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.

Adult myocardium adapts to changing functional demands by hyper- or hypotrophy while the developing heart reacts by hyper- or hypoplasia. How embryonic myocardial architecture adjusts to experimentally altered loading is not known. We subjected the chick embryonic hearts to mechanically altered loading to study its influence upon ventricular myoarchitecture. Chick embryonic hearts were subjected to conotruncal banding (increased afterload model), or left atrial ligation or clipping, creating a combined model of increased preload in right ventricle and decreased preload in left ventricle. Modifications of myocardial architecture were studied by scanning electron microscopy and histology with morphometry. In the conotruncal banded group, there was a mild to moderate ventricular dilatation, thickening of the compact myocardium and trabeculae, and spiraling of trabecular course in the left ventricle. Right atrioventricular valve morphology was altered from normal muscular flap towards a bicuspid structure. Left atrial ligation or clipping resulted in hypoplasia of the left heart structures with compensatory overdevelopment on the right side. Hypoplastic left ventricle had decreased myocardial volume and showed accelerated trabecular compaction. Increased volume load in the right ventricle was compensated primarily by chamber dilatation with altered trabecular pattern, and by trabecular proliferation and thickening of the compact myocardium at the later stages. A ventricular septal defect was noted in all conotruncal banded, and 25% of left atrial ligated hearts. Increasing pressure load is a main stimulus for embryonic myocardial growth, while increased volume load is compensated primarily by dilatation. Adequate loading is important for normal cardiac morphogenesis and the development of typical myocardial patterns.

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Retinoid-dependent pathways play a central role in regulating cardiac morphogenesis. Recently, we characterized gene-targeted RXR ␣ ϪրϪ embryos, which display an atriallike ventricular phenotype with the development of heart failure and lethality at embryonic day 14.5. To quantitate the frequency and complexity of cardiac morphogenic defects, we now use microdissection and scanning electron microscopy to examine 107 wild-type, heterozygous, and homozygous embryos at embryonic day 13.5, 14.5, and 15.5. RXR ␣ ϪրϪ embryos display complex defects, including ventricular septal, atrioventricular cushion, and conotruncal ridge defects, with double outlet right ventricle, aorticopulmonary window, and persistent truncus arteriosus. In addition, heterozygous RXR ␣ embryos display a predisposition for trabecular and papillary muscle defects, ventricular septal defects, conotruncal ridge defects, atrioventricular cushion defects, and pulmonic stenosis. Lastly, we show that the intermediate anatomic phenotype displayed by heterozygous embryos is mirrored in the molecular marker MLC-2a. The intermediate phenotype of RXR ␣ heterozygous embryos documents a gene dosage effect for RXR ␣ in maintaining normal cardiac morphogenesis. In addition, some defects in RXR ␣ mutant mice are phenocopies of human congenital heart defects, thereby suggesting that a relative deficiency in RXR ␣ or molecules downstream in its signaling pathway may represent congenital heart disease-susceptibility genes. ( J. Clin. Invest. 1996. 98:1332-1343.)

Background Numerous studies describing myocardial architecture have been performed on the adult heart but considerably fewer have been made during embryonic or fetal development. To serve as a basis for interspecies comparison of ventricular morphology, and as a reference for studying the effects of experimental perturbations, we examined the development of chick throughout the entire incubation period. Methods: Chick hearts from stage 14 (day 2) to stage 46 (day 21) were perfusion‐fixed, and sectioned in transverse, frontal and sagittal planes. The ventricular myocardial architecture was examined and photographed in the scanning electron microscope. Results: At embryonic stage 16 and earlier, the smooth‐walled heart loop had an outer myocardial mantle, cardiac jelly, and endocardium. From stage 18, there was an outer compact and inner trabeculated myocardium. Trabeculated myocardium could be subdivided into the outer (basal) portion adjacent to the compact layer and the central (luminal) part. The outer basal layer could be distinguished from the inner luminal by shorter and finer trabeculae with small, round intertrabecular spaces. From stage 24, the patterns of trabeculae and intertrabecular spaces were ventricle‐specific. Between stages 24 to 31, abundant trabeculations were present throughout both ventricular cavities. The trabeculae were initially radially arranged, but later adopted a spiral course, which persisted in a simplified form into adulthood. Conclusions The ventricular myocardium undergoes distinctive morphogenesis, characterized by changes in trabecular patterning and orientation. We speculate that the embryonic trabecular architecture reflects the directions of the main stresses. Unlike fetal and adult hearts, which rely mostly on the compact myocardial layer, the trabeculae play a crucial role in the contractile function of the embryonic heart. Anat. Rec. 248:421‐432, 1997. © 1997 Wiley‐Liss, Inc.