces of the remaining cardiac segment and to record the salient features on superimposed transparent paper. On the superior aspect the following lines were constructed (Fig. 2A): I. Through the posterior margins of the A-V rings (ACB). II. Through the anterior margins of the same rings (FG). III. Through the mid-points of the semilunar valve rings (AFE). IV. Along the plane of the interatrial septum (CD). The angles of the great arteries (a) and the interatrial septum (c) were then calculated relative to the line ACB. In the normal hearts these measurements were recorded before the outflow tracts were sectioned. On the inferior surface of the specimens of Fallat’s tetralogy the following lines were constructed (Fig. 2B): I. Along the posterior interventricular septum (XY). II. Along the anterior interventricular septum (YZ). III. Along the conal septum (WY). The angles subtended by the conal septum (y’) and the anterior septum (y”) were then recorded relative to the posterior septum. The recorded measurements from these various procedures are indicated in Table I. For comparative purposes the observations were presented as follows: A. The length of the infundibulum (a) was recorded as
TABLE
ET AL.
II
Data Submitted to Statistical Analysis Using Student’s t test*
Measurements(see Fig. 1) Length of pulmonary conus expressed as part of length RV I(a/(a + b)l Proportion of embry onic conus occupied by pulmonary conus [e/(c + d + e)l Circumference of pulmonary artery compared with that of aorta (g/f) Angle of great arteries a” *Values
Fallot (14 specimens)
Normal (10 specimens)
P
0.36 + 0.08
0.28 zk 0.03
>0.005
0.18 zk 0.05
0.43 It 0.02
>0.005
0.50 & 0.16
1.02 + 0.05
>0.005
53.5 f
>0.005
32 i
6.04
7.59
expressed
as mean z!= standard deviation. (hearts with tetralogy vs. normal RV = right ventricle.
P = level of significance specimens);
a fraction of the entire right ventricular length (a + b) recorded as unity. B. The proportion of the total width of the embryonic bulbus (c + d + e), expressed as unity, as occupied by the aortic outflow tract (c), conal septum (d) and pulmonary tract (e). C. The ratio of the circumference of the pulmonary artery compared with that of the aorta expressed as unity. D. The angle of the great vessels in two groups. In the same diagram it was also possible to illustrate the position of the aorta by constructing circles to indicate the relation of the aortic valve ring to the lines FG and CD. The data used for each of these comparisons were subsequently submitted to statistical analysis using Student’s t test and a confidence level of 0.5 percent (Table II).
Results Basic Anatomy of the Right Ventricle In the normal heart, the right ventricle possesses inflow and outflow portions, the boundary between the two being the annulus formed by the conal septum, its parietal extension and the trabecula septomarginalis (Fig. 3). In Fallot’s tetralogy these morphologic features are not observed, since the septal insertion of the conal septum is anterior to the trabecula septomarginalis (Fig. 4). Since the parietal insertion is also deviated anteriorly, the conal septum and conovetitricular flange form distinct structures (Fig. 3). The infundibulum is a narrow channel situated anteriorly in the right ventricle. An intermediate ventricular segment communicates with the left ventricular outflow tract. The septal defect between this segment and the aortic outflow tract is bounded by the following structures: (1) anteriorly by the septal inser-
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FIGURE 3. Photographs of specimens of normal hearts. A, taken as if looking from the right ventricular apex directly into the pulmonary outflow tract. The normal crista supraventricularis (CSV) separates the tricuspid (TV) and pulmonary valves. Its septal insertion (thick arrow) is between the anterior (A) and posterior (P) limbs of the trabecula septomarginalis (TSM). B, taken from the ventricular apex looking towards the tricuspid valve (TV). Note that a promiment trabecula extends from the parietal insertion of the crista supraventricularis (double arrows) toward the ventricular apex, where it joins with the trabecula septomarginalis. The right ventricle is therefore divided into an inflow and an outflow portion. Again note the septal insertion (thick arrow) of the crista supraventricularis between the limbs of the trabecula septomarginalis.
FIGURE 4. Specimen of Fallot’s tetralogy, viewed from the apex of the right ventricle looking toward the pulmonary valve (compare with Fig. 3A). The conal septum (CS) is divorced from the right margin of the conoventricular flange (CVF). The septal (single arrow) and parietal (double arrows) insertions of the conal septum are both deviated anteriorly, thus constricting the pulmonary outflow tract. The septal insertion is anterior to the trabecula septomarginalis (TSM), which together with the muscular ventricular septum forms the floor of the defect (VSD). At the posterior edge of the defect an area of tricuspid-aortic continuity is visible (*). The roof of the defect is formed by the subaortic conus, between the conoventricular flange and the conal septum.
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tion of the conal septum, which fuses with the anterior segment of the ventricular septum in front of the trabecula septomarginalis; (2) inferiorly by the crest of the muscular septum, which is reinforced by the trabecula septomarginalis; (3) posteriorly by the ventricular septal structures fusing with the atrioventricular annulus; and (4) above the atrioventricular annulus by the right margin of the conoventricular flange, which forms the aortic conus in this position. The degree of development of the conoventricular flange varied in different specimens. In the majority, there was direct fibrous continuity between the aortic and tricuspid valves (Fig. 4). In some specimens the flange completely separated these two valves, but the tricuspid valve was continuous with the mitral valve and thence with the aortic valve by way of the central fibrous body (Fig. 5A). In two specimens, however, a bar of muscle completely separated the aortic and tricuspid valves, stretching to the crest of the ventricular septum and producing a complete muscular rim to the ventricular septal defect (Fig. 5B). Although the ridge appeared as a thick band from its inferior aspect, dissection from above suggested that it represented a reduplication of the heart wall (Fig. 6A); bisection of the ridge resulted in confirmation of this opinion (Fig. 6B). Morphometric
Observations
In the normal hearts the fraction of the right ventricular length (a + b) occupied by the pulmonary conus (a) averaged 0.28. In the specimens of tetralogy of Fallot (Fig. 7) this fraction was generally larger, falling below the normal mean value in only three specimens. The average value for the malformed specimens was 0.36 and the extreme was 0.50. The
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FIGURE 5. Specimens of Fallot’s tetralogy showing various degrees of separation between aortic (AV) and tricuspid (TV) valves. A, specimen viewed from below after division of the ventricular septum ( l) in which the right margin of the conoventricular flange (CVF) separates the greatest part of the valve rings. However, fibrous continuity is present between the tricuspid and mitral (MV) valves by way of the central fibrous body (CFB), and forms the posterior margin of the ventricular septal defect. Through the central fibrous body, continuity is also established between the aortic and tricuspid valves. B, specimen in which the ventricular septum has again been divided ( l) to demonstrate the inferior aspect of the aortic valve. Although aortic-mitral valvular continuity is present (single arrow) a complete bar of muscle separates the aortic and tricuspid valves, and fuses with the tip of the ventricular septum (double arrows). The muscle bar forms the roof and posterior wall of the defect, and is the right margin of the conoventricular flange. The defect has been sectioned through its floor. CS = conal septum; POT = pulmonary outflow tract. l
l
FIGURE 6. Photographs of the specimen shown in Figure 58, illustrating the nature of the muscular bar between the tricuspid and aortic valves. A, superior view, the bar is dissected to demonstrate that although it appears as a solid ridge from below (Fig. 58). it represents a reduplication of the heart wail (double arrows). B, the ledge after its bisection, viewed from the septal aspect. The reduplication is demonstrated, and the bulbar (a) and ventricular (b) components are clearly visible. AV = aortic valve; MV = mitral valve: TV = tricuspid valve.
