Dr. David Sedmera
Myocardial architecture features some common principles that are shared in phylogenesis and ontogenesis. The way to increase cardiac mass without coronary perfusion is development of ventricular trabeculae. Further increase of generated pressure is possible with thick vascularized compact layer of complex three-dimensional myofiber architecture. Developmental studies have led to improved understanding of mechanisms of myocardial development as well as to its constraints, as many of the deviations from the normal situation result in early lethality due to embryonic heart failure.
Development of the myocardium starts during gastrulation with the precardiac mesoderm, organized into cardiac crescent (15). Anteriorly localized cells would normally give rise to the left ventricle, while posteriorly located ones would mostly contribute to the atrial tissues; however, their fates are not set in stone and are plastic in response to local environment cues. There is also the second, by some called secondary or anterior, heart field, which would give later on rise to the right ventricle and outflow tract (see Robert Kelly’s text on outflow tract development on this site, ). As the cells migrate towards the midline, they start to organize themselves into two tubular structures with presumptive endocardium on the inside and myocardium on the outside. In the midline, the fusion process starts first with the endocardial tubes, and later on with myocardium. If this fusion process is perturbed (mechanically, or by retinoid deficiency (16)), an embryonic lethal malformation known as cardia bifida (Figure 2) results.
The primitive cardiac tube is initially straight, and is composed, from outside to inside, of myocardium, acellular cardiac jelly, and endocardium. It contains the portion that will become the left ventricle and presumptive atria are located at the inflow (posterior) end. The first contractions commence in the ventricular segment, and soon, the pacemaking area is localized at the inflow (venous) pole (9, 13) and circulation of blood starts. The crucial process for further morphogenesis and septation of the heart is termed cardiac looping. In a strict sense, the initially straight tube is thus transformed into a cardiac loop, and at that period begins expansion of atrial and ventricular chambers, which acquire their molecular identity. The original (“primitive”, slowly conducting and contracting) myocardium flanks the atrial and ventricular segments, forming sinus venosus at the inflow (venous) end, atrioventricular canal between the atria and ventricle, and myocardial outflow tract at the outflow (arterial) end. This process is well described from morphological point of view by Manner (19), and the molecular fingerprints of chambers are continuously updated by the Moorman lab (24). From a clinical standpoint, people are most interested in further morphogenesis of chamber myocardium, since its architecture is an important determinant of heart pumping function (27). In the atrial chambers, two compartments can be distinguished: the original embryonic atrium, which contains the pectinate muscles that vary in form and extent considerably among species (31, 33), and outline the atrial appendages or auricles. Their complex labyrinth can be a site of thrombus formation due to slowing of blood flow, and is used clinically for wedging the atrial pacing electrode (in the right atrial appendage, which is considerably larger in humans and this difference also defines the morphological laterality of the atrial chambers). The pectinate muscles appear slightly later (31, 33) than ventricular trabeculae, described in detail below. Formation of trabeculae in the ventricular chambers is the hallmark of their differentiation and distinguishes these segments morphologically from the rest of the looped heart, where the myocardium is organized into a circular, multilayered tube, resembling tunica media of the blood vessels. Ventricular trabeculae express different patterns of genes, such as connexin40 (3, 23) that contributes to its higher conduction velocity. A molecular pathway considered responsible for trabeculation is the neuregulin pathway (8, 17, 21), but lack of trabeculation together with early (~ED10) embryolethality was reported in other null mice as well (for review, see (39)). It is believed that the primary reason for trabeculation is the necessity to provide sufficient nutrition for increased myocardial mass in the (initial) absence of coronary circulation (22). Indeed, the ventricles of some adult lower vertebrates are organized in such way (36), even though there are coronary arteries present in different parts of those hearts (32). Such trabeculated hearts work well as volume pumps, but are ill-suited for generating higher pressure necessary for sustained aerobic performance. Not surprisingly, a different morphological form of the ventricle, dependent primarily on the thick, vascularized outer compact layer, is found in large, fast-swimming fish species (1, 26). During ontogenesis of higher vertebrates, compaction of the trabeculae coincides with the functional deployment of coronary circulation (Figures 3, 4, 5, (31)). The importance of this process is emphasized by ~ED14 lethality of mouse mutants with generalized failure of compaction (reviewed in (39)). It should be noted, however, that there are other cardiac causes of embryonic lethality, such as grossly abnormal cushion or valve development, that are only recently being revealed due to advances in non-invasive prenatal imaging (25, 28). This “ventricular non-compaction”, by some called “the puny heart syndrome” is associated with deletion of genes from different pathways, from transcription factors (WT1) through retinoid receptors (RXR) to vasculogenic molecules (VCAM). It is possible that the similarity of these phenotypes is only superficial, and detailed comparative morphological and molecular examination would reveal subtle yet potentially important differences. All these mutants are, however, significantly different from recently recognized human condition called isolated left ventricular non-compaction (6, 10, 38), or non-compaction cardiomyopathy, which is localized rather than general, and typically leads to cardiac failure during postnatal life. Details of this cardiomyopathy and its possible developmental origins are detailed below.
