Straddling mitral and tricuspid valves: morphologic differences and developmental backgrounds.

The anatomy of 25 hearts with a straddling mitral or tricuspid valve, or both, is described. Malalignment of atrial and ventricular septa is an essential feature of a straddling tricuspid valve, creating an inlet septal defect. Across this defect, the tricuspid valve straddles into the opposite (left ventricular) chamber, where it is separated from the mitral valve by a posterior muscular ridge, the posteromedial muscle. A straddling mitral valve requires an infundibular septal defect, predominantly of the malalignment type, in which the anterior part of the ventricular septum deviates to the left of the infundibular septum. The mitral valve straddles into the opposite (right ventricular) chamber, anterior to the trabecula septomarginalis. From normal developmental stages, it is concluded that valve formation takes place only after completion of ventricular septation. Any malformation of the valves is therefore considered to be superimposed on a primary malformation of the septum. The ventricular septum itself develops from three different components. Malseptation in the inlet portion of the embryonic heart lead to the characteristic septal malformation seen in straddling tricuspid valve. Malseptation in the outlet portion may lead to the septal malformation that characterizes straddling mitral valve.

Muscular ventricular septal defects: a reappraisal of the anatomy.

Among 79 autopsy specimens of heart with an isolated ventricular septal defect, there were 29 cases of muscular defect. Among 60 hearts with complete transposition of the great arteries and a ventricular septal defect, there were 13 cases with a muscular defect. All muscular defects could be classified in three different types, based on the specific pathologic anatomy of the ventricular septum. The central and posterior defects were usually large and single, the marginal defects were frequently small and multiple. In hearts with transposition, central muscular defects were extremely rare, whereas these defects were by far the most frequent muscular defects in isolated ventricular septal defect. Alternatively, the posterior type was more common in cases of transposition. Marginal muscular defects were rare in both groups of malformations.

Relation between aortic arch hypoplasia of variable severity and central muscular ventricular septal defects: emphasis on associated left ventricular abnormalities.

Among 25 heart specimens with a central muscular ventricular septal defect (including 3 with the architecture of a spontaneously closed defect), only 6 (24 percent) had an aortic arch of normal size and configuration. Isthmus atresia was present in one case, isthmus hypoplasia in eight cases, local coarctation in six and a combination of isthmus hypoplasia and local coarctation in another four. A study of the left ventricular morphologic features of the 25 hearts revealed the presence of a spectrum of additional anomalies. The aortic valve was bicuspid in 16 and mitral valve anomalies were present in 13 specimens. Mitral valve deformities present in the 13 specimens included congenital stenosis (5), deficient chordae tendineae (4), parachute valve (2), adherent valve leaflets (1) and a hypoplastic posteromedial papillary muscle (1). Furthermore, there was a large incidence of abnormal left ventricular muscular structures that could be classified into three basic types: (1) the anteroseptal "twist": thickening and deviation of the anterobasal septum and anterior wall, resulting in a relatively posterior position of the aortic ostium (16 cases); (2) a prominent anterolateral muscle (9 cases); and (3) a posteromedial muscle (9 cases). It is concluded that a central muscular ventricular septal defect is not an isolated malformation but is commonly part of a complex developmental anomaly. This complex of associated inflow and outflow tract lesions presumably may cause reduced aortic flow during morphogenesis, resulting in aortic arch hypoplasia of various degrees of severity.

Ventricular septal defect with normally connected and with transposed great arteries.

The morphologic characteristics of 50 hearts with ventricular septal defect (VSD) and ventriculoarterial (VA) discordance were compared with those of 105 hearts with VSD and VA concordance. Of the 7 VSD types in VA concordant hearts, the 3 that occur most frequently--central muscular (26%), perimembranous with leftward malalignment of the outlet septum (18%) and perimembranous with overriding posterior artery (15%)--were absent in VA discordant hearts. Of the 6 with VA discordance, 2 principal VSD types (perimembranous with rightward outlet septum malalignment [25%] and muscular infundibular with leftward outlet septum malalignment [15%]) did not occur in VA concordant specimens. Thus, 4 VSD types occurred with VA concordance as well as with VA discordance: subarterial (12% concordance, 3% discordance); perimembranous inlet (15%, 27%); muscular inlet (10%, 27%); and membranous (4%, 3%). Of these 4 common groups, perimembranous inlet VSD with VA concordance was accompanied by tricuspid valve anomalies; however, mitral valve anomalies complicated this type of VSD with VA discordance. It is concluded that in hearts with VA concordance vs hearts with VA discordance the spectrum of VSD and ventricular morphology is different.

