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Keywords:

  • compact myocardium;
  • embryonic heart;
  • myocardial architecture;
  • trabeculation

Abstract

  1. Top of page
  2. Abstract
  3. HEURISTIC CONSIDERATIONS
  4. ONTOGENETIC DEVELOPMENT OF THE MYOCARDIUM
  5. COMPACT LAYER
  6. ADULT MYOARCHITECTURE
  7. EXPERIMENTALLY MODIFIED MYOARCHITECTURE
  8. HUMAN PATHOLOGY
  9. Acknowledgements
  10. LITERATURE CITED

The heart in higher vertebrates develops from a simple tube into a complex organ with four chambers specialized for efficient pumping at pressure. During this period, there is a concomitant change in the level of myocardial organization. One important event is the emergence of trabeculations in the luminal layers of the ventricles, a feature which enables the myocardium to increase its mass in the absence of any discrete coronary circulation. In subsequent development, this trabecular layer becomes solidified in its deeper part, thus increasing the compact component of the ventricular myocardium. The remaining layer adjacent to the ventricular lumen retains its trabeculations, with patterns which are both ventricle- and species-specific. During ontogenesis, the compact layer is initially only a few cells thick, but gradually develops a multilayered spiral architecture. A similar process can be charted in the atrial myocardium, where the luminal trabeculations become the pectinate muscles. Their extent then provides the best guide for distinguishing intrinsically the morphologically right from the left atrium. We review the variations of these processes during the development of the human heart and hearts from commonly used laboratory species (chick, mouse, and rat). Comparison with hearts from lower vertebrates is also provided. Despite some variations, such as the final pattern of papillary or pectinate muscles, the hearts observe the same biomechanical rules, and thus share many common points. The functional importance of myocardial organization is demonstrated by lethality of mouse mutants with perturbed myocardial architecture. We conclude that experimental studies uncovering the rules of myocardial assembly are relevant for the full understanding of development of the human heart. Anat Rec 258:319–337, 2000. © 2000 Wiley-Liss, Inc.

During the course of evolution, the heart became essential when the needs of the organism could no longer be met by diffusion because of increased size and activity. Within this evolutionary period, different forms of hearts, and heart-like organs arose to meet different demands. The similarity of the transcriptional regulation of cardiac development in Drosophila and vertebrates suggests that the prototypical heart was established prior to divergence of vertebrates and invertebrates. Within the phylum of vertebrates, comparison of the arrangement of the cardiac components permits rules to be established for analysis of patterning on the basis of those peculiarities which appear due to specialization. Study of the ontogenetic development of these components makes it possible to recognize the adaptations occurring after birth which were necessary to keep pace with evolution, such as the changes of partial pressure of oxygen, and in the flow of blood. Experimental studies designed to perturb these developmental mechanisms have demonstrated the functional plasticity of the myocardium, while analysis of various mutants provides the evidence for the genetic involvement, and may provide models for human disease.

As with skeletal or smooth muscle, the arrangement of the myocardial cells is not random, but shows certain patterns which change during ontogenetic development. Such organization is important to ensure the efficiency of the myocardial pump. The level of organization increases with the performance of the heart. Various techniques have been developed to study this feature, and show that it is perturbed in certain pathological conditions.

In this review, we collate the changes of myocardial organization seen during ontogenesis in higher vertebrates, comparing the development of human myocardial architecture with that seen in commonly used laboratory species, and also the arrangement of hearts of adult lower vertebrates. Despite subtle differences, the major mechanisms influencing the remodeling of the tubular heart into a mature four-chamber organ share many similarities. We provide selected and appropriate examples of perturbation, by gene targeting or alterations in loading conditions, which have induced modifications of myocardial architecture, comparing them with conditions known to exist in malformed human hearts.

HEURISTIC CONSIDERATIONS

  1. Top of page
  2. Abstract
  3. HEURISTIC CONSIDERATIONS
  4. ONTOGENETIC DEVELOPMENT OF THE MYOCARDIUM
  5. COMPACT LAYER
  6. ADULT MYOARCHITECTURE
  7. EXPERIMENTALLY MODIFIED MYOARCHITECTURE
  8. HUMAN PATHOLOGY
  9. Acknowledgements
  10. LITERATURE CITED

It is self-evident that, when studying the myoarchitecture of embryonic hearts, the techniques must be adapted to take note of size. Scanning electron microscopy can be combined with microdissection to demonstrate the luminal appearances of developing hearts. Such techniques have been widely used in the chick (Pexieder, 1978; Icardo and Fernandez-Teran, 1987; Ben-Shachar et al., 1985; Sedmera et al., 1997), the mouse (Vuillemin and Pexieder, 1989), the dog (Pexieder and Patterson, 1984), and in humans (Pexieder and Janecek, 1984). Routine histology has the advantage of demonstrating intracellular structures, but three dimensional interpretation is difficult and time-consuming (Rychter and Rychterova, 1981; Ben- Shachar et al., 1985). Advances in computing techniques, however, have now permitted three-dimensional reconstructions to be made relatively swiftly from confocal slices. As shown by Germroth and colleagues (1995), preparation of thick polyacrylamide slabs is most suitable for this purpose, combining the facility to provide accurate spatial information with the possibility to see internal structures.

Computers have proved particularly helpful in quantifying the proportions of the different myocardial components. Such analysis is vital when charting the extent of the compact myocardium relative to the thickness occupied by trabeculations, a ratio which, as we will see, changes substantially both in phylogenesis and ontogenesis (Blausen et al., 1990). Stereological techniques are also powerful tools that permit evaluation of local and developmental variations in parameters, such as the size of cells (Knaapen et al., 1995, 1996), and their perturbation by disease (Reinhold-Richter et al., 1982). Using stereology, absolute volumes of individual components can be calculated on the basis of the Cavalieri principle (Cavalieri, 1635; Mandarin-de-Lacerda et al., 1993; Bouman et al., 1997). Mathematical modeling has proved a useful complement to experimental studies, bypassing some of the technical difficulties inherent in measuring material properties in the embryonic heart (Yang et al., 1994). Such modeling gives insight into the functional significance of the structure of the myocardium. This is now validated by the recently developed technique of magnetic resonance tagging (Fogel et al., 1995) which has already demonstrated the nonuniformity of left ventricular contraction (Naito et al., 1996), and the abnormal patterns of contraction of the hypertrophic right ventricle (Young et al., 1996). To be useful in functional developmental studies, these techniques need yet to be miniaturized, as was the case for ultrasonography, Doppler, or magnetic resonance microscopy.