differences between the values in the two groups was statistically significant (P >0.005). In the normal heart the embryonic bulbus was divided approximately evenly between the aortic (c) and pulmonary (e) outflow tracts, the respective average values being 45 and 43 percent, whereas the conal septum (d) occupied 12 percent of the width of the bulbus. In Fallot’s tetralogy the conal septum was grossly enlarged (average 25 percent) at the expense of the pulmonary conus (average 20 percent), whereas the aortic conus was also expanded (average 55 percent), again at the expense of the pulmonary conus (Fig. 8). The differences between the normal hearts and specimens of Fallot’s tetralogy were statistically significant (P >0.005). In normal specimens the pulmonary circumference was similar to the aortic circumference (1.02 to 1.00). In the specimens of Fallot’s tetralogy, as might be expected, lg it was markedly diminished, the average value being 0.50 with extremes of 0.70
and 0.16 (Fig. 9). The differences were again of considerable statistical significance (P >0.005). Geometric Measurements
These measurements showed that although the angle of the interatrial septum (c) was virtually identical in malformed and normal specimens (95” vs. 94’), the angle of the great arteries (a) was markedly different. In normal specimens this angle was 53.5O (range 44O to 67’); in specimens of tetralogy it was 32” (range 17” to 40”). These studies additionally showed that the aortic valve was dextroposed (in relation to the interatrial septum) and anteriorly deviated in the hearts with tetralogy compared with the normal hearts (Fig. 10). As with the other results, this finding was statistically significant (P >0.005). In the normal hearts the angle of the conal septum (y’) was difficult to measure, but it subtended less than 90’ to
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N- 1
2
4 EB
Fallot
Normal
‘sTetralogy
Hearts
Aortic Conus
5
6
7
8
9 10 11 12 13 14
0 ConusSeptum
InEm Pulm.Conus
0.70
t Pulm.Art.
c 0.16
FIGURE 7 (upper left). Diagram illustrating the length of the infundibulum (measurement a) expressed as a ratio of the right ventricular length (measurement a -I b). The illustrated infundibular length indicates the average value of this ratio in hearts with tetralogy of Fallot and normal specimens, and the scales indicate the range of measurements of the infundibular lengths. FIGURE 8. (upper right) Diagram illustrating the mode of division of the embryonic bulbus in hearts with tetralogy of Fallot and normal specimens. The hatched portions represent measurements of the aortic conus (c), conal septum (d) and the pulmonary (Pulm.) conus (e) expressed as ratios of the measurement c + d + e. Column N represents the average values of 10 normal hearts, columns 1 to 14 represent individual measurements in the specimens with tetralogy of Fallot. FIGURE 9 (lower left). Diagram showing the circumference of the pulmonary artery (Pulm. Art.) expressed as a ratio of the aortic circumference. Each circle represents the circumference of the pulmonary artery from individual specimens with Fallot’s tetralogy, and the figures give the range of values. The ratio in the 10 normal hearts was 0.98 to 1.00.
the posterior septum. In the majority of specimens of Fallot’s tetralogy this angle was equal to or greater than 90°. Discussion This study was based upon morphometric and geometric measurements obtained from formalin-fixed specimens. Undoubtedly artifacts have been introduced and some of the measurements may not be completely without bias. However, we believe that this quantitative approach gives a more reliable answer to the questions posed than could be provided by mere inspection of such hearts. Conal Rotation and Malseptation Our results are in agreement with findings in the similar morphometric and geometric study conducted by Goor et a1.,7 and we agree with these workers that Fallot’s tetralogy is characterized by the morphogenetic features of conal rotation and conal malseption. The conal rotation is manifested by the demonstrated aortic dextroposition. Although Van
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Praagh et al.‘j considered this feature to be present only in cases with “severe pulmonary outflow tract obstruction,” we agree with Goor et a1.7 that it is a hallmark of the anomaly. However, we also found that the aortic valve was anteriorly displaced in relation to the atrioventricular valve rings, and no longer occupied its normal “wedge” position (Fig. 10). Indeed, although we agree with Van Praagh et a1.6 that the normal aorta overrides the ventricular septum (Fig. llA), we consider that the associated anterior deviation of the aortic valve in Fallot’s tetralogy forms the major difference between the two conditions (Fig. 11B). The conal malseption is shown by the anterior deviation of the conal septum. The rotation of the conus itself may have rotated the conal septum as judged by the divorce of its parietal insertion from the conoventricular flange. However, additional anterior deviation is indicated by the position of the septal insertion in front of the trabecula septomarginalis. This feature was described as a T insertion by
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Fallot’sTetralogy
A
FIGURE
10. Diagrams
ET AL.
9s
illustrating the geometric
values for hearts with Fallot’s tetralogy
(A) and normal hearts (C).
Photographs
of typical speci-
mens viewed from above are shown for comparison. B is a specimen with tetralogy of Fallot and D is a normal heart. Note that in Fallot’s tetralogy. the angle of the great vessels is reduced and the aortic valve ring (Ao) is deviated anteriorly and to the right. Each circle in the position of the aorta in Panels A and C represents the position in an individual specimen. The figures indicate the average and extreme values for the angle of the great arteries (a) and the angle of the interatrial septum (c). PA = pulmonary artery; MV = mitral valve; TV = tricuspid valve.
Goor et ah7 and was present in all our specimens. In this respect our findings are in agreement with theirs. Since they demonstrate that the conus is malseptated at the expense of the pulmonary artery, their data could be construed as supporting the classic hypothesis of truncal malseptationl Truncal malseptation cannot explain all features of the anomaly, since it alone could not produce the dextroposed and anteriorly deviated aorta. Additional conal malrotation is necessary to explain these features. Since both malrotation and malseptation are necessary, it also follows that we are unable to support the concept of the monology proposed by Van Praagh et al.” This concept itself was based upon conal maldevelopment, but its main point was lack of growth of the subpulmonary conus. However, our results, like those of Goor et a1.,7 indicate that the pulmonary infundibulum is of normal or increased length in Fallot’s tetralogy. The question must now be posed whether Van Praagh himself considers the infundibulum underdeveloped, since in a personal communication to Goor and colleagues,7 he stated that his measurements indicated the infundibulum to be of normal length.
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Differential
Conal Absorption
Hypothesis
It is also significant that the embryologic observations11~13~14 now favor the differential conal absorption hypothesis originally propounded by Pernkopf and Wirtinger12 and other embryologists of the “German school.” When Paul et a1.20 first considered the concept of conal absorption, they believed that it was insufficiently supported by embryologic evidence and promoted instead a conal growth hypothesis2’ that they considered to be supported by anatomic facts. Since then, the embryologic studies have vindicated the concept of conal absorption, and Van PraaghY2 now refers to “differential conal development.” We can speculate on the significance of differential conal development to the morphogenesis of tetralogy of Fallot. A vital feature of normal embryogenesis is the normal “inversion” of the conus that brings the aorta to a dextroposterior position.r4 At this stage a myoblastic ledge separates the developing semilunar and atrioventricular valves, and this ledge is the conoventricular portion of the inner curvature of the heart tube, or the conoventricular flange” (Fig. 12A). Subsequent absorption of this ledge accounts for a
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A
B
FIGURE 11. Photographs of a specimen with tetralogy of Fallot (A) and a normal heart (6) dissected to demonstrate the relation between the aortic valve ring and the ventricular septum. In each heart the frontal cut was made in similar positions, but in A did not remove the auricular tips. In the specimen with tetralogy of Fallot the conal septum is not visible, and a large defect (VSD) exists between the right margin of the aortic valve and the ventricular septum (VS). The aorta in this position arises from the right extremity of the conoventricular flange (CVF). The entire ‘posterior rim of the aortic valve is visible, and areas of tricuspid-aortic (single arrow), mitral-aortic (double arrow) and tricuspid-mitral continuity are seen. In the normal specimen (B), the conal septum (CS) is seen blocking the space between the ventricular septum and the conoventricular flange, and the aortic valve arises from the conal seotum. The area of mitral-aortic continuity is not visible owing to the “wedge” position of the aortic valve ring. Note the normal overriding position of the aortic valve.