Morphology of ventricular septal defect in complete transposition of the great arteries.

The morphologic characteristics of ventricular septal defect (VSD) was studied in 50 hearts with complete transposition of the great arteries. Except for 1 membranous and 1 subarterial defect, all VSDs could be classified into 1 of 4 categories. Group A included 14 specimens with a perimembranous defect extending into inlet and trabecular septum with rightward malalignment of the outlet septum; in this group aortic arch anomalies (6 hearts) and tricuspid valve abnormalities (7 hearts) were frequently present. Group B comprised 13 hearts with perimembranous defects extending into the inlet septum; 11 hearts in this group also had an anomalous mitral valve. Group C included 13 hearts with muscular inlet defects, with signs of spontaneous closure by marginal fibrosis in 10 cases. Group D included 8 hearts with muscular infundibular defects; in 6 of these hearts the outlet septum was malaligned to the left, causing different degrees of subpulmonary stenosis. A small second VSD was present in 5 hearts. Thus, the spectrum of VSD in transposition of the great arteries is different from that of isolated VSD.

The conducting tissues in primitive ventricle with outlet chamber. Two different possibilities.

The conducting tissues have been studied in two cases of primitive ventricle with outlet chamber. In one case the outlet chamber was to the right and in the other, to the left. In both cases there was an anterior node related to the anterior part of the right atrioventricular anulus. In the specimen with a left-sided outlet chamber (l-loop), the bundle passed through the atrioventricular-semilunar fibrous continuity and was intimately related to the posterior artery. Such a relation was absent in the specimen with a right-sided outlet chamber (d-loop), wherein the bundle directly descended on the posterior part of the septum between the main and outlet chambers. The septum is not considered to be the true ventricular septum but rather a hypertrophied trabecula septomarginalis.

Development of the papillary muscles of the mitral valve: morphogenetic background of parachute-like asymmetric mitral valves and other mitral valve anomalies.

OBJECTIVES: To understand papillary muscle malformations, such as in parachute mitral valves or parachute-like asymmetric mitral valves, we studied the development of papillary muscles. METHODS: Normal human hearts at between 5 and 19 weeks of development were studied with immunohistochemistry, three-dimensional reconstructions, and gross inspection. Scanning electron microscopy was used to study human and rat hearts. RESULTS: In embryonic hearts a prominent horseshoe-shaped myocardial ridge runs from the anterior wall through the apex to the posterior wall of the left ventricle. In the atrioventricular region this ridge is continuous with atrial myocardium and covered with cushion tissue. The anterior and posterior parts of the trabecular ridge enlarge and loosen their connections with the atrial myocardium. Their lateral sides gradually delaminate from the left ventricular wall, and the continuity between the two parts is incorporated in the apical trabecular network. In this way the anterior and posterior parts of the ridge transform into the anterolateral and the posteromedial papillary muscles, respectively. Simultaneously, the cushions remodel into valve leaflets and chordae. Only the chordal part of the cushions remains attached to the developing papillary muscles. CONCLUSIONS: Disturbed delamination of the anterior or posterior part of the trabecular ridge from the ventricular wall, combined with underdevelopment of chordae, seems to be the cause of asymmetric mitral valves. Parachute valves, however, develop when the connection between the posterior and anterior part of the ridge condenses to form one single papillary muscle. Thus parachute valves and parachute-like asymmetric mitral valves originate in different ways.

The parachute-like asymmetric mitral valve and its two papillary muscles.