To obtain the specimens presented in this paper, we used microdissection and routine preparation for scanning electron microscopy as described in detail previously (Pexieder, 1978; Vuillemin and Pexieder, 1989; Sedmera et al., 1997). Mouse matings were timed with precision of 2 hr, and detection of the plug was considered hr 0, 1st day. Human hearts were obtained from different sources (Pexieder and Janecek, 1984). Apart from gestational age, they were staged according to the Carnegie collection (O'Rahilly, 1979). Neonatal rat, and adult mouse and frog hearts were prepared using essentially the same technique, apart from prolonging all steps of dehydration because of the increased size of the specimens. A zebrafish heart, kindly provided by Norman Hu, was prepared for low-vacuum scanning electron microscopy. Histology was performed on paraformaldehyde-fixed tissue processed for paraffin serial sectioning.

ONTOGENETIC DEVELOPMENT OF THE MYOCARDIUM

  1. Top of page
  2. Abstract
  3. HEURISTIC CONSIDERATIONS
  4. ONTOGENETIC DEVELOPMENT OF THE MYOCARDIUM
  5. COMPACT LAYER
  6. ADULT MYOARCHITECTURE
  7. EXPERIMENTALLY MODIFIED MYOARCHITECTURE
  8. HUMAN PATHOLOGY
  9. Acknowledgements
  10. LITERATURE CITED

Most information concerning the development of myocardial organization has come from studies of the mouse and chick (Laane, 1972), with little known concerning lower vertebrates (Burggren and Warburton, 1994). The information available, however, emphasizes the marked differences between species. This, in turn, points to danger should these findings in laboratory animals be compared uncritically with the situation in man.

The development of myocardial architecture of the heart wall passes through several distinct steps: firstly, in the early tubular heart, the myocardium has an epithelial nature with just two layers of cells. The second step is the cavity-specific formation of sheet-like myocardial protrusions into the lumen, so-called trabeculations. The third step is solidification of the basal portions of these trabeculations, which correlates with invasion of the coronary vascular system from the epicardium. The final fourth stage is the development of multilayered spiral system in the ventricles. The details of these processes, as well as their timing in different species, will be discussed in the following paragraphs.

Early Development

The heart takes its origin from paired cardiac mesodermal primordiums which fuse in the midline to produce a primitive tubular heart (reviewed by Yutzey and Bader, 1995). Although already differentiated functionally (Kamino, 1991), there is minimal variation in structure along the cardiac tube. In section, the tube is composed of a myocardial mantle of one or two cells thick, an acellular cardiac jelly, and the endocardium. The first morphological myocardial diversification can be perceived in the circumferential arrangement of actin and fibronectin (Shiraishi et al., 1995). This diversification can be correlated with the appearance of a differentiated outer layer at about stage 12+ in the developing chick (Tokuyasu, 1990). Regional differences in myofibrillar patterns become obvious at the stage of looping in the rat heart (Wenink et al., 1988; Price et al., 1996). Also at this stage, Manasek et al. (1984) showed an inhomogeneous arrangement of the cytoskeleton in the outer myocardial layer in the chick. Whether such regional asymmetry is responsible for the process and direction of looping has yet to be clarified; looping, nonetheless, can be altered by focal disruption of actin organization patterns (Itasaki et al., 1991).

Emergence of Trabeculations

Only after looping is it possible to discern changes in the luminal appearance of the different components of the tube, with trabeculations first becoming evident along the inner myocardial layers near the maximum or greater curvature of the looped primitive ventricle (Challice and Viragh, 1973; Steding et al., 1982; Ben-Shachar et al., 1985; Icardo and Fernandez-Teran, 1987; Fig. 1). This occurs in chick at stage 16/17, in mouse at 10.5 days of gestation, rat at 11.5 days, and in humans at the end of the fourth week of gestation. This is Carnegie stage 12, when the embryo is approximately 4 mm long (Mall, 1912). Differences in physiological properties (Kamino, 1991), and in the size of cells (Knaapen et al., 1996), however, have been noted even earlier. The pattern of primitive trabecular ridges (Fig. 1) runs dorsoventrally (circumferential to the heart tube) and appears similar in different species (Figs. 1, 2). Trabeculations thus formed have no free ends, and their form bears little resemblance to the finger-like protrusions proposed by Marchionni (1995; cf. Sedmera and Thomas, 1996). At this early stage, the tube itself continues to contract in peristaltoid fashion, and the maximal stresses and most advanced differentiation concentrated in the myocardial layers adjacent to the lumen may stimulate early trabecular formation (Thompson et al., 2000). The spacing of such trabecular sheets, however, in essence a process of breaking of symmetry (Stewart and Golubitsky, 1993), may depend upon buckling of that initially uniformly curved surface in response to compression along its longitudinal axis. In a simplified model, imagine a long carpet, pushed from both ends. With increasing length, one can obtain more than one hump. The folds produced will be spaced in regular intervals dependent on material properties, thus relieving the tension. Whatever the forces underlying their formation, early trabeculations effectively increase surface area (Fig. 3), enabling the myocardial mass to increase in the absence of a coronary circulation, and may serve to route blood flow as separate ventricular streams evolve or become functional (Van Mierop and Kutsche, 1984).

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Figure 1. Early trabeculation in the ventricular apex (arrows) in chick and mouse. a: Chick, transverse dissection, stage 18. b: Mouse, transverse dissection, 11th day. Note the dorsoventral ridges in the left ventricles (LV), in contrast to radially arranged stick-like trabeculae (arrowheads) in the future right ventricles (RV), and the emerging interventricular septum, externally apparent as interventricular fold in the mouse. Scale bars = 100 μm.

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Figure 2. The early myocardial trabeculations in the future ventricular apex of the chick aged 3.5 days (stage 21) (a,b) and a human heart of 27–28 days (Carnegie stage 12) (c,d), both sagittally dissected. The trabecular ridges (arrows) are spaced in regular intervals along the ventricular (V) perimeter and have a dorsoventral alignment. Note that the inner surface of the atrium (dissected out in the human embryo) and the distal component of the ventricular loop is smooth. OT, outflow tract. The scale bars (100 μm) show that the chicken heart is considerably larger at this stage than the human.

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Figure 3. Conceptualization of the development of ventricular trabeculations as a process of breaking of symmetry. The buckling of an ellipsoid subjected to stress (a) occurs in the area of its maximal curvature. This results in non-uniform distribution of stresses, resulting in “pulling” of the ridges centripetally (b), transforming them into trabecular sheets (c). Schematic drawing in frontal section plane.