further shift of the aorta to the left ventricle and for the fibrous continuity normally present between the aortic and mitral valves (Fig. 12B). Should the normal inversion of the conus be incomplete, then the aorta would be in dextroposition (Fig. 12C). Absorption from this position would be insufficient to carry the aorta into its normal position above the left ventricle but could produce mitral-aortic continuity. Additional absorption would also be possible permitting fibrous continuity with the tricuspid valve (Fig. 12D). From this it follows that various degrees of absorption in the latter position would account for the observed discrepancies in aortic-tricuspid continuity (Fig. 3, A to C) in Fallot’s tetralogy. It also follows that, when complete separation of the valves is present, it is the persisting right portion of the conoventricular flange that separates them (Fig. 6 A and B). Rosenquist et al.g described identical findings, but interpreted this muscle bar as the inferior and proximal part of the infundibular septum. They therefore termed this structure the “parietal band” and considered that it fused with the deviated distal infundibular septum, which they termed the “crista supraventricularis,” in the floor of the defect. Consequently, they described the defect as intracristal. We believe that the differences in interpretation relate in part to the usage and abusage of the term “crista supraventricularis.” Opinions differ about the structure composing the “crista supraventricularis,” even in the normal heart. Our observations substan-
tiate that part of the concept of Van Praagh23 in which the “septal band” is separated from the crista. The “septal band” is the proximal extension of the structure originally described by Tandle+ as the trabecula septomarginalis. The viewpoint that it is not a cristal structure is endorsed by the embryologic observations of Goor et a1.,14 and Anderson et al.,ll who substantiated the isolated opinion of Pernkopf and Wirtinger.ls Furthermore, the studies of Anderson et al.” indicated that the normal crista supraventricularis, or the “parietal band” of Van Praagh,23 had two components, namely, the parietal insertion of the conal septum and the right margin of the conoventricular flange. This concept is in contrast with the opinion of Paul et aL2* and the data of Goor et a1.,i4 each of which correlated the “parietal band” solely with the conal septum. The opinion of Paul et a1.20 was illustrated by reference to truncus specimens in which the “parieta1 band,” or crista, was believed to be absent. However, others24 have indicated that a diminutive crista persists in truncus specimens, correlating well with the hypothesis that this structure represents the right extension of the conoventricular flange as now espoused. Furthermore, Van Mierop25 recently suggested a further modification of this nomenclature based upon his embryologic observations. He would restrict the term “crista supraventricularis” to that part of the ventricular tissues derived from the fused conal ridges. He considers that the parietal and septal bands are separate from the crista, both anatomically and embryologically. When all three structures
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CFB FC
Normal
VSD
El
m
llrm
CVF CFB AV-AoC FIGURE 12. Diagrams illustrating the concept of “lack of conal inversion”‘3 and conal absorption. lo A represents the position in the normal heart after normal conal inversion. The conal ridges are in dextroposterior (DPCR) and sinistro-anterior (SACR) positions, and their orientation is indicated by line 1. 6, absorption of the conoventricular flange (CVF) allows the aorta (Ao) to migrate above the left ventricle. This process also facilitates the occurrence of mitral-aortic fibrous continuity (MAFC) and establishment of the central fibrous body (CFB). The final angle of the arteries differs from the orientation of the conal ridges (compare lines 1 and la). C shows the situation of the conus after postulated “lack of conal inversion” (compare lines 1 and 2). It also shows anterior deviation, considered to be a morphogenetic feature in Fallot’s tetralogy. Conal absorption from the position (D) would enhance fibrous continuity between both the tricuspid valve (TAFC) and the mitral valve (MV) with the aortic valve (AV-AoC). The angle of the great arteries would be less than the normal (compare lines 2a and la). AVC = atrioventricular canal; C = conus; IEC = inferior endocardial cushion: PA = pulmonary artery; SEC = superior endocardial cushion; TV = tricuspid valve.
are correctly aligned, as in the normal heart, such a definition cannot be faulted. However, Van Mierop25 has indicated that the components may not be so aligned. If, when the components are not aligned, this definition is adhered to and the term “crista supraventricularis” is restricted to the conal septum, then the nomenclature would continue to be admirable. However, we have demonstrated that other investigators have used widely varying definitions of the terms parietal and septal bands, and have regarded them as integral parts of the “crista.” Thus, within the definition of Rosenquist et a1.,g the defect in Fallot’s tetralogy with aortic-tricuspid discontinuity is indeed intracristal. However, if any of the other definitions indicated is applied to this situation, then the defect cannot be considered intracristal. This is because the cases of Fallot’s tetralogy with aortic-tricuspid discontinuity represent cases in which the building blocks of the normal right ventricle are not correctly aligned, but are recognizable as discrete structures. Thus, in our opinion, the muscle
FIGURE 13. Diagram showing the spectrum of anomalies possible after various degrees of conal rotation and anterior deviation of the conal septum. In the normal position, the gap between ventricular and conal septa is filled by the membranous septum (solid black line). After minimal conal rotation, it can be postulated that the membranous septum would not fill this gap, and a ventricular septal defect (VSD) would result. Further rotation together with anterior deviation of the conal septum would result in Fallot’s tetralogy. From this point, increased anterior deviation would produce pseudotruncus arteriosus. whereas continued rotation coupled with a normally positioned septum would result in double outlet right ventricle (DORV). Ao = aorta; PA = pulmonary artery.
bar that separates the aortic and tricuspid valves is the conoventricular flange, or the parietal band of Van Mierop.25 Rosenquist et a1.,g in contrast, believe it to be the proximal conal septum. The muscular tissues separating the arterial outflow tracts are considered by us to represent the conal septum, and would be termed the crista supraventricularis by Van Mierop.25 Rosenquist et a1.g would name this structure the distal conal septum. The muscular tissue forming the floor of the defect and reinforcing the muscular ventricular septal crest is the trabecula septomarginalis, or the septal band of Van Mierop,25 whereas Rosenquist et a1.g have described this structure as another part of the proximal conal septum. Van Mieropz5 has moved away from his earlier definition of the trabecula septomarginalis which we have adopted. Nonetheless, neither his nor our present definitions
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would include this structure as part of the “crista,” and neither would the definition of Van Praagh.2S Therefore, when any of the latter definitions are used, the septal defect is not intracristal but infracristal. It is evident that disagreement in this respect is dependent upon nomenclature of the “crista supraventricularis” itself and embryologic theories regarding its origin. In order that the two should be distinguished, we believe that usage of the term “crista” should be restricted to a right ventricular structure of the normal heart until a standard nomenclature is adopted for application to supraventricular and septal muscle masses in malformed hearts. Until such a nomenclature is agreed upon, we believe that these muscular masses should be described in terms of their interpreted embryologic origin. Spectrum of Anomalies Associated with “Lack of Conal Inversion”
should not be regarded as a well defined entity. Van Mierop and Wiglesworth5 indicated the transition that exists from Eisenmenger complex (defined as ventricular septal defect with aortic dextroposition) to Fallot’s tetralogy, and this view was endorsed by Goor et a1.7 Both anomalies are linked by the “lack of embryonic conal inversion,” whereas the difference between them is produced by anterior deviation of the conal septum. Greater degrees of this anterior deviation would result in the anomaly of “pseudo-truncus arteriosus” or extreme tetralogy of Fallot, whereas lesser degrees of “lack of conal inversion” with normal septation would result in simple isolated ventricular septal defects. Similarly, greater degrees of “lack of conal inversion” will lead to the anomalous condition generally referred to as double outlet right ventricle, as indicated by the recent studies of Goor and Edwardsz6 and Anderson et a1.27 (Fig. 13). Acknowledgment
Consideration of the developmental process outlined leads to the conclusion that Fallot’s tetralogy
We thank Mr. R. E. Verhoeven for excellent photography.
References 1. VOn Rokitansky KF: Die Defekte der Scheidewtinde des Herzens. Vienna, Braumtiller, 1875. 2. Abbot M: Congenital cardiac disease. In, Osler and Melrae’s Modern Medicine, vol. 4. Philadelphia and New York, Lea and Febiger, 1915, p 384 3. Df! la Cruz MV, da Rocha JP: An ontogenetic theory for the explanation of congenital malformations involving the truncus and conus. Am Heart J 51:782-805, 1956 4. De la Cruz MV, Espino-Vela J, Attie F, et al: An embryologic theory for ventricular inversions for their classification. Am Heart J 73: 777-793, 1967 5. Van Mierop LHS, Wigiesworlh FW: Pathogenesis of transposition complexes. II. Anomalies due to faulty transfer of the posterior great artery. Am J Cardiol 12: 226-232, 1963 6. Van Praagh R, Van Praagh S, Nebesar RA, et al: Tetralogy of Fallot: underdevelopment of the pulmonary infundibulum and its sequela. Am J Cardiol 26:24-33, 1970 7. Goor DA, Lillehei CW, Edwards JE: Ventricular septal defects and pulmonic stenosis with and without dextroposition. Anatomic features and embryologic implications. Chest 60: 117-l 28, 1971 8. Lev M, Eckner FAO: The pathologic anatomy of tetralogy of Fallot and its variations. Dis Chest 45:251-261, 1964 9. Rosenquist GC, Sweeney LJ, Stempie DR, et al: Ventricular septal defect in tetralogy of Fallot. Am J Cardiol 31:749-754, 1973 Van Mierop LHS, Alley RD, Kausei HN, et al: Pathogenesis of transposition complexes. I. Embryology of the ventricles and great arteries. Am J Cardiol 12:216-225, 1963 11. Anderson RH, Wilkinson JL, Arnold R, et al: Morphogenesis of bulboventricular anomalies. I. Embryogenesis in the normal heart. Br Heart J 36:242-255, 1974 12. Pernkopf E, Wirtinger W: Die Transposition der Herzostien, ein Versuch der Erklarung dieser Erscheinung. 2 Anat Entwicklungsgesch 100:563-7 11, 1933 10.