OBJECTIVES: The morphologic features of parachute-like asymmetric mitral valves are described to discriminate this anomaly from parachute mitral valves. BACKGROUND: Mitral valves with unifocal attachment of chords have been called "parachute valves," independent of the number of papillary muscles. Therefore the anomaly involving two papillary muscles has not received separate attention. METHODS: The gross anatomy of 29 mitral valves with focalized attachment of chords was studied. RESULTS: In 28 of the autopsy specimens asymmetric mitral valves with two papillary muscles were present, and one of the muscles was elongated, located higher in the left ventricle with its tip reaching to the anulus, and attached at both its base and lateral side to the left ventricular wall. The valve leaflets could be directly attached to this abnormal muscle that received few chords or, in three hearts, no chords at all, resulting in an oblique and eccentric orifice. Because of the focalized attachment of chords to one of the two papillary muscles, we call this malformation "parachute-like asymmetric mitral valve," We found only one "true parachute mitral valve," that is, one having a single papillary muscle that received all chords. CONCLUSIONS: The morphologic features of asymmetric mitral valves are essentially different from those of true parachute valves. A distinction between these two anomalies will contribute to recognition by the pediatric cardiologist and surgeon.

Tricuspid atresia. Morphology of the outlet chamber with special emphasis on surgical implications.

An anatomic study of 28 heart specimens with tricuspid atresia showed 15 hearts with ventriculoarterial concordance and a right-sided anterior outlet chamber. Of these 15 hearts, 12 showed evidence of restricted pulmonary blood flow. In eight of these 12 specimens, an anterior deviation of the outlet septum, relative to the primary septum, was present. This deviation caused a narrowing inside the outlet chamber and functioned as infundibular pulmonary stenosis. The outlet chambers of the 15 hearts with ventriculoarterial concordance were compared with those of 13 hearts with tricuspid atresia and ventriculoarterial discordance and also a right-sided anterior outlet chamber. In the latter group of 13 hearts, five showed evidence of restricted pulmonary blood flow, at least partially caused by posterior deviation of the outlet septum relative to the primary septum. A clear difference in outlet chamber morphology was found without exception between specimens with and without ventriculoarterial concordance. Clinical data in three long-term survivors of the Fontan procedure demonstrate that the special morphology of the outlet chamber can pose surgical problems. Especially in patients with ventriculoarterial concordance, when the outlet chamber is incorporated into the pulmonary circuit, the surgeon must give special attention to the specific morphology to prevent undesirable sequelae.

Tricuspid atresia. Microscopic findings in relation to "absence" of the atrioventricular connexion.

In 10 out of 31 cases of tricuspid atresia (absent atrioventricular connexion), gross examination of the morphologically right ventricle suggested the presence of a tiny inlet portion in addition to the trabecular portion. Serial sections of two of these hearts have proven this diagnosis: a fibrous remnant in continuity with the central fibrous body was present not only above the left ventricle but also above the right ventricle. We interpreted this as a remnant of the atrioventricular valve and we also observed that the ventricle had a hypoplastic inlet portion. This inlet portion was bounded by a microscopically small septomarginal trabeculation containing the right bundle branch. Therefore, the diagnosis of absent connexion, which after clinical or gross anatomical investigation remains an appropriate one, cannot always be maintained after microscopical study if it is considered that the fibrous remnant represents evidence of a connexion initially present between the right ventricle and the right atrium.

Morphology of sections through the fetal heart.

Two human embryos, of 28 and 29 mm crown-rump length, were studied. One had been serially sectioned in the transverse plane, the other in the sagittal plane. With the help of a graphic reconstruction method two new sets of sectioning planes were constructed. One set started from the transverse plane, which was gradually angulated towards the frontal plane. The other set started from the sagittal plane, which, too, was angulated towards the frontal plane. These procedures were carried out at various levels in both cases. We produced a continuous series of sectioning planes of the young fetal heart, which together give a clear representation of spatial morphology. We believe that these images can be of help in the interpretation of fetal echocardiograms. The morphology of these young fetuses differs considerably from older stages in that the atrioventricular septum is not yet present. Full development of the tricuspid valve and the mitral valve can only later lead to the different septal attachments of the two valves.

Developmental aspects of atrioventricular septal defects.

Three human embryos with an atrioventricular septal defect were studied. Their morphology was compared with that of 67 autopsy specimens, in which particular attention was paid to the septal attachments of the bridging leaflets. The malformed embryos showed deficiency of the inlet component of the ventricular septum. They had distinct superior and inferior bridging leaflets, which were nearly completely muscular. Myocardial undermining had taken place at two independent sites but had not been able to lead to the formation of a valve of mitral morphology. Normal delamination of myocardium to form the leaflets could not continue directly below the aortic root because the rim of the inlet septum had a more apical position. From this, we conclude that the deficiency of the inlet septum is the cause of the typical morphology of the left valve in these hearts. The role of endocardial cushion tissue is probably restricted to glueing together myocardial structures, thus determining the variable septal attachment of the bridging leaflets in atrioventricular septal defect.