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Trabeculated Period

After buckling, the distribution of stresses is no longer uniform. This favors centripetal growth of the trabeculations (Fig. 3), which become transformed into fenestrated trabecular sheets (Ben-Shachar et al., 1985; Icardo and Fernandez-Teran, 1987; Sedmera et al., 1997). Patterns of trabeculation specific for the morphologically left, as opposed to the right, ventricles become apparent at the beginning of ventricular septation, but the differences are more pronounced in birds than in mammals. In the avian left ventricle, the trabeculations are thicker and more sheet-like than in the right ventricle, with the major bundles maintaining their original dorsoventral orientation (Rychter and Rychterova, 1981; Steding et al., 1982; Ben-Shachar et al., 1985; Icardo and Fernandez-Teran, 1987; Sedmera et al., 1997; Fig. 4). In the right ventricle, the trabeculations show finer and shorter branches, and are arranged in a fan-like pattern radiating from the site of formation of the septum. In the mammalian heart, in contrast, the differences between the patterns of trabeculation of the left and right ventricles are much less evident. Indeed, quantification is required to demonstrate differences (Wenink, 1992; Pham, 1997; Fig. 1). The trabeculations in the left ventricle are generally thicker at these stages, and the corresponding intertrabecular spaces are larger. The spaces themselves are circular, or spheroidal when seen in three dimensions, in mammalian ventricles, in contrast to their more-or-less-ellipsoidal shape in the bird (Fig. 4). Despite this, the patterns of trabeculation in the pre-septation heart are similar (Fig. 5). Trabecular remodeling, nonetheless, starts before the completion of septation in birds, but it is postponed after its completion in mammals. Apart from enhancing contractility (Challice and Viragh, 1973), the trabeculations are also important in coordinating intraventricular conduction (de Jong et al., 1992), and in compartmentalizing the blood in the heart prior to its septation (Hogers et al., 1995).

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Figure 4. Secondary trabeculation in chick (a, 5th day/stage 27) and mouse (b, 14th day) hearts, both transversely dissected. Note the difference in the nature of the interventricular septum (stars), which is trabecular in the chick but clearly compact in the mouse. The trabeculae are finer in the chick, and the difference in their pattern between the left (LV) and right (RV) ventricle is much more pronounced than in the mouse, where it is merely quantitative (slightly thicker trabeculae and larger intertrabecular spaces in the left ventricle). Scale bars = 100 μm.

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Figure 5. Sagittal dissection of trabeculated chick (a–c, 6th day/stage 29) and human (d–f, 41 days, Carnegie stage 18) hearts. Panels a,b and d,e show the parietal and septal half of the right ventricle, c and f parietal portion of the left ventricle. Note the similarities such as radial arrangement of trabeculae in the right ventricle (though they are finer and more complex in the chick), left ventricular trabecular pattern (now finer in human, also finer than in human right ventricle), and mechanism of closure of the interventricular foramen (star). Ao, aorta; LA, left atrium; Pu, pulmonary artery. Scale bars = 100 μm.

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When assessing the appearance of the trabeculations, note should be taken of the mechanism of formation of the muscular part of the ventricular septum. In the bird, the septum arises by fusion of trabecular sheets (Harh and Paul, 1977; Ben-Shachar et al., 1985; De La Cruz et al., 1997). In mammals, in contrast, the septum has a compact arrangement from the onset (Figs. 1, 4). The mammalian septum can be considered as being pulled centrally due to expansive growth of the apexes of the left and right ventricles (Mall, 1912; Lamers et al., 1992; Anderson and Brown, 1996; Figs. 1, 6). Indeed, the interventricular fold is much more prominent than in birds.

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Figure 6. Transformation of the embryonic trabecular pattern into the fetal one seen at the end of cardiac septation. Due to longitudinal ventricular growth and expansion, the radial arrangement is changed to one with an apicobasal orientation, with the expanding lumen pushing the trabeculations towards the outer compact layer, to which they contribute substantially. A chick heart on the 8th embryonic day (a; stage 34) with trabecular patterns markedly different in the two ventricles. The tight ventricular coupling is different from that seen in the frontally cut mouse heart on the 14th day (b), where the trabecular arrangement is similar in the two ventricles, which are separated externally by a prominent interventricular sulcus. Note also the developing pectinate muscles in the atrial appendages (arrows). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Scale bars = 100 μm.

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At this stage, the distal part of the heart loop, also known as the outflow tract, conotruncus, or bulbus cordis (see Pexieder, 1995 for a discussion of different nomenclature) is contractile. Conduction through the outlet, however, is slow (de Jong et al., 1992). This feature, combined with the fact that the outlet remains contracted for the major part of the cardiac cycle (Moorman and Lamers, 1994), suggests that it functions as a sphincter to prevent the reflux of blood in the absence of valves. Its relation to the outflow segments of lower vertebrates is not entirely clear. In elasmobranchs, the outflow chamber is called conus arteriosus, has a myocardial wall and is also contractile. It presents high variability, having several rows of valves (Rychter and Rychterova, 1981). In teleosts, on the other hand, the conus is very short, and has a single bicuspid or tricuspid valve. Bulbus arteriosus, also enclosed in the pericardial cavity, has no myocardium. It is composed entirely from smooth muscle and acts rather as an elastic reservoir (Icardo et al., 1999). Bulbus arteriosus is shorter in amphibians, and possesses a spiral valve which separates the streams of blood to the lungs and skin from those going to the rest of the body (Van Mierop and Kutsche, 1984). During further development, in reptiles and higher vertebrates, the myocardium will partially regress as this distal part of the ventricular segment divides to produce the subaortic and subpulmonary outlets (Thompson and Fitzharris, 1979). The development and pathology of this outlet component is of major importance in the context of cardiac malformations (Pexieder, 1978, 1995; Thompson and Fitzharris, 1985), but is of less significance with regard to the trabeculations.