Figure 3 Figure 4 Figure 5
Development of the heart of higher vertebrates has in recent years received considerable attention, primarily in the context of pathogenesis of congenital heart defects, which are the most common congenital anomaly (~1%). Most studies are focused on cardiac (mal) septation, since this is the prevalent form of CHD. Primary non-ischemic diseases of the myocardium are rare, and apart from tumors, myocarditis or secondary metabolic disorders, are called cardiomyopathies. There are different ways to classify them, but most common division is into hypertrophic, dilated, arrhythmogenic, and non-compacted. Sometimes the boundaries are not quite distinct, and manifestations of the same gene mutations (which now seem to be the underlying cause of most cases) can change in time (6, 14). More longitudinal information from clinical studies outlining the natural history of these diseases will be necessary before we will be able to decide if these conditions are indeed congenital, and relate them in any way to described models of mouse trabecular non-compaction. Even after compaction, the structure of the compact myocardium develops further, primarily by increasing the number of myocyte layers and the spiraling of their course (27, 29). This process is, at least in part, regulated by functional loading, as was shown by studies in chick embryos subjected to altered loading conditions (30, 35). Increased pressure loading leads not only to premature compaction and spiraling of trabeculae, but also to accelerated development of a transmural gradient in fibre inclination in the compact myocardium. Conversely, the hypoplastic left ventricle presents a more immature pattern of myofiber orientation. This process is spread over a longer time period in humans, occurring during the second trimester of gestation (11, 12). It is believed that such three dimensional architecture (2) is important for ventricular contractile function, and can be one reason for late failure of univentricular hearts with a single pumping chamber of right ventricular morphology in the setting of Fontan circulation (18, 34).
1. Agnisola C and Tota B. Structure and function of the fish cardiac ventricle: flexibility and limitations. Cardioscience 5: 145-153, 1994. 2. Anderson RH, Smerup M, Sanchez-Quintana D, Loukas M, and Lunkenheimer PP. The three-dimensional arrangement of the myocytes in the ventricular walls. Clin Anat 22: 64-76, 2009. 3. Becker DL, Cook JE, Davies CS, Evans WH, and Gourdie RG. Expression of major gap junction connexin types in the working myocardium of eight chordates. Cell Biol Int 22: 527-543, 1998. 4. Burggren WW. Cardiac design in lower vertebrates: what can phylogeny reveal about ontogeny? Experientia 44: 919-930, 1988. 5. Burggren WW and Warburton SJ. Patterns of form and function in developing hearts: contributions from non-mammalian vertebrates. Cardioscience 5: 183-191, 1994. 6. Captur G and Nihoyannopoulos P. Left ventricular non-compaction: Genetic heterogeneity, diagnosis and clinical course. Int J Cardiol, 2009. 7. Davidson B. Ciona intestinalis as a model for cardiac development. Semin Cell Dev Biol 18: 16-26, 2007. 8. Gassmann M, Casagranda F, Orioli D, Simon H, Lai C, Klein R, and Lemke G. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378: 390-394, 1995. 9. Gourdie RG, Harris BS, Bond J, Justus C, Hewett KW, O'Brien TX, Thompson RP, and Sedmera D. Development of the cardiac pacemaking and conduction system. Birth Defects Research 69C: 46-57, 2003. 10. Jenni R, Oechslin E, Schneider J, Jost CA, and Kaufmann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart 86: 666-671., 2001. 11. Jouk PS, Usson Y, Michalowicz G, and Grossi L. Three-dimensional cartography of the pattern of the myofibres in the second trimester fetal human heart. Anat Embryol (Berl) 202: 103-118, 2000. 12. Jouk PS, Usson Y, Michalowicz G, and Parazza F. Mapping of the orientation of myocardial cells by means of polarized light and confocal scanning laser microscopy. Microsc Res Tech 30: 480-490, 1995. 13. Kamino K. Optical approaches to ontogeny of electrical activity and related functional organization during early heart development. Physiol Rev 71: 53-91, 1991. 14. Kelley-Hedgepeth A, Towbin JA, and Maron MS. Images in cardiovascular medicine. Overlapping phenotypes: left ventricular noncompaction and hypertrophic cardiomyopathy. Circulation 119: e588-589, 2009. 15. Kirby ML. Cardiac Development. New York: Oxford University Press, 2007. 16. Kostetskii I, Jiang Y, Kostetskaia E, Yuan S, Evans T, and Zile M. Retinoid signaling required for normal heart development regulates GATA-4 in a pathway distinct from cardiomyocyte differentiation. Dev Biol 206: 206-218, 1999. 