The role of atrioventricular endocardial cushions in the septation of the heart.

The hearts of human embryos, ranging from 3.6 to 25 mM crown-rump length, have been studied in view of the problem of the possible contribution of the atrioventricular endocardial cushions to septation. Serial sections and graphic reconstructions were used. It is concluded that the cushions do not materially contribute to the mature muscular septum.

Embryology of the mitral valve.

Development of the aortic (anterior) leaflet of the mitral valve was studied in human embryos from 3.6 to 25 mm crown-rump length. The notion that endocardial cushion tissue does not materially contribute to the atrioventricular valves has yet to be investigated for this particular leaflet. The study showed that the fused endocardial cushions act as an intermediary between the antero-superior and postero-inferior components of the valve leaflet. These latter components derive from the primary fold and the inlet septum, respectively. The cushion tissue itself is incorporated in a small portion of the leaflet which is continuous with the aortic-mitral intervalvar fibrous tissue.

Developmental considerations of mitral valve anomalies.

Atrioventricular valve development is described as following the general principle of junctional invagination and myocardial undermining. We have added considerations of the topographic relations of the developing mitral valve to these principles. Two groups of malformations are then distinguished: the first comprises disturbances of the general principle, the second is related to topographic abnormalities. It is shown that the atrioventricular septal defect, the straddling mitral valve and the isolated mitral cleft all have their own specific developmental backgrounds.

Tricuspid atresia with overriding imperforate tricuspid membrane: an anatomic variant.

An anatomical study of 34 specimens presenting with tricuspid atresia, in which particular emphasis was devoted to the atrioventricular junctional area, revealed 5 cases with an imperforate valve. In 1 heart the valve was completely committed to the right ventricle. In the other 4, however, the membrane was related not only to the right ventricle but also to the left ventricle. A hypoplastic right ventricular inlet portion was found in these 4 specimens. In 2 cases the tricuspid membrane overrode an inconspicuous inlet septal defect. In the other 2 hearts, as studied macroscopically, no defect was present underneath the membrane, which was connected to both right and left ventricles. These 4 specimens also had other ventricular septal defects. In classical tricuspid atresia, characterized by absence of the inlet portion of the right ventricle, the inlet septum is absent. In contrast, these 4 hearts did have an hypoplastic inlet septum.

Abnormal architecture of the ventricles in hearts with an overriding aortic valve and a perimembranous ventricular septal defect ("Eisenmenger VSD").

Among 111 hearts with so-called "isolated" ventricular septal defect, 18 specimens were found to have a subaortic perimembranous defect with an overriding aortic valve but without pulmonary stenosis. The ventricular architecture was characterized by several abnormalities. A constant finding was the wide right ventricular outflow tract. The outlet septum had its normal continuity with the septomarginal trabecula, but its parietal extension was located relatively far anteriorly. Part of the aortic valve thus inserted to the right ventricular component of the ventriculo-infundibular fold in the gap between the outlet septum and the tricuspid valve. Left ventricular abnormalities comprised mitral valve anomalies in all cases. There was an anteroseptal twist (leftward thickening of the anterior part of the ventricular septum) in 16 cases. A bicuspid aortic valve and/or malformed cusps were observed in 4 cases. Because of the linking phenomenon of aortic override, we also examined 10 hearts with tetralogy of Fallot and, in the latter, such abnormalities were not found. Our observations indicate that this seemingly simple type of defect is part of a complex malformation involving both septation and valve formation. Awareness of the existence of the architectural abnormalities might make them accessible for echocardiographic diagnosis. It was noteworthy that 11 of the 18 patients had chromosomal abnormalities, 9 of them presenting with trisomy-18.

Myocardial capillaries: increase in number by splitting of existing vessels.