Trabecular Remodeling

With the completion of ventricular septation (chick: stage 34/8th embryonic day, mouse 14.5th day, rat 15.5th day, human 8 weeks/Carnegie stage 22), further growth of the ventricular mass results in the radial trabecular arrangement becoming reorganized to an apico-basal orientation (Fig. 6). This patterning, to a large extent, is determined by the shape of the ventricles, cylindrical for the left and crescent-like for the right (Fig. 7). With the increase in ventricular volumes, and concomitant luminal increase, the trabeculations effectively become compressed within the ventricular wall. This results in a significant increase of proportion and thickness of the compact myocardium (Rychterova, 1971; Pham, 1997; Sedmera et al., 1997). The trabeculations which remain on the luminal aspect then become rearranged so as to produce the definitive patterns specific both for the ventricles and the species (Figs. 7, 8). Despite minor differences, the arrangement of papillary muscles in mammals is rather uniform. Heine (1971) divided the papillary muscles of the placental mammals into two groups. One is old phylogenetically, namely the papillary muscles supporting the two leaflets of the mitral valve in the left ventricle, and the small papillary muscles of the septal leaflet of the tricuspid valve in the right ventricle (Fig. 8e). The other group, originating at the transition between the inlet and outlet of the right ventricle (large and subarterial papillary muscles), is phylogenetically new. In the mammalian left ventricle, some of the luminal trabeculations coalesce to produce the anterior and posterior papillary muscles of the mitral valve, while the apical trabeculations transform into fine honeycomb-like reliefs on the inner ventricular surface (Anderson and Becker, 1980; Figs. 7, 8). Similar reliefs are seen in the avian left ventricle, but the main bundles do not fuse until the very end, retaining instead their pattern of radial symmetry. The tension apparatus of the mitral valve is markedly short in the bird (Figs. 7, 8). In contrast, the more abundant apical trabeculations in the morphologically right ventricles in both birds and mammals attain spiral configurations, turning in counterclockwise direction as they run from apex to base when viewed toward the apex. In addition to such patterning, further differences are seen in the coarseness of the apical trabeculations, these being fine in the mammalian left ventricle (Wenink, 1992) but generally coarser in birds (Sedmera et al., 1997). This difference in mammals occurs only after completion of ventricular septation, and the earlier trabeculations in primitive left and right ventricles are quite similar to each other (Wenink and Gittenberger-de Groot, 1982; Pham, 1997; Figs. 4, 6).

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Figure 7. Remodeling of the fetal myocardial pattern to the adult arrangement in the chick between the 10th (a) and to the 19th (b) days, and in the mouse from the 17th day (c) to the adult (d). Note the thickening of the compact myocardium and diminution of proportion of the trabeculations in the mouse, in contrast to a mere increase in size in the chick. In the mouse left ventricle (LV), the abundant trabeculations partially fuse to produce the two principal papillary muscles (mp), while in the chick the principal apico-basal bundles retain their regular symmetry spaced along the ventricular perimeter. The spiral arrangement of the right ventricular (RV) trabeculations is similar between the hearts, the more abundant pattern in the chick being caused in part by its less advanced development and because the plane of section is closer to the apex. Scale bars = a,c, 100 μm; b,d, 1 mm.

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Figure 8. Fetal chick (a–c, 16th day) and human (d–f, 10 weeks), sagittal dissection (same as in Figure 5). While the trabecular reliefs in the left ventricle are quite similar, apart from more elongated shape and shorter papillary muscles in the chick, human right ventricle shows an apico-basal alignment of the trabeculae with distinct papillary muscles (mp) supporting the tricuspid valve, while in the chick the trabeculae form a spiraled fan radiating from the interventricular septum, and the parietal leaflet of the right atrioventricular valve has a muscular flap-like morphology without clearly defined papillary muscle complex. Ao, aorta; Pu, pulmonary artery. Scale bars = 1 mm.

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The structure of the right atrioventricular valve is another marked difference in ventricular structure, the parietal leaflet being formed by a muscular flap in birds (Komarek et al., 1982; King and McLelland, 1986) but being fibrous in mammals, similar to the mitral valve. In the overloaded avian right ventricle seen in a model of left ventricular hypoplasia (Rychter et al., 1979; Sedmera et al., 1999), however, the right atrioventricular valve can become a fibrous bicuspid structure resembling the mitral valve. Similarly, in human hearts with Ebstein's malformation, myocardialization of the antero-superior leaflet can occur (Zuberbuhler et al., 1979). This shows that the character of valvar leaflets is influenced by the haemodynamic conditions, a fact well known to cardiac surgeons. The precise patterns of trabeculation show appreciable variability between individuals, and, like fingerprints, they seem to be unique for each individual heart. The arrangement of the moderator band, which contains conduction tissue, the septomarginal trabeculation or septal band, and the anatomy of the medial papillary muscle complex are more uniform, but by no means constant (Liu et al., 1982; Restivo et al., 1989).

COMPACT LAYER

  1. Top of page
  2. Abstract
  3. HEURISTIC CONSIDERATIONS
  4. ONTOGENETIC DEVELOPMENT OF THE MYOCARDIUM
  5. COMPACT LAYER
  6. ADULT MYOARCHITECTURE
  7. EXPERIMENTALLY MODIFIED MYOARCHITECTURE
  8. HUMAN PATHOLOGY
  9. Acknowledgements
  10. LITERATURE CITED

Marked developmental modifications occur in the compact myocardium itself which are significant in terms of both structure and function. Some have argued that the compact layer is non-existent in early embryonic stages in mammals, and also in hearts of lower vertebrates (Tota et al., 1983; Greer Walker et al., 1985; Kitsukawa et al., 1995). In these situations, almost the entire thickness of the ventricular wall is made up of a trabecular layer, with no coronary vascularization, and with the outer myocardial mantle enclosing the cavity rather than contributing much to contractile activity. To avoid the need for a separate term, therefore, we suggest that a compact layer can be considered present in all hearts, but a layer with marked changing structure and purpose.

Early Phase—Proliferation

If the existence of such a compact myocardial layer is accepted from the start, its thickness increases initially only slightly, from one or two cell layers to three or four layers, during the stages preceding major compaction (Rychterova, 1971; Pham, 1997; Figs. 9, 10). Much of the increase in myocardial mass, and hence in pumping function, is due to the continuing formation of trabeculations (Blausen et al., 1990; Wenink et al., 1996). The initial outer compact layer (Fig. 9) also serves as a source of new cells (Jeter and Cameron, 1971). Its proliferative activity is higher, and its level of differentiation lower, than in the newly formed trabeculations themselves (Markwald, 1969; Challice and Viragh, 1973; Rumyantsev, 1977; Rychter and Rychterova, 1981; Tokuyasu, 1990; Thompson et al., 1990, 1995; Mikawa et al., 1992). There exists gradient of decreasing proliferation and increasing differentiation from the outside towards the center of the ventricle, where the cells of prospective ventricular conduction system differentiate terminally, exiting the cell cycle permanently as early as at the 2nd day of incubation in the chick (Thompson et al., 1995). The growth of the heart is mainly by apposition at the periphery. But, as the thickness of the compact layer is limited by diffusion of the oxygen and nutrients from the inside, the innermost cells move into the trabeculations, where they continue to proliferate though at a slower rate.

