Chapter 2

As described in Chapter 1, the developing heart undergoes a series of extremely complex processes during structural organogenesis. Considerable insight into the genetic control of these pathways has been gained in recent years. Of equal importance are the functional changes in cardiac contraction and relaxation that must accompany the morphological development of the cardiovascular system. However, much less is known about the genetic, molecular, and cellular processes that control cardiac contractile function in the mammalian heart during embryonic development and fetal maturation.

Although age-related changes occur in the cardiac responses to virtually every pharmacological or physiological intervention, understanding of the underlying mechanisms is generally incomplete. In particular, there is relatively little known about fundamental mechanisms of excitation-contraction coupling and regulation of contractile function in the immature human heart. It is only by gaining a thorough understanding of the basic molecular and cellular processes governing contractile function that we can develop more rational and age-appropriate pharmacological strategies for fetal