13.
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schlichen Herzen mit besonderer Berticksichtigung der sogenannten Bulbusdrehung. Z Anat Entwicklungsgesch 128:1-17, 1969 14. Goor DA, Dische R, Liliehei CW: The conotruncus. I. Its normal inversion and conus absorption. Circulation 46:375-384, 1972 15. Wolff CF: Acta Acad. Scien. Petropol. 1781. Cited in Ref 16 16. Tandler J: Anatomie des Herzens, Jena, Gustav Fischer, 1913, P 64 Keith A: The fate of the bulbus cordis in the human heart. Lancet 2: 1267-1272, 1924 18. Lev M, Saphir 0: Transposition of the large vessels. J Tech Meth 17:126-162, 1937 19. Lev M, Rinoldi HJA, Rowlatt UF: The quantitative anatomy of cyanotic tetralogy of Fallot. Circulation 30:531-538, 1964 20. Paul MH, Van Praagh S, Van Praagh R: Transposition of the great arteries. In, Pediatric Cardiology (Watson H, ed). London, Lloyd Luke, 1968, p 582 21. Van Praagh R, Van Praagh S: Isolated ventricular inversion: A consideration of the morphogenesis, definition and diagnosis of nontransposed and transposed great arteries. Am J Cardiol 17: 395-406, 1966 22. Van Praagh R: Do side-by-side great arteries merit a special name? Am J Cardiol32:874-876, 1973 23. Van Praagh R: What is the Tauss,ig-Bing malformation? Circulation 381445-449, 1968 24. Bruins C, Dekker A: Truncus arteriosus. In Ref. 20, p 651 25. Van Mierop LHS: Anatomy and embryology of the right ventricle. In, The Heart (Edwards JE, Lev M, Abell MR, ed). Baltimore, Williams & Wilkins, 1974, p 1-16 26. Goor DA, Edwards JE: The spectrum of transposition of the great arteries: with specific reference to developmental anatomy of the conus. Circulation 48:406-415, 1973 27. Anderson RH, Wilkinson JL, Arnold R, et al: Morphogenesis of bulboventricular anomalies. II. Observations on malformed hearts. Br Heart J 36:948-970, 1974 17.
im men-
of CARDIOLOGY
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35
ANTON
E. BECKER,
MD,
FACC
MIKE CONNOR, MB, ChB ROBERT H. ANDERSON, MD*
Amsterdam, The Netherlands
From the Department of Pathology, Wilhelmina Gasthuis, University of Amsterdam, Amsterdam, The Netherlands. Manuscript accepted July 17, 1974. M. R. C. Travelling Fellow United Kingdom. Present address: Brompton Hospital, London, England. Address for reprints: Anton E. Becker, MD, Department of Pathology, Wilhelmina Gasthuis, University of Amsterdam, Amsterdam, The Netherlands.
March 1975
Study
Fourteen examples of tetralogy of Fallot were studied by morphometric and geometric methods, and the findings compared with results from 10 normal hearts. The data show that in Fallot’s tetralogy the conal septum is deviated anteriorly. The infundibulum, although narrow, is similar to, or of greater length than, that of the normal heart. This finding is not in agreement with recent observations suggesting that the anomaly represents lack of growth of the pulmonary conus. Our results further demonstrate that the aorta is dextroposed in Fallot’s tetralogy and that in the majority of cases absorption of the right extremity of the conoventricular flange has led to aortic-tricuspid fibrous continuity. The overall findings indicate that conal rotation has occurred in addition to anterior deviation. The data are interpreted as supporting a hypothesis of “lack of conal inversion” and conal malseptation as the morphogenetic mechanisms in tetralogy of Fallot.
The embryogenesis of the underlying malformations of tetralogy of Fallot is still much debated. The “classic” concept of this anomaly was propounded by Von Rokitanskyl in 1875. He suggested that malseptation of the truncus at the expense of the pulmonary artery produced the tetralogy since the anteriorly deviated conal septum would no longer be able to contribute to the formation of the ventricular septum. This concept was subsequently supported by Abbott,2 De La Cruz and his co-workers3,4 and Van Mierop and Wiglesworth.5 It was challenged by Van Praagh et a1.6 in 1970, who considered that the pulmonary infundibulum in Fallot’s tetralogy was “too short, too narrow and too shallow.” They stated that this feature and others in tetralogy could best be explained on the basis of underdevelopment of the subpulmonary infundibulum. However, in a morphometric and geometric study demonstrating that the pulmonary infundibulum was of normal length in Fallot’s tetralogy, Goor et a1.7 suggested that the condition was typified by dextroposition of the aorta, counterclockwise rotation of the conus and anterior deviation of the conal septum. In view of this uncertainty regarding morphogenesis, we investigated cases of tetralogy of Fallot using geometric and morphometric techniques and compared our results with similar measurements of normal hearts. In addition, we paid particular attention to the structures surrounding the ventricular septal defect, since some recent investigators8,g have described an “intracristal” defect in some cases of tetralogy.
Material
l
492
and Geometric
and Methods
Definition of Terms A clear definition of terms is necessary since confusion exists regarding the terminology of conal structures. This is particularly evident with relation to We therefore present a definition of the term “crista supraventricularis.”
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FIGURE 1. Morphometric measurements. A, diagram showing the measurements made in specimens of tetralogy of Fallot. The letters a to g indicate the dimensions recorded as described in the text. B, photograph of a specimen of a normal heart after bisection in the sagittal plane. Note how the specimen approximates the situation in Fallot’s tetralogy and how directly comparable measurements can be taken. Ao = aorta; CFB = central fibrous body: CS = conal septum: Inf = infundibulum; PA = pulmo-
nary artery; RA = rlght atrium; RV = right ventricle; VSD = ventricular septal defect.
terms in which we believe the controversial aspects are minimized. Conal septum: This structure is the embryonic septum between the aortic and pulmonary conuses. As thus defined, it may occupy different positions in normal and abnormal specimens. In the normal heart it can be considered to possess two segments. The first segment lies between the aortic and pulmonary valves and forms part of the interventricular septum, blocking the sinistro-anterior portion of the primary bulboventricular foramen. The second segment stretches from this septal component to the parietal wall of the right ventricle and forms an integral part of the crista supraventricularis. In hearts with tetralogy of Fallot, the entire proximal edge of the septum is considered to span the cavity of the
Superior aspect
FIGURE2.
Geometric
measurements.
right ventricle as a supraventricular structure. In these hearts, therefore, the septum possesses a free edge and septal and parietal insertions. Conoventricular flange: This structure is considered to represent the inner curvature of the heart tube after bulboventricular looping. lo21l It is the small segment of ventricular musculature that, after the looping process, intervenes between the atria1 and bulbar (or conal) segments of the heart tube. In a recent embryologic study’l it was termed the bulboatrioventricular ledge to indicate that it was originally composed of components from all three cardiac segments. During the normal development of the heart, the middle portion of the flange is absorbed to allow the aortic outflow tract to contact the left ventricle. This process, first described by Pernkopf and Wirtingerls and subse-
D
Inferior aspect
X
A, diagram of the superior
aspect of the heart after removal of the atrial chambers and the great arteries. diagram of measurements and angles taken on inferior surface of the mv = mitral valve; pa = pulmonary artery; rv = right ventricle; tv = tricuspid valve.
The lines constructed and angles measured are indicated. B, similar heart. ao = aorta; inf = infundibulum; See text for letter abbreviations.