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Figure 9. Development of the compact myocardial layer in the chick. At stage 12 (a), the tubular myocardium (My) is about 2–3 cells thick, and is separated from the endocardium (En) by acellular cardiac jelly (CJ). At stage 21 (b), most of the myocardial mass is made up by the trabeculations (Tr), which are nourished by diffusion from the blood circulating through the intertrabecular spaces (ITS). The outer compact myocardium (Co) is thin, and forms about 20% of the myocardial mass. Note that at this stage, it is already covered by epicardium (arrowhead). By the 6th embryonic day (c, stage 29), in the left ventricle, the compact layer has thickened and become invaded by developing coronaries (star) coming from the epicardium. In the neonatal (Day 10) heart (d) the multilayered architecture of the left ventricular compact layer is clearly apparent, and the three major components (outer longitudinal, middle circular, and inner longitudinal) are easily discernible. The fibers in the papillary muscles (mp), firmly attached to the wall along the most of the ventricular length, are also oriented longitudinally. On the right side of each photo is a schematic drawing, which conceptualizes the major steps in development of ventricular myoarchitecture. Scale bars = a,b,c, 100 μm; d, 500 μm.

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Figure 10. Comparison of development of compact layer thickness in chick (a) and mouse (b, after Pham, 1997). Although not easily apparent from the graphs, the thickness actually increases slightly even before compaction occurs (arrows). Note also the difference in left to right ratio between birds and mammals.

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Further Compaction and Vascularization

Subsequent thickening occurs due to compaction of the trabeculations, this process coinciding with invasion by the developing coronary vasculature from the epicardium (Rychterova, 1971; Rychter and Ostadal, 1971; Vrancken Peeters et al., 1997; Fig. 9). The origin of the coronary vessels, including the capillaries, was for a long period controversial. Recent studies using retroviral targeting (Mikawa and et al., 1992) and chick-quail chimeras (Poelman et al., 1993) clearly showed the extracardiac origin of the angioblasts, and corrected the concept of participation of the trabecular endocardium in the definitive coronary bed, or sprouting of coronary arteries from the aorta. Indeed, connection to the aorta is the final stage of development (reviewed by Tomanek, 1996). The stimulus for the angioblast invasion is probably hypoxia, most pronounced in the outermost subepicardial layers. The mediators are fibroblast and vascular endothelial growth factors. Interestingly, the process of vascularization itself does not seem to be dependent on ventricular load, as shown by work by Rongish et al. (1996). They used the avascular rat embryonic heart transplanted into anterior eye chamber to study the relationship of the various components of the extracellular matrix to coronary vascularization, and found that the vascular invasion occurs even in the absence of functional loading. The coronary arterial system is completely independent from the sinusoidal system of the early embryonic heart, or the trabeculated system of some lower vertebrates.

The contribution of the compact layer to the total myocardial mass then becomes much more significant than that of the remaining luminal trabeculations (Blausen et al., 1990; Kim et al., 1992). These trabeculations differ from the earlier stage, as they do from those in fishes, by being nourished by coronary vessels rather than by diffusion from the lumen (Rychterova, 1971). Compaction is more pronounced in the left ventricle (Fig. 10), which is mainly a pressure pump, and substantial further growth and compaction occur postnatally (Hirokawa, 1972).

Multilayering

The progressive thickening of the compact myocardium is accompanied by an improved level of its organization. Already Malpighi (1672) had observed that “spiral muscle fibers were successively wrapped” around both ventricles of the chick from the 5th day of incubation onwards. This process results in development of a three-layered spiral system of myocardial fibers (Streeter, 1979; Greenbaum et al., 1981; McLean et al., 1989; Sanchez-Quintana et al., 1995; Jouk et al., 1996). The spiral alignment of the fibers (Mall, 1912) probably reflects the twisting pattern of contraction (Fig. 11). This twisting, according to the mathematical modeling studies of Yang et al. (1994), can be observed as early as the first stages of trabeculation. The reason for this probably lies in the material properties of the heart, which favor twist during contraction-induced deformation, and may be also linked to continuing looping, as there is little evidence of spiraling in the trabeculated hearts of lower vertebrates.

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Figure 11. The mechanism of spiralization of cardiomyocytes induced by contraction. In the relaxed, early state (a) the alignment is circular, but due to forces generated by contraction (indicated by arrows), spiralization occurs (b). This is yet another example of breaking of symmetry, similar to patterns of flow of liquid in rotating cylinders when speed is increased (Stewart and Golubitsky, 1993).

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ADULT MYOARCHITECTURE

  1. Top of page
  2. Abstract
  3. HEURISTIC CONSIDERATIONS
  4. ONTOGENETIC DEVELOPMENT OF THE MYOCARDIUM
  5. COMPACT LAYER
  6. ADULT MYOARCHITECTURE
  7. EXPERIMENTALLY MODIFIED MYOARCHITECTURE
  8. HUMAN PATHOLOGY
  9. Acknowledgements
  10. LITERATURE CITED

Much more information is available concerning the ventricular myoarchitecture in adults. In comparison with the late fetal or neonatal (Fig. 12) arrangement, the pattern of trabeculation is less rich, and the proportion of the compact myocardium further increased. A comprehensive review of the spiral system of the myofibers was provided by Streeter (1979). Of considerable clinical interest are the functional changes which occur during the cardiac cycle, and the modifications to be seen in various pathological conditions (see below). When making comparisons, it helps to study hearts arrested in a defined state of contraction, since this markedly influences their shape (Hutchins et al., 1978). Regional changes can be found in the sizes of cells, with larger myocytes being found in the left ventricle, and subendocardially rather than subepicardially (Mandarin de Lacerda et al., 1993; Gerdes et al., 1986). The individual cells also show regional differences in their orientation, reflecting the direction of major stresses (Jouk et al., 1995). The prevailing direction is parallel with the long axis, but more complex patterns are seen in the ventricular septum. Middle circular layer shows circumferential arrangement, and is implicated in pressure generation. Recent data from ultrasound and magnetic resonance tagging have correlated those differences with regionally different contractility (Naito et al., 1996).

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Figure 12. Comparison of four chamber views of embryonic 19th day chick (a), neonatal (Day 10) rat (b), and 16-year-old human (c) hearts. Note the difference in shape between the chick and rat, shorter papillary muscles and different right ventricular trabecular patterns in the chick. Human atria are more spacious than in rodents, and the heart shape is less rounded. Abbreviations as in Figure 6. Scale bars = a,b, 1 mm; c, 1 cm.