To study myocardial vascular development, stereological parameters were estimated in 24 Wistar rat hearts of six different age groups, from newborn to adult. The vascular surface density showed a sharp increase in the first 2 weeks, a peak around the age of 2 weeks, and then a steady decrease until it flattened in adulthood. In contrast, the vascular volume percentage, when plotted against age, decreased continuously with the greatest change in the first week, after which the curve flattened. These findings are compatible with an increase in the number of capillaries with a concomitant decrease of their diameters. Qualitative scrutiny of the histology did indeed support the idea that vessels become thinner. Reconstructions of the histological sections showed the same change three dimensionally. The reconstructions also demonstrated very small holes that seemed to go through the capillaries in the younger stages. Corrosion casts of the blood vessels were made using a casting resin. This was injected into the umbilical artery of rat embryos from 15 days gestation to birth. In postnatal rats of six age groups methacrylate was injected directly into the left ventricle. These casts supported the stereological data by showing an increase in number and decrease in diameter of capillaries, while during pre- and postnatal development, the intervascular spaces lengthened from small, irregular spaces to long, rectangular ones. Small holes, the probable precursors of such spaces, were clearly visible in the wider vessels of the youngest stages. All data point to an interesting mode of capillary growth, i.e. growth by division of existing vessels.

Development of myocardial fiber organization in the rat heart.

Confocal laser-scanning microscopy of phalloidine-stained actin fibers is a relatively new tool for studying the development of myocardial fiber organization. It seems to show orientation of myocytes in rather early embryonic stages. To further evaluate the differentiation of the myocardium, this technique was compared with transmission electron microscopy in rat embryos aged between 11 and 18 days. Although the confocal images of actin filament patterns pointed to early myocyte orientation, the electron micrographs revealed that even at 17 days the ventricular myocardium was far from mature. Myofibrils never completely filled the myocytes, and lack of organization was the rule rather than the exception. The organized structure as revealed by confocal microscopy was based on cell-to-cell continuity, whereas electron microscopy showed crossing and disarray within individual myocytes. Exceptions were in the ventricular trabeculations, which showed precocious myofiber differentiation. The trabeculations probably support ventricular systole in those stages in which the free walls do not yet provide efficient contractions. The other exception was the wall of the outflow tract, which showed well-oriented myofibrils from early stages onwards. Apparently, the outflow tract has a different function in these stages. The differences found between confocal microscopy and electron microscopy suggest that some caution is indicated in the interpretation of fluorescent images of relatively low magnification.

HNK-1 expression patterns in the embryonic rat heart distinguish between sinuatrial tissues and atrial myocardium.

HNK-1 expression was studied by immunohistochemistry in serial sections of embryonic and fetal rat hearts from 11.5 to 16.5 embryonic days. Graphic reconstructions were made to obtain detailed 3D information on the localization of immunoreactive tissues. The antibody used appeared to stain most parts of the venous sinus and the sinuatrial transitional zone as well as the atrioventricular transitional zone, but the patterns varied through the different developmental stages. At 11.5 days, positive myocardium was found in the right atrium and on top of the ventricular septal primordium. At 13.5 days, the left venous valve and the posterior atrial wall containing the orifice of the pulmonary vein were immunoreactive, and so were the right venous valve, the septum spurium and the superior, right-lateral and inferior parts of the atrioventricular canal. From the latter, immunoreactivity continued onto the crest of the ventricular septum. At 15.5 days, HNK-1 positivity in the two venous valves had become continuous, whereas the right-lateral part of the atrioventricular canal had lost its positivity, thus making the positive areas in the superior and inferior parts of this canal discontinuous. From the venous valves immunoreaction continued into the venous sinus septum but this area remained discontinuous with the inferior part of the atrioventricular canal. It is concluded that the entirety of venous sinus and sinuatrial transitional zone expresses the HNK-1 antigen and that the orifice of the pulmonary vein belongs to this complex, rather than to the embryonic atrium proper, which is HNK-1 negative. Extrapolation of these data to the adult human atrium leads to the conclusion hat most "atrial septal structures" are of sinuatrial origin, leaving the flap valve of the oval fossa (atrial septum primum) as the only really atrial structure. It is suggested that the atrioventricular node is derived from the inferior portion of the atrioventricular canal, and that two expansions of sinuatrial tissue form the substrate for anterior and posterior atrionodal inputs which in the literature have been described as internodal tracts.