Iv = left ventricle;
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TABLE I Measurements
Case no.
in 10 Normal
Hearts and 14 Hearts with Tetralogy Length Infund. (a)
Age (yr)
(mm)
Length RV (b) (mm)
of Fallot
Aortic Conus (c)
Conal Septum (d)
Pulmonary Conus (e)
Aortic Circumf. (f)
Pulm. Circumf. (g)
Angle of GA (a)
(mm)
(mm)
(mm)
(mm)
(mm)
(“)
(“)
6 8 12 6.5 18 12 10 7.5 8 16
27 33 42 25 58 42 34 30 28 58
28 35 42 25 60 48 34 22 28 56
44 57 48 58 60 53 57 46 45 67
94 95 87 96 95 101 99 93 97 96
18 44 32 51 25 50 31 75 25 23 19 21 32 67
9 31 13 33 11 14 3 39 13 15 10 12 19 33
17 40 32 38 37 32 26 28 29 32 31 38 31 37
97 94 93 94 98 93 96 93 98 95 94 100 96 93
Pulm.
= pulmonary;
Angle of IAS (c)
A. Normal Hearts 1 2 3 4 5 6 7 8 9 10
10/12 1 9/12 5 1 36 5 1 10/12 8/12 8/12 14
12 13 21 11 25 20 14 12 15 16
30 38 52 21 70 53 35 29 33 55
6 10 13 7 17 12 11 8 9 17
2 1.5 2.5 2 5 3 2.5 3 2 2.5
B. Hearts with Tetralogy of Fallot 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Circumf. ventricle.
37
9 22 15 20 12 21 9 29 14 10 10 15 23 23
12 36 21 36 19 42 34 49 20 20 28 20 23 61
= circumference;
GA = great
arteries;
7 8 7
hr 7112 6112 3112
6 7112 43 4112 3/52 3112 2112 18/12
5 17 12 20 10 20 12 22 9 7 9 10 11 15 IAS = interatria!
quent German embryologists, has been recently endorsed by several investigators.11J3J4 After this normal absorption, the right extension of this flange persists and, together with the parietal part of the conal septum, forms the normal crista supraventricularis.ll However, in malformed specimens the flange can produce aortic-atrioventridular valve discontinuity.5 Crista supraventricularis: This term will be used here only to describe a structure in the normal heart. It is considered to be the supraventricular muscle mass that separates the pulmonary and tricuspid valves.15 It is formed from two components,11J2 the right extension of the conoventricular flange as the outer component and the parietal part of the conal septum as the inner component. In some hearts, the latter component extends toward the apex of the ventricle, where it fuses with a well formed septal trabecula (see later). This septal trabecula is not considered part of the crista supraventricularis. Trabecula septomarginalis: This term is used to describe the extensive septal trabecula that extends from a position just beneath the pulmonary valve toward the ventricular apex and continues as the moderator band onto the parietal wall of the ventricle. This definition corresponds to that given by Tandler16 for a common variation of his trabecula septomarginalis. It is also in keeping with Keith’s description17 of the left sep-
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2 3 4 5 3 4 2 10 3 2 3 4 6 9
3 8 4 8 4 10 4 10 6 5 4 5 7 8 septum;
Infund.
= infundibulum;
RV = right
tal band and the description by Lev and SaphiP of the septal muscle bundle. Although the term trabecula septomarginalis is now commonly used to describe only the moderator band, it is evident from the descriptions cited that the latter structure is a continuation of the septal trabeculation. Van Mierop et al.1° used the term trabecula septomarginalis to describe both the septal band and the moderator band, and we follow their precedent. The trabecula septomarginalis is therefore considered to possess anterior and posterior limbs at its superior extent. The septal part of the conal septum is inserted between these limbs in the normal heart, and the papillary muscle of the conus arises from the posterior limb. The anterior papillary muscle arises from the trabecula septomarginalis toward the ventricular apex, and the moderator band frequently fuses with the parietal extension of the conal septum after it has crossed the ventricular cavity. An annulus is therefore formed between the conal septum, its parietal extension and the trabecula septomarginalis. Case Material Twenty-four hearts were studied, 14 specimens of tetralogy of Fallot and 10 normal hearts. To be considered an example of tetralogy, a heart was required to possess the combination of pulmonary infundibular narrowing, ventricular
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septal defect, overriding aorta and right ventricular hypertrophy in the presence of mitral-aortic fibrous continuity. Patients with Fallot’s tetralogy ranged in age from 7 hours to 43 years. The normal subjects were 8 months to 36 years old (Table I).
Morphometric Measurements The following morphometric observations were recorded in all specimens (Fig. 1): I. The infundibular length (a) was measured from the septal commissure of the pulmonary valve to the most inferior point of the conal septum. II. The length of the right ventricle (b) was recorded from the ventricular apex to the most inferior part of the conal septum. III. The proportions of the embryonic bulbus occupied by aortic (c) and pulmonary (e) outflow tracts and the thickness of the conal septum (d) were noted. In the specimens of Fallot’s tetralogy these measurements were taken on a line that passed from the most posterior part of the aortic outflow tract, beneath the conal septum to the anterior wall of the right ventricle (Fig. 1A). To produce a comparable situation in the normal hearts it was necessary to make a sagittal section through the heart that bisected the aortic outflow tract. This section then delineated the dimensions of both outflow tracts together with the thickness of the conal septum (Fig. 1B). IV. The circumferences of the aortic (f) and pulmonary (g) external orifices were measured.
Geometric Measurements These measurements were recorded after removal of the atria1 chambers and great arteries had revealed the fibrous valvular rings and a transverse cut through the ventricles had been made in the plane of the atrioventricular rings. These procedures made it possible to place a glass sheet upon the superior and inferior surfaces of the remaining cardiac segment and to record the salient features on superimposed transparent paper. On the superior aspect the following lines were constructed (Fig. 2A): I. Through the posterior margins of the A-V rings (ACB). II. Through the anterior margins of the same rings (FG). III. Through the mid-points of the semilunar valve rings (AFE). IV. Along the plane of the interatrial septum (CD). The angles of the great arteries (a) and the interatrial septum (c) were then calculated relative to the line ACB. In the normal hearts these measurements were recorded before the outflow tracts were sectioned. On the inferior surface of the specimens of Fallat’s tetralogy the following lines were constructed (Fig. 2B): I. Along the posterior interventricular septum (XY). II. Along the anterior interventricular septum (YZ). III. Along the conal septum (WY). The angles subtended by the conal septum (y’) and the anterior septum (y”) were then recorded relative to the posterior septum. The recorded measurements from these various procedures are indicated in Table I. For comparative purposes the observations were presented as follows: A. The length of the infundibulum (a) was recorded as
TABLE
ET AL.
II
Data Submitted to Statistical Analysis Using Student’s t test*
Measurements(see Fig. 1) Length of pulmonary conus expressed as part of length RV I(a/(a + b)l Proportion of embry onic conus occupied by pulmonary conus [e/(c + d + e)l Circumference of pulmonary artery compared with that of aorta (g/f) Angle of great arteries a” *Values
Fallot (14 specimens)
Normal (10 specimens)
P
0.36 + 0.08
0.28 zk 0.03
>0.005
0.18 zk 0.05
0.43 It 0.02
>0.005
0.50 & 0.16
1.02 + 0.05
>0.005
53.5 f
>0.005
32 i
6.04
7.59
expressed
as mean z!= standard deviation. (hearts with tetralogy vs. normal RV = right ventricle.
P = level of significance specimens);
a fraction of the entire right ventricular length (a + b) recorded as unity. B. The proportion of the total width of the embryonic bulbus (c + d + e), expressed as unity, as occupied by the aortic outflow tract (c), conal septum (d) and pulmonary tract (e). C. The ratio of the circumference of the pulmonary artery compared with that of the aorta expressed as unity. D. The angle of the great vessels in two groups. In the same diagram it was also possible to illustrate the position of the aorta by constructing circles to indicate the relation of the aortic valve ring to the lines FG and CD. The data used for each of these comparisons were subsequently submitted to statistical analysis using Student’s t test and a confidence level of 0.5 percent (Table II).