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The hearts of mammals are of remarkably uniform design, and directly comparable in embryonic development (Pexieder et al., 1984; Icardo, 1996). Differences, when seen, are mostly due to size, although differences in the development of the inner trabecular relief, particularly in the arrangement of the papillary muscles, were noted by Heine (1971). It is also of interest to note that, in some large cetaceans, the ventricles are almost completely separated apically, producing in effect a hollow “septum” (James et al., 1995). A similar arrangement is found in another large aquatic mammalian group, the Sirenia (Tenney, 1958). We have already emphasized many differences in the architecture of the bird heart compared to mammals, such as the arrangement of the atrioventricular valves. Another striking difference is the increased thickness of the compact layer of the left ventricle. This is about three times as thick as that of the right ventricle in mammals, but five times thicker in birds (Komarek et al., 1982; King and MacLelland, 1986; Fig. 10). Most of this difference, however, is the result of postnatal hypertrophy. In the newly hatched chick, the left to right ratio is about 3:1, and below 2:1 in neonatal mammals. The subsequent differential increase may be an adaptation of birds to enable the greater blood supply for the muscles of flight. This feature still persists even in domestic birds which do not fly very much.

Lower Vertebrates

The design of the heart in lower vertebrates was often used inappropriately to provide missing embryological data (Laane, 1972). Nonetheless, careful comparisons of function can provide valid supplementary information (Holmes, 1975; Van Mierop and Kutsche, 1984; Burggren, 1988), especially with regard to myocardial architecture. There is a resemblance between an adult anuran heart (Fig. 13) and the trabeculated hearts of embryonic mammals and especially chick. It should be noted, nonetheless, that the amphibian heart is a specialized product of adaptation to the combination of aquatic and terrestrial modes of life while the chick heart becomes transformed into a fully septated and vascularized high-performance pump for an animal with much higher metabolic needs. The trabecular sheets have probably the same functions, namely compartmentalization of blood and enhanced contractility, as in the embryonic chick, but they never fuse to divide the primitive ventricle. Functional similarity in the arrangement of the atrioventricular canal, composed of slowly conducting myocardium, also exists between adult urodeles or reptiles (Alanis et al., 1973) and embryonic higher vertebrates (de Jong et al., 1992). In both cases, it assures the necessary delay between atrial and ventricular contraction, and serves as a filter against transmission of potentially dangerous supraventricular tachyarhythmias to the ventricle, as does the atrioventricular node in mammals.

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Figure 13. Examples of hearts of adult lower vertebrates. a: Sagittally dissected zebrafish heart shows heavily trabeculated and non-septated atrium (A) and ventricle (V), which connects directly to the bulbus arteriosus (BA). Dorsal half or frontally dissected frog heart (Rana sp., b) shows clear separation between the left (LA) and right (RA) atrium. Note that both these hearts show thin outer compact myocardium. The ventricular trabeculations in the zebrafish are thin and radial, but seem to be less organized than in the embryogenesis of higher vertebrates (compare with Figures 4, 6). Though there are trabecular bands anchoring to the atrioventricular junction, the leaflets of the bicuspid atrioventricular valve are free with no tension apparatus. The trabecular sheets in frog ventricle (V) are more strictly radially aligned, forming deep intertrabecular pockets. The tension apparatus of the atrioventricular valve is very short, without any clearly defined papillary muscles. The atrial trabeculations (pectinate muscles) in frog are flatter than in birds or mammals. The conus arteriosus (CA) possesses a spiral valve which in conjunction with ventricular trabecular sheets assures fairly efficient blood compartmentalization. Scale bars = a, 250 μm; b, 1 mm.

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Fascinating specializations are to be found within the hearts of fishes. The anatomy varies considerably in correlation with workload and with circulatory demands. Tubular hearts can be found in some species, with abundant trabeculations and very thin compact layers in the absence of any coronary vasculature (Greer Walker et al., 1985). Other hearts, such as in tuna, have thick and vascularized compact layers, with a spiral arrangement of the cardiomyocytes (Sanchez-Quintana and Hurle, 1987). According to Santer and Greer Walker (1980), the differences are conditioned by lifestyle, with active species having thicker compact layers. In contrast, Ostadal and Schiebler (1971) found that the proportion of the compact myocardium correlates with body size, and thus with blood pressure rather than phylogenetic position. The luminal trabeculations are generally radial, again respecting the direction of main stresses (Sanchez-Quintana and Hurle, 1987). However, they seem much less strictly organized than in amphibians (compare Figures 13a and b) or in the embryonic higher vertebrates. The atria are thin and extensively trabeculated (Greer Walker et al., 1985).

The incompletely septated hearts of reptiles are neither a direct transition between amphibians and mammals, nor “primitive.” For the first time in evolution, a partially separated pulmonary cavity, right ventricle, appears. A special feature of unclear importance is the presence of two aortas. The incomplete septation is advantageous in crocodiles, allowing blood to be diverted from the lungs during diving (Holmes, 1975). As in amphibians, an appreciable level of ventricular blood compartmentalization is achieved by the presence of dorsoventral trabecular sheets.

The Atrial Myoarchitecture

The development of atrial myoarchitecture has received much less attention, perhaps because of its lesser functional importance. However, the topic is deserving of attention. Trabeculations are seen within the atrial appendages at a later stage than in the ventricles, appearing at approximately stage 27/5th incubation day in the chick (Malpighi, 1672, plate XVIII), on the 12th day of gestation in the mouse (Challice and Viragh, 1973; Vuillemin and Pexieder, 1989), and 5 weeks/Carnegie stage 16 in human (Mall, 1912). The pattern again resembles buckling of a sphere. In the chick, the roughening of the initially smooth luminal relief coincides with an increase of the atrioventricular pressure gradient (Hu and Keller, 1995). This can thus be regarded as a means of increasing atrial contractility. The pattern of roughening produces the pectinate muscles, which resemble the veins of a leaf (Fig. 14), although individual muscles can traverse the atrial lumen. In the atrial chambers, it is the extent of the pectinate muscles, rather than their specific pattern, which is the morphological marker of sidedness (Anderson and Brown, 1996; Fig. 6). The differences between species in the extent of the pectinate muscles are considerable (Figs. 6, 12, 13, 14), but some parts of the atrial chambers, notably the venous sinuses and the atrioventricular vestibules, always remain smooth. Similar to ventricular trabeculations, the pectinate muscles might help enhance atrial contractility, as evidenced by their better myofibrillar alignment demonstrable by phalloidin staining (our unpublished data), and their coarsening in the setting of pressure overload induced by banding of the outflow tract (Sedmera et al., 1999). The possible role of the pectinate muscles in atrial conduction has yet to be elucidated. Although there are no insulated tracts running through the atrial walls to be compared with the atrioventricular conduction axis (Anderson et al., 1981), the parallel orientation of the individual fibers within the pectinate muscles certainly favors preferential conduction. The functional importance of Purkinje-like cells in the atria, as well as internodal fascicles such as bundle of Bachman, is not clear. As demonstrated by electrophysiology and gap junction distribution (Lichtenberg et al., 1999), the aligned bundles such as in crista terminalis can also serve as barriers to conduction perpendicular to their orientation. It was shown by Wu et al. (1998) that the fiber orientation creates local conduction heterogeneities. These heterogeneities are a possible morphological substrate for reentry and atrial fibrillation.