17. Lee KF, Simon H, Chen H, Bates B, Hung MC, and Hauser C. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378: 394-398, 1995. 18. Mahle WT, Spray TL, Wernovsky G, Gaynor JW, and Clark BJ, 3rd. Survival after reconstructive surgery for hypoplastic left heart syndrome: A 15-year experience from a single institution. Circulation 102: III136-141, 2000. 19. Manner J. Cardiac looping in the chick embryo: a morphological review with special reference to terminological and biomechanical aspects of the looping process. Anat Rec 259: 248-262., 2000. 20. McGaw IJ and Reiber CL. Cardiovascular system of the blue crab Callinectes sapidus. J Morphol 251: 1-21, 2002. 21. Meyer D and Birchmeier C. Multiple essential functions of neuregulin in development. Nature 378: 386-390, 1995. 22. Minot CS. On a hitherto unrecognised circulation without capillaries in the organs of Vertebrata. Proc Boston Soc Nat Hist 29: 185-215, 1901. 23. Miquerol L, Meysen S, Mangoni M, Bois P, van Rijen HV, Abran P, Jongsma H, Nargeot J, and Gros D. Architectural and functional asymmetry of the His-Purkinje system of the murine heart. Cardiovasc Res 63: 77-86, 2004. 24. Moorman AF and Christoffels VM. Cardiac chamber formation: development, genes, and evolution. Physiol Rev 83: 1223-1267, 2003. 25. Nomura-Kitabayashi A, Phoon CKL, Kishigami S, Rosenthal J, Yamauchi Ÿ, Abe K, Yamamura K, Samtani R, Lo CW, and Mishina Y. Outflow tract cushions perform a critical valve-like function in the early embryonic heart requiring BMPRIA-mediated signaling in cardiac neural crest. Am J Physiol Heart Circ Physiol XX: XX-XX, 2009. 26. Ostadal B and Schiebler TH. [The terminal blood bed in the heart of fish]. Z Anat Entwicklungsgesch 134: 101-110, 1971. 27. Sedmera D. Form follows function: developmental and physiological view on ventricular myocardial architecture. Eur J Cardiothorac Surg 28: 526-528, 2005. 28. Sedmera D. Pathways to embryonic heart failure. Am J Physiol Heart Circ Physiol 297: H1578-1579, 2009. 29. Sedmera D and McQuinn T. Embryogenesis of the heart muscle. Heart Fail Clin 4: 235-245, 2008. 30. Sedmera D, Pexieder T, Rychterova V, Hu N, and Clark EB. Remodeling of chick embryonic ventricular myoarchitecture under experimentally changed loading conditions. Anat Rec 254: 238-252, 1999. 31. Sedmera D, Pexieder T, Vuillemin M, Thompson RP, and Anderson RH. Developmental patterning of the myocardium. Anat Rec 258: 319-337, 2000. 32. Sedmera D, Reckova M, DeAlmeida A, Sedmerova M, Biermann M, Volejnik J, Sarre A, Raddatz E, McCarthy RA, Gourdie RG, and Thompson RP. Functional and morphological evidence for a ventricular conduction system in the zebrafish and Xenopus heart. Am J Physiol Heart Circ Physiol 284: H1152-H1160, 2003. 33. Sedmera D, Wessels A, Trusk TC, Thompson RP, Hewett KW, and Gourdie RG. Changes in activation sequence of embryonic chick atria correlate with developing myocardial architecture. Am J Physiol Heart Circ Physiol 291: H1646-1652, 2006. 34. Takahashi K, Inage A, Rebeyka IM, Ross DB, Thompson RB, Mackie AS, and Smallhorn JF. Real-time 3-dimensional echocardiography provides new insight into mechanisms of tricuspid valve regurgitation in patients with hypoplastic left heart syndrome. Circulation 120: 1091-1098, 2009. 35. Tobita K, Garrison JB, Li JJ, Tinney JP, and Keller BB. Three-dimensional myofiber architecture of the embryonic left ventricle during normal development and altered mechanical loads. Anat Rec A Discov Mol Cell Evol Biol 283: 193-201, 2005. 36. Tota B, Cimini V, Salvatore G, and Zummo G. Comparative study of the arterial and lacunary systems of the ventricular myocardium of elasmobranch and teleost fishes. Am J Anat 167: 15-32, 1983. 37. Valasek P, Macharia R, Neuhuber WL, Wilting J, Becker DL, and Patel K. Lymph heart in chick--somitic origin, development and embryonic oedema. Development 134: 4427-4436, 2007. 38. Varnava AM. Isolated left ventricular non-compaction: a distinct cardiomyopathy? Heart 86: 599-600., 2001. 39. Wessels A and Sedmera D. Developmental anatomy of the heart: a tale of mice and man. Physiol Genomics 15: 165-176, 2003. 40. Zaffran S, Reim I, Qian L, Lo PC, Bodmer R, and Frasch M. Cardioblast-intrinsic Tinman activity controls proper diversification and differentiation of myocardial cells in Drosophila. Development, 2006.
Acknowledgements. To Drs. Robert Kelly and Diego Franco I am grateful for their insightful coments. My current research is supported by Ministry of Education VZ 0021620806, Academy of Sciences AV0Z50450515, AV0Z50110509, and Purkinje Fellowship, and Grant Agency of the Czech Republic 304/08/0615.
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