Results Basic Anatomy of the Right Ventricle In the normal heart, the right ventricle possesses inflow and outflow portions, the boundary between the two being the annulus formed by the conal septum, its parietal extension and the trabecula septomarginalis (Fig. 3). In Fallot’s tetralogy these morphologic features are not observed, since the septal insertion of the conal septum is anterior to the trabecula septomarginalis (Fig. 4). Since the parietal insertion is also deviated anteriorly, the conal septum and conovetitricular flange form distinct structures (Fig. 3). The infundibulum is a narrow channel situated anteriorly in the right ventricle. An intermediate ventricular segment communicates with the left ventricular outflow tract. The septal defect between this segment and the aortic outflow tract is bounded by the following structures: (1) anteriorly by the septal inser-
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FIGURE 3. Photographs of specimens of normal hearts. A, taken as if looking from the right ventricular apex directly into the pulmonary outflow tract. The normal crista supraventricularis (CSV) separates the tricuspid (TV) and pulmonary valves. Its septal insertion (thick arrow) is between the anterior (A) and posterior (P) limbs of the trabecula septomarginalis (TSM). B, taken from the ventricular apex looking towards the tricuspid valve (TV). Note that a promiment trabecula extends from the parietal insertion of the crista supraventricularis (double arrows) toward the ventricular apex, where it joins with the trabecula septomarginalis. The right ventricle is therefore divided into an inflow and an outflow portion. Again note the septal insertion (thick arrow) of the crista supraventricularis between the limbs of the trabecula septomarginalis.
FIGURE 4. Specimen of Fallot’s tetralogy, viewed from the apex of the right ventricle looking toward the pulmonary valve (compare with Fig. 3A). The conal septum (CS) is divorced from the right margin of the conoventricular flange (CVF). The septal (single arrow) and parietal (double arrows) insertions of the conal septum are both deviated anteriorly, thus constricting the pulmonary outflow tract. The septal insertion is anterior to the trabecula septomarginalis (TSM), which together with the muscular ventricular septum forms the floor of the defect (VSD). At the posterior edge of the defect an area of tricuspid-aortic continuity is visible (*). The roof of the defect is formed by the subaortic conus, between the conoventricular flange and the conal septum.
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tion of the conal septum, which fuses with the anterior segment of the ventricular septum in front of the trabecula septomarginalis; (2) inferiorly by the crest of the muscular septum, which is reinforced by the trabecula septomarginalis; (3) posteriorly by the ventricular septal structures fusing with the atrioventricular annulus; and (4) above the atrioventricular annulus by the right margin of the conoventricular flange, which forms the aortic conus in this position. The degree of development of the conoventricular flange varied in different specimens. In the majority, there was direct fibrous continuity between the aortic and tricuspid valves (Fig. 4). In some specimens the flange completely separated these two valves, but the tricuspid valve was continuous with the mitral valve and thence with the aortic valve by way of the central fibrous body (Fig. 5A). In two specimens, however, a bar of muscle completely separated the aortic and tricuspid valves, stretching to the crest of the ventricular septum and producing a complete muscular rim to the ventricular septal defect (Fig. 5B). Although the ridge appeared as a thick band from its inferior aspect, dissection from above suggested that it represented a reduplication of the heart wall (Fig. 6A); bisection of the ridge resulted in confirmation of this opinion (Fig. 6B). Morphometric
Observations
In the normal hearts the fraction of the right ventricular length (a + b) occupied by the pulmonary conus (a) averaged 0.28. In the specimens of tetralogy of Fallot (Fig. 7) this fraction was generally larger, falling below the normal mean value in only three specimens. The average value for the malformed specimens was 0.36 and the extreme was 0.50. The
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FIGURE 5. Specimens of Fallot’s tetralogy showing various degrees of separation between aortic (AV) and tricuspid (TV) valves. A, specimen viewed from below after division of the ventricular septum ( l) in which the right margin of the conoventricular flange (CVF) separates the greatest part of the valve rings. However, fibrous continuity is present between the tricuspid and mitral (MV) valves by way of the central fibrous body (CFB), and forms the posterior margin of the ventricular septal defect. Through the central fibrous body, continuity is also established between the aortic and tricuspid valves. B, specimen in which the ventricular septum has again been divided ( l) to demonstrate the inferior aspect of the aortic valve. Although aortic-mitral valvular continuity is present (single arrow) a complete bar of muscle separates the aortic and tricuspid valves, and fuses with the tip of the ventricular septum (double arrows). The muscle bar forms the roof and posterior wall of the defect, and is the right margin of the conoventricular flange. The defect has been sectioned through its floor. CS = conal septum; POT = pulmonary outflow tract. l
l
FIGURE 6. Photographs of the specimen shown in Figure 58, illustrating the nature of the muscular bar between the tricuspid and aortic valves. A, superior view, the bar is dissected to demonstrate that although it appears as a solid ridge from below (Fig. 58). it represents a reduplication of the heart wail (double arrows). B, the ledge after its bisection, viewed from the septal aspect. The reduplication is demonstrated, and the bulbar (a) and ventricular (b) components are clearly visible. AV = aortic valve; MV = mitral valve: TV = tricuspid valve.
differences between the values in the two groups was statistically significant (P >0.005). In the normal heart the embryonic bulbus was divided approximately evenly between the aortic (c) and pulmonary (e) outflow tracts, the respective average values being 45 and 43 percent, whereas the conal septum (d) occupied 12 percent of the width of the bulbus. In Fallot’s tetralogy the conal septum was grossly enlarged (average 25 percent) at the expense of the pulmonary conus (average 20 percent), whereas the aortic conus was also expanded (average 55 percent), again at the expense of the pulmonary conus (Fig. 8). The differences between the normal hearts and specimens of Fallot’s tetralogy were statistically significant (P >0.005). In normal specimens the pulmonary circumference was similar to the aortic circumference (1.02 to 1.00). In the specimens of Fallot’s tetralogy, as might be expected, lg it was markedly diminished, the average value being 0.50 with extremes of 0.70
and 0.16 (Fig. 9). The differences were again of considerable statistical significance (P >0.005). Geometric Measurements
These measurements showed that although the angle of the interatrial septum (c) was virtually identical in malformed and normal specimens (95” vs. 94’), the angle of the great arteries (a) was markedly different. In normal specimens this angle was 53.5O (range 44O to 67’); in specimens of tetralogy it was 32” (range 17” to 40”). These studies additionally showed that the aortic valve was dextroposed (in relation to the interatrial septum) and anteriorly deviated in the hearts with tetralogy compared with the normal hearts (Fig. 10). As with the other results, this finding was statistically significant (P >0.005). In the normal hearts the angle of the conal septum (y’) was difficult to measure, but it subtended less than 90’ to
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N- 1
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4 EB
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Normal
‘sTetralogy
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Aortic Conus
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6
7
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9 10 11 12 13 14
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t Pulm.Art.
c 0.16
FIGURE 7 (upper left). Diagram illustrating the length of the infundibulum (measurement a) expressed as a ratio of the right ventricular length (measurement a -I b). The illustrated infundibular length indicates the average value of this ratio in hearts with tetralogy of Fallot and normal specimens, and the scales indicate the range of measurements of the infundibular lengths. FIGURE 8. (upper right) Diagram illustrating the mode of division of the embryonic bulbus in hearts with tetralogy of Fallot and normal specimens. The hatched portions represent measurements of the aortic conus (c), conal septum (d) and the pulmonary (Pulm.) conus (e) expressed as ratios of the measurement c + d + e. Column N represents the average values of 10 normal hearts, columns 1 to 14 represent individual measurements in the specimens with tetralogy of Fallot. FIGURE 9 (lower left). Diagram showing the circumference of the pulmonary artery (Pulm. Art.) expressed as a ratio of the aortic circumference. Each circle represents the circumference of the pulmonary artery from individual specimens with Fallot’s tetralogy, and the figures give the range of values. The ratio in the 10 normal hearts was 0.98 to 1.00.
the posterior septum. In the majority of specimens of Fallot’s tetralogy this angle was equal to or greater than 90°. Discussion This study was based upon morphometric and geometric measurements obtained from formalin-fixed specimens. Undoubtedly artifacts have been introduced and some of the measurements may not be completely without bias. However, we believe that this quantitative approach gives a more reliable answer to the questions posed than could be provided by mere inspection of such hearts. Conal Rotation and Malseptation Our results are in agreement with findings in the similar morphometric and geometric study conducted by Goor et a1.,7 and we agree with these workers that Fallot’s tetralogy is characterized by the morphogenetic features of conal rotation and conal malseption. The conal rotation is manifested by the demonstrated aortic dextroposition. Although Van
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Praagh et al.‘j considered this feature to be present only in cases with “severe pulmonary outflow tract obstruction,” we agree with Goor et a1.7 that it is a hallmark of the anomaly. However, we also found that the aortic valve was anteriorly displaced in relation to the atrioventricular valve rings, and no longer occupied its normal “wedge” position (Fig. 10). Indeed, although we agree with Van Praagh et a1.6 that the normal aorta overrides the ventricular septum (Fig. llA), we consider that the associated anterior deviation of the aortic valve in Fallot’s tetralogy forms the major difference between the two conditions (Fig. 11B). The conal malseption is shown by the anterior deviation of the conal septum. The rotation of the conus itself may have rotated the conal septum as judged by the divorce of its parietal insertion from the conoventricular flange. However, additional anterior deviation is indicated by the position of the septal insertion in front of the trabecula septomarginalis. This feature was described as a T insertion by
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10. Diagrams
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9s
illustrating the geometric
values for hearts with Fallot’s tetralogy
(A) and normal hearts (C).