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Figure 14. a: The trabeculations (pectinate muscles) in the chick atria on the 14th embryonic day are similar to leaf veins, and help the atria to contract in umbrella-like manner. b: In an adult mouse right atrial appendage, the trabeculations are extensive, crossing the lumen and producing a three dimensional labyrinth. LA, left atrium; RA, right atrium. Scale bars = a, 1 mm; b, 100 μm.

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In summary, the key stages in the development of the vertebrate myocardium are: 1) formation of the primitive tubular heart, similar to those of the invertebrates; 2) trabecular formation, first in the ventricle, later in the atrium; this is the final state for some fishes and amphibians; 3) compaction of the basal portions of the trabeculations, which increases the proportion of the compact layer, and coincides with coronary vascularization from the epicardium; and 4) development of the three-layered architecture of the compact myocardium, best present in the left ventricle of both birds and mammals and enabling efficient pumping at high systemic pressure. We have presented the description from perhaps a bit simplistic biomechanic point of view, but we do not deny the important contribution of genetic regulation to these events. All kinds of perturbations of these processes have dramatic consequences, as we will illustrate in the next two sections.

EXPERIMENTALLY MODIFIED MYOARCHITECTURE

  1. Top of page
  2. Abstract
  3. HEURISTIC CONSIDERATIONS
  4. ONTOGENETIC DEVELOPMENT OF THE MYOCARDIUM
  5. COMPACT LAYER
  6. ADULT MYOARCHITECTURE
  7. EXPERIMENTALLY MODIFIED MYOARCHITECTURE
  8. HUMAN PATHOLOGY
  9. Acknowledgements
  10. LITERATURE CITED

Gene Targeting

Genetic influences on myocardial assembly have become increasingly evident as mutant mice are recognized with perturbed myoarchitecture due to disruption of certain genes. Table 1 gives an overview of some of the genes known to be essential for the fundamental morphogenetic steps in cardiac development. The amount of information about the different null phenotypes is increasing steadily, so this table can be neither exhaustive nor up-to date. The latest information can be obtained from Mouse Knockout & Mutation Database (http://biomednet.com/db/mkmd), which featured 120 entries with a cardiac phenotype as of July 31, 1999. Most of the phenotypes severely compromise heart function, and result in embryonic lethality, thus emphasizing the importance of appropriate myocardial assembly.

Table 1. Examples of genes involved in the key phases of myocardial morphogenesis
Process affectedGene(s) involvedReferences
Initial cardiomyocyte assemblyN-cadherinLinask et al. (1997) Nakagawa and Takeichi (1997)
Trabecular formationneuregulin ErB4 erbB2 Nkx2.5Meyer and Birchmaier (1995) Gassmann et al. (1995) Lee et al. (1995) Lyons et al. (1995)
Trabecular growth and alignmentPDGF-A α subunitSchatteman et al. (1995)
Trabecular compaction (compact layer thickening)RXRα neuropilin (overexpression) WT-1 N-myc βARKSucov et al. (1994); Kastner et al. (1994) Kitsukawa et al. (1995) Kreidberg et al. (1993) Moens et al. (1993) Jaber et al. (1996)
Coronary vascularizationVCAMKwee et al. (1995)
Contractile functionvarious genesJames and Robins (1997) (review)
Cardiomyocyte alignmentvarious genesScheuermann (1993) (review)

Chemical Influences

Implication of retinoid receptors in trabecular compaction (Table 1; Gruber et al., 1996) suggests that retinoid signaling plays a role in myocardial morphogenesis. Indeed, retinoid deficiency in quail embryos is lethal early in development (Kostetskii et al., 1999) and results in truncation of the heart tube or failure of fusion of the paired primitive tubes (cardia bifida). Excess retinoic acid in the chick embryo has teratogenic effects on multiple morphogenetic systems (Peterka and Pexieder, 1994), and influences also the developing heart (Bouman et al., 1995). The malformed hearts have decreased contractility, and diminished volume of the right ventricular compact layer (Bouman et al., 1997), which is also thinner than normal (Peterka and Sedmera, unpublished observations). In a mouse model, the myocardium shows an abnormal composition with increased proportion of collagenous protein (Pexieder et al., 1995). This points to as yet unrecognized influences of prenatal administration of chemical substances on cardiac morphogenesis, producing a functionally abnormal heart without causing distinct morphological phenotypes.

Altered Loading Conditions

The heart can respond to an increased pressure load either by dilation (Faggiano et al., 1994) or by hypertrophy and/or hyperplasia. The response occurs according to the speed and magnitude of the change and the developmental stage of the heart (Zak, 1974; Hutchins et al., 1978). The embryonic heart is able to respond by pure hyperplasia when the pressure load is increased (Clark et al., 1989), or by hypoplasia when the load is decreased (Clark et al., 1991). The myocardial organization is also changed in these models, primarily by an increase or decrease in the proportion of the compact myocardium (Sedmera et al., 1998, 1999). In embryonic myocardial hyperplasia induced by pressure overload, vascularization kept pace maintaining the vascular density in normal limits (Tomanek et al., 1999). In contrast, the adult left ventricular hypertrophy induced by hypertension often presents with myocardial ischemia. A hyperplastic response to an increased pressure load is also characteristic for the fetal heart (Bical et al., 1990; Saiki et al., 1997), and may extend to the early neonatal period. The exact time point of the switching from the hyperplastic to a hypertrophic response to pressure load is controversial. It probably depends on species and the myocardial compartment (Rumyantsev, 1977). If the overload is severe, such as in case of pulmonary atresia, hypertrophy can also occur in addition to hyperplasia in the fetal heart (Toussaint et al., 1998). Evidence of DNA synthesis can be found in the adult ventricular cardiomyocytes (Anversa and Kajstura, 1998), but due to its low incidence, and the real possibility of binucleation or polyploidy, it is questionable whether the increase in number of ventricular cardiomyocytes seen during life can be of quantitative importance. Recently, studies on mice with muscular dystrophy (Bittner et al., 1999) raised the possibility of using extracardiac stem cells to replace the disappearing ventricular cardiomyocytes.

