Myocardium and Development Jeffrey Robbins, Jeanne James Abstract Function depends on form During embryogenesis, the heart is the first functional organ to develop, underlying its essential function during development and life This chapter outlines cardiac development in terms of the interplay of the different cell types as they differentiate form common precursor pools as well as the roles these cell types play in normal heart development and function We then discuss some of the processes that can underlie cardiac disease, with an emphasis on the contractile machinery since the heart’s central role is as a muscle that continually contracts The focus then turns to the cardiomyocyte with a discussion on the nuclear and cytoplasmic processes that underlie its function Finally, we present a discussion in which perturbations in cardiac form and function are directly causative for human disease and discuss how a more complete understanding of cardiac genetics, morphology, and function will lead to new therapeutic approaches for directly treating heart disease Keywords development; heart; cardiac disease; fibrosis; cardiomyocyte; sarcomere A functional myocardium is necessary for viability during embryonic and fetal development As such, the heart is the first functional organ because its ability to distribute essential nutrients to the developing embryo is essential for viability and normal progression of development In the human embryo, a beating heart is apparent by 22 to 25 days postcoitum,1,2 and continued development and viability depend on the heart's ability to maintain circulation in the developing embryo, fetus, and for the rest of the organism's life Considering the necessity for vigorous cardiac function, it is not surprising that both congenital and acquired cardiac disease remain a major problem and is the most common cause of death in the adult population worldwide.3 This chapter reviews the origins of critical cardiac components and defines some of the basic components that underlie their function during development Early Myocardial Development Different terminology exists regarding the timing of human embryologic development and terms, such as “conception,” “gestation,” and “pregnancy,” can lead to confusion that is further compounded by variations in defining the onset of development as occurring at the time of fertilization or implantation Estimated gestational age is based on the time since the female's last menstrual period (LMP) and is measured in weeks, but includes the roughly 14 days from the LMP to oocyte fertilization Thus a woman who is 16 weeks pregnant based on her LMP is carrying a 14-week-old fetus An alternative developmental measurement is the Carnegie staging (CS) system, which is widely used by embryologists to define embryo maturity The CS system is based on external features of the embryo and ranges from CS 1 to CS 23, encompassing the time from postovulatory day 1 (CS 1) to approximately 53 to 58 days (CS 23) postovulation In this chapter, cardiac embryology will be described primarily in terms of weeks postovulation with reference to CS A comprehensive description of the morphogenic movements of the primordial heart progenitors is beyond the scope of this chapter, but the reader is referred to the many reviews2,4–6 as well as outstanding online resources (e.g., www.ncbi.nlm.nih.gov/pmc/articles/PMC1767747/) that detail these important processes Cardiac Looping Structure underlies and ultimately determines function Our understanding of the identity of the cells that populate and function in the heart, and their origins, has changed radically in the past 15 to 20 years The generally accepted concept of an early heart tube containing all the necessary precursors of what will become a mature heart has been shattered by new technologies that allow the detailed dissection of cell lineages, sites of proliferation, and migration Studies from the worm, fly, chicken, and mouse have enriched our understanding of human heart development as well, and we now know that many of the precursors for the various cell types in a mature heart are added to the primary heart tube at both the venous and arterial poles Molecular genetics has provided the tools to carry out detailed cell lineage tracings, showing clearly where the different precursors for the various