Photographs
of typical speci-
mens viewed from above are shown for comparison. B is a specimen with tetralogy of Fallot and D is a normal heart. Note that in Fallot’s tetralogy. the angle of the great vessels is reduced and the aortic valve ring (Ao) is deviated anteriorly and to the right. Each circle in the position of the aorta in Panels A and C represents the position in an individual specimen. The figures indicate the average and extreme values for the angle of the great arteries (a) and the angle of the interatrial septum (c). PA = pulmonary artery; MV = mitral valve; TV = tricuspid valve.
Goor et ah7 and was present in all our specimens. In this respect our findings are in agreement with theirs. Since they demonstrate that the conus is malseptated at the expense of the pulmonary artery, their data could be construed as supporting the classic hypothesis of truncal malseptationl Truncal malseptation cannot explain all features of the anomaly, since it alone could not produce the dextroposed and anteriorly deviated aorta. Additional conal malrotation is necessary to explain these features. Since both malrotation and malseptation are necessary, it also follows that we are unable to support the concept of the monology proposed by Van Praagh et al.” This concept itself was based upon conal maldevelopment, but its main point was lack of growth of the subpulmonary conus. However, our results, like those of Goor et a1.,7 indicate that the pulmonary infundibulum is of normal or increased length in Fallot’s tetralogy. The question must now be posed whether Van Praagh himself considers the infundibulum underdeveloped, since in a personal communication to Goor and colleagues,7 he stated that his measurements indicated the infundibulum to be of normal length.
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Differential
Conal Absorption
Hypothesis
It is also significant that the embryologic observations11~13~14 now favor the differential conal absorption hypothesis originally propounded by Pernkopf and Wirtinger12 and other embryologists of the “German school.” When Paul et a1.20 first considered the concept of conal absorption, they believed that it was insufficiently supported by embryologic evidence and promoted instead a conal growth hypothesis2’ that they considered to be supported by anatomic facts. Since then, the embryologic studies have vindicated the concept of conal absorption, and Van PraaghY2 now refers to “differential conal development.” We can speculate on the significance of differential conal development to the morphogenesis of tetralogy of Fallot. A vital feature of normal embryogenesis is the normal “inversion” of the conus that brings the aorta to a dextroposterior position.r4 At this stage a myoblastic ledge separates the developing semilunar and atrioventricular valves, and this ledge is the conoventricular portion of the inner curvature of the heart tube, or the conoventricular flange” (Fig. 12A). Subsequent absorption of this ledge accounts for a
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A
B
FIGURE 11. Photographs of a specimen with tetralogy of Fallot (A) and a normal heart (6) dissected to demonstrate the relation between the aortic valve ring and the ventricular septum. In each heart the frontal cut was made in similar positions, but in A did not remove the auricular tips. In the specimen with tetralogy of Fallot the conal septum is not visible, and a large defect (VSD) exists between the right margin of the aortic valve and the ventricular septum (VS). The aorta in this position arises from the right extremity of the conoventricular flange (CVF). The entire ‘posterior rim of the aortic valve is visible, and areas of tricuspid-aortic (single arrow), mitral-aortic (double arrow) and tricuspid-mitral continuity are seen. In the normal specimen (B), the conal septum (CS) is seen blocking the space between the ventricular septum and the conoventricular flange, and the aortic valve arises from the conal seotum. The area of mitral-aortic continuity is not visible owing to the “wedge” position of the aortic valve ring. Note the normal overriding position of the aortic valve.
further shift of the aorta to the left ventricle and for the fibrous continuity normally present between the aortic and mitral valves (Fig. 12B). Should the normal inversion of the conus be incomplete, then the aorta would be in dextroposition (Fig. 12C). Absorption from this position would be insufficient to carry the aorta into its normal position above the left ventricle but could produce mitral-aortic continuity. Additional absorption would also be possible permitting fibrous continuity with the tricuspid valve (Fig. 12D). From this it follows that various degrees of absorption in the latter position would account for the observed discrepancies in aortic-tricuspid continuity (Fig. 3, A to C) in Fallot’s tetralogy. It also follows that, when complete separation of the valves is present, it is the persisting right portion of the conoventricular flange that separates them (Fig. 6 A and B). Rosenquist et al.g described identical findings, but interpreted this muscle bar as the inferior and proximal part of the infundibular septum. They therefore termed this structure the “parietal band” and considered that it fused with the deviated distal infundibular septum, which they termed the “crista supraventricularis,” in the floor of the defect. Consequently, they described the defect as intracristal. We believe that the differences in interpretation relate in part to the usage and abusage of the term “crista supraventricularis.” Opinions differ about the structure composing the “crista supraventricularis,” even in the normal heart. Our observations substan-
tiate that part of the concept of Van Praagh23 in which the “septal band” is separated from the crista. The “septal band” is the proximal extension of the structure originally described by Tandle+ as the trabecula septomarginalis. The viewpoint that it is not a cristal structure is endorsed by the embryologic observations of Goor et a1.,14 and Anderson et al.,ll who substantiated the isolated opinion of Pernkopf and Wirtinger.ls Furthermore, the studies of Anderson et al.” indicated that the normal crista supraventricularis, or the “parietal band” of Van Praagh,23 had two components, namely, the parietal insertion of the conal septum and the right margin of the conoventricular flange. This concept is in contrast with the opinion of Paul et aL2* and the data of Goor et a1.,i4 each of which correlated the “parietal band” solely with the conal septum. The opinion of Paul et a1.20 was illustrated by reference to truncus specimens in which the “parieta1 band,” or crista, was believed to be absent. However, others24 have indicated that a diminutive crista persists in truncus specimens, correlating well with the hypothesis that this structure represents the right extension of the conoventricular flange as now espoused. Furthermore, Van Mierop25 recently suggested a further modification of this nomenclature based upon his embryologic observations. He would restrict the term “crista supraventricularis” to that part of the ventricular tissues derived from the fused conal ridges. He considers that the parietal and septal bands are separate from the crista, both anatomically and embryologically. When all three structures
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CVF CFB AV-AoC FIGURE 12. Diagrams illustrating the concept of “lack of conal inversion”‘3 and conal absorption. lo A represents the position in the normal heart after normal conal inversion. The conal ridges are in dextroposterior (DPCR) and sinistro-anterior (SACR) positions, and their orientation is indicated by line 1. 6, absorption of the conoventricular flange (CVF) allows the aorta (Ao) to migrate above the left ventricle. This process also facilitates the occurrence of mitral-aortic fibrous continuity (MAFC) and establishment of the central fibrous body (CFB). The final angle of the arteries differs from the orientation of the conal ridges (compare lines 1 and la). C shows the situation of the conus after postulated “lack of conal inversion” (compare lines 1 and 2). It also shows anterior deviation, considered to be a morphogenetic feature in Fallot’s tetralogy. Conal absorption from the position (D) would enhance fibrous continuity between both the tricuspid valve (TAFC) and the mitral valve (MV) with the aortic valve (AV-AoC). The angle of the great arteries would be less than the normal (compare lines 2a and la). AVC = atrioventricular canal; C = conus; IEC = inferior endocardial cushion: PA = pulmonary artery; SEC = superior endocardial cushion; TV = tricuspid valve.