Extensive remodeling is seen in the hypoplastic left heart syndrome (Friedman et al., 1951) and is well demonstrated in its experimental chick model (Rychter et al., 1979; Rychter and Rychterova, 1981). In the model, the reaction of the right ventricle to the increased volume load was slow. Compensation occurred primarily by dilation and proliferation of the trabeculations, with thickening and augmentation of the compact layer occurring at later stages where it had to function as a systemic pump (Sedmera et al., 1999). This shows that while pressure load is a powerful stimulus for growth of the heart, volume load is not. This can explain in part the poor prognosis of this disease.

In unloaded embryonic rat hearts transplanted into the anterior eye chamber (Tucker et al., 1992), growth occurred by both hyperplasia and hypertrophy, similar to the situation in vivo. There was no difference in size, however, between the atrial and ventricular myocytes normally present in the embryonic heart (Knaapen et al., 1996), indicating the importance of loading for compartment-specific differentiation. Absence of sympathetic innervation in the grafts reduced the size of the graft but not the size of the cells, suggesting that the adrenergic signaling pathway is more important for proliferation than for hypertrophy of the developing myocardium.

HUMAN PATHOLOGY

  1. Top of page
  2. Abstract
  3. HEURISTIC CONSIDERATIONS
  4. ONTOGENETIC DEVELOPMENT OF THE MYOCARDIUM
  5. COMPACT LAYER
  6. ADULT MYOARCHITECTURE
  7. EXPERIMENTALLY MODIFIED MYOARCHITECTURE
  8. HUMAN PATHOLOGY
  9. Acknowledgements
  10. LITERATURE CITED

Changes in the proportions of compact and trabecular myocardium are well recognized in morphologically abnormal hearts. The thickness of the compact myocardium, as well as the proportion of extracellular matrix, was shown to be increased in the right ventricle of humans with ventricular septal defect by Reinhold-Richter et al. (1982). Localized absence of myocardium was found to be associated with heart failure in the first year of postnatal life, or sudden cardiac death in adulthood (Waller et al., 1980). The significance of so-called spongy embryonic myocardium (Dusek et al., 1975) still has to be established. This condition is seen in various congenitally abnormal hearts, and probably is not a single entity. When describing this anomaly, it should be noted whether the area does have any coronary perfusion, whether there are anastomoses between coronary vessels and intertrabecular sinusoids, what is the morphology of the trabeculations, the extent of fibrosis and any related pathology, such as abnormal origin of the coronary arteries. Only then will it be reasonable to speculate about its possible pathogenesis. One model proposed by Dusek et al. (1975) considered the possibility of local failure of coronary invasion, resulting in failure of compaction due to lack of oxygen and nutrients. This can certainly predispose the developing myocardium to further pathological processes, such as focal necrosis, fibrosis, and formation of aneurysms. A recent study by Junga et al. (1999) did show decreased myocardial perfusion and flow reserve in this area in the affected infants. The authors hypothesized that this could predispose to arrhythmias, which could then result in sudden death or pump failure.

It is well recognized that the heart is capable of remodeling, although this is not always desirable. Bano-Rodrigo et al. (1980) pointed to the need for anatomical correction of complete transposition prior to the regression of the ventricular compact myocardium in the left ventricle, functioning as a low-pressure pulmonary pump. This is now current practice in neonatal and infant cardiac surgery, where corrective operations are performed as soon as possible (Castaneda et al., 1994).

The architecture of ventricular muscle is changed markedly in the heterogeneous group of cardiomyopathies, which often present with myofibrillar disarray (reviewed by Scheuermann, 1993). These changes have also been studied in an experimental model (Li et al., 1994). The extent of the microvascularization was shown to be improved by bradycardia induced by pacing in pigs (Brown et al., 1994). These beneficial changes, including an improved cardiac performance, persisted even in the long term. Recently, beneficial effects of pacing were demonstrated in patients with hypertrophic cardiomyopathy (Kappenberger et al., 1997). Thus, improving our knowledge of the nature of remodeling can influence the therapeutic approaches for the future. This is because the mode of assembly of the cardiomyocytes correlates with functional requirements at a given point in time, and remodeling occurs concomitant with the changes in functional needs. Undoubtedly, these processes are controlled by activation of various gene cascades, many of which remain yet to be elucidated. Studying and understanding the mechanisms of these adaptations in man and animals must surely give a better insight into the pathology of some myocardial diseases, offering the possibility of influencing these processes so as to provide more efficient treatment.

Acknowledgements

  1. Top of page
  2. Abstract
  3. HEURISTIC CONSIDERATIONS
  4. ONTOGENETIC DEVELOPMENT OF THE MYOCARDIUM
  5. COMPACT LAYER
  6. ADULT MYOARCHITECTURE
  7. EXPERIMENTALLY MODIFIED MYOARCHITECTURE
  8. HUMAN PATHOLOGY
  9. Acknowledgements
  10. LITERATURE CITED

Our thanks are due to Dr. Si Minh Pham (Lausanne) for discussion of his unpublished data and supplying Figures 1b, 4b and 7c. Figure 13a was kindly provided by Dr. Norman Hu (Salt Lake City). Mr. Franco Ardizzoni (Lausanne) is acknowledged for excellent technical support with scanning electron microscopy, and Martina Sedmerova (Charleston) for drawing Figures 3 and 9. Our gratitude goes also to the two anonymous reviewers, whose pertinent comments helped significantly to improve this manuscript. We dedicate the manuscript to the memory of our friend, colleague and mentor, Tomas Pexieder, who sadly died prior to its completion.

LITERATURE CITED

  1. Top of page
  2. Abstract
  3. HEURISTIC CONSIDERATIONS
  4. ONTOGENETIC DEVELOPMENT OF THE MYOCARDIUM
  5. COMPACT LAYER
  6. ADULT MYOARCHITECTURE
  7. EXPERIMENTALLY MODIFIED MYOARCHITECTURE
  8. HUMAN PATHOLOGY
  9. Acknowledgements
  10. LITERATURE CITED
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