are correctly aligned, as in the normal heart, such a definition cannot be faulted. However, Van Mierop25 has indicated that the components may not be so aligned. If, when the components are not aligned, this definition is adhered to and the term “crista supraventricularis” is restricted to the conal septum, then the nomenclature would continue to be admirable. However, we have demonstrated that other investigators have used widely varying definitions of the terms parietal and septal bands, and have regarded them as integral parts of the “crista.” Thus, within the definition of Rosenquist et a1.,g the defect in Fallot’s tetralogy with aortic-tricuspid discontinuity is indeed intracristal. However, if any of the other definitions indicated is applied to this situation, then the defect cannot be considered intracristal. This is because the cases of Fallot’s tetralogy with aortic-tricuspid discontinuity represent cases in which the building blocks of the normal right ventricle are not correctly aligned, but are recognizable as discrete structures. Thus, in our opinion, the muscle
FIGURE 13. Diagram showing the spectrum of anomalies possible after various degrees of conal rotation and anterior deviation of the conal septum. In the normal position, the gap between ventricular and conal septa is filled by the membranous septum (solid black line). After minimal conal rotation, it can be postulated that the membranous septum would not fill this gap, and a ventricular septal defect (VSD) would result. Further rotation together with anterior deviation of the conal septum would result in Fallot’s tetralogy. From this point, increased anterior deviation would produce pseudotruncus arteriosus. whereas continued rotation coupled with a normally positioned septum would result in double outlet right ventricle (DORV). Ao = aorta; PA = pulmonary artery.
bar that separates the aortic and tricuspid valves is the conoventricular flange, or the parietal band of Van Mierop.25 Rosenquist et a1.,g in contrast, believe it to be the proximal conal septum. The muscular tissues separating the arterial outflow tracts are considered by us to represent the conal septum, and would be termed the crista supraventricularis by Van Mierop.25 Rosenquist et a1.g would name this structure the distal conal septum. The muscular tissue forming the floor of the defect and reinforcing the muscular ventricular septal crest is the trabecula septomarginalis, or the septal band of Van Mierop,25 whereas Rosenquist et a1.g have described this structure as another part of the proximal conal septum. Van Mieropz5 has moved away from his earlier definition of the trabecula septomarginalis which we have adopted. Nonetheless, neither his nor our present definitions
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would include this structure as part of the “crista,” and neither would the definition of Van Praagh.2S Therefore, when any of the latter definitions are used, the septal defect is not intracristal but infracristal. It is evident that disagreement in this respect is dependent upon nomenclature of the “crista supraventricularis” itself and embryologic theories regarding its origin. In order that the two should be distinguished, we believe that usage of the term “crista” should be restricted to a right ventricular structure of the normal heart until a standard nomenclature is adopted for application to supraventricular and septal muscle masses in malformed hearts. Until such a nomenclature is agreed upon, we believe that these muscular masses should be described in terms of their interpreted embryologic origin. Spectrum of Anomalies Associated with “Lack of Conal Inversion”
should not be regarded as a well defined entity. Van Mierop and Wiglesworth5 indicated the transition that exists from Eisenmenger complex (defined as ventricular septal defect with aortic dextroposition) to Fallot’s tetralogy, and this view was endorsed by Goor et a1.7 Both anomalies are linked by the “lack of embryonic conal inversion,” whereas the difference between them is produced by anterior deviation of the conal septum. Greater degrees of this anterior deviation would result in the anomaly of “pseudo-truncus arteriosus” or extreme tetralogy of Fallot, whereas lesser degrees of “lack of conal inversion” with normal septation would result in simple isolated ventricular septal defects. Similarly, greater degrees of “lack of conal inversion” will lead to the anomalous condition generally referred to as double outlet right ventricle, as indicated by the recent studies of Goor and Edwardsz6 and Anderson et a1.27 (Fig. 13). Acknowledgment
Consideration of the developmental process outlined leads to the conclusion that Fallot’s tetralogy
We thank Mr. R. E. Verhoeven for excellent photography.
References 1. VOn Rokitansky KF: Die Defekte der Scheidewtinde des Herzens. Vienna, Braumtiller, 1875. 2. Abbot M: Congenital cardiac disease. In, Osler and Melrae’s Modern Medicine, vol. 4. Philadelphia and New York, Lea and Febiger, 1915, p 384 3. Df! la Cruz MV, da Rocha JP: An ontogenetic theory for the explanation of congenital malformations involving the truncus and conus. Am Heart J 51:782-805, 1956 4. De la Cruz MV, Espino-Vela J, Attie F, et al: An embryologic theory for ventricular inversions for their classification. Am Heart J 73: 777-793, 1967 5. Van Mierop LHS, Wigiesworlh FW: Pathogenesis of transposition complexes. II. Anomalies due to faulty transfer of the posterior great artery. Am J Cardiol 12: 226-232, 1963 6. Van Praagh R, Van Praagh S, Nebesar RA, et al: Tetralogy of Fallot: underdevelopment of the pulmonary infundibulum and its sequela. Am J Cardiol 26:24-33, 1970 7. Goor DA, Lillehei CW, Edwards JE: Ventricular septal defects and pulmonic stenosis with and without dextroposition. Anatomic features and embryologic implications. Chest 60: 117-l 28, 1971 8. Lev M, Eckner FAO: The pathologic anatomy of tetralogy of Fallot and its variations. Dis Chest 45:251-261, 1964 9. Rosenquist GC, Sweeney LJ, Stempie DR, et al: Ventricular septal defect in tetralogy of Fallot. Am J Cardiol 31:749-754, 1973 Van Mierop LHS, Alley RD, Kausei HN, et al: Pathogenesis of transposition complexes. I. Embryology of the ventricles and great arteries. Am J Cardiol 12:216-225, 1963 11. Anderson RH, Wilkinson JL, Arnold R, et al: Morphogenesis of bulboventricular anomalies. I. Embryogenesis in the normal heart. Br Heart J 36:242-255, 1974 12. Pernkopf E, Wirtinger W: Die Transposition der Herzostien, ein Versuch der Erklarung dieser Erscheinung. 2 Anat Entwicklungsgesch 100:563-7 11, 1933 10.
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schlichen Herzen mit besonderer Berticksichtigung der sogenannten Bulbusdrehung. Z Anat Entwicklungsgesch 128:1-17, 1969 14. Goor DA, Dische R, Liliehei CW: The conotruncus. I. Its normal inversion and conus absorption. Circulation 46:375-384, 1972 15. Wolff CF: Acta Acad. Scien. Petropol. 1781. Cited in Ref 16 16. Tandler J: Anatomie des Herzens, Jena, Gustav Fischer, 1913, P 64 Keith A: The fate of the bulbus cordis in the human heart. Lancet 2: 1267-1272, 1924 18. Lev M, Saphir 0: Transposition of the large vessels. J Tech Meth 17:126-162, 1937 19. Lev M, Rinoldi HJA, Rowlatt UF: The quantitative anatomy of cyanotic tetralogy of Fallot. Circulation 30:531-538, 1964 20. Paul MH, Van Praagh S, Van Praagh R: Transposition of the great arteries. In, Pediatric Cardiology (Watson H, ed). London, Lloyd Luke, 1968, p 582 21. Van Praagh R, Van Praagh S: Isolated ventricular inversion: A consideration of the morphogenesis, definition and diagnosis of nontransposed and transposed great arteries. Am J Cardiol 17: 395-406, 1966 22. Van Praagh R: Do side-by-side great arteries merit a special name? Am J Cardiol32:874-876, 1973 23. Van Praagh R: What is the Tauss,ig-Bing malformation? Circulation 381445-449, 1968 24. Bruins C, Dekker A: Truncus arteriosus. In Ref. 20, p 651 25. Van Mierop LHS: Anatomy and embryology of the right ventricle. In, The Heart (Edwards JE, Lev M, Abell MR, ed). Baltimore, Williams & Wilkins, 1974, p 1-16 26. Goor DA, Edwards JE: The spectrum of transposition of the great arteries: with specific reference to developmental anatomy of the conus. Circulation 48:406-415, 1973 27. Anderson RH, Wilkinson JL, Arnold R, et al: Morphogenesis of bulboventricular anomalies. II. Observations on malformed hearts. Br Heart J 36:948-970, 1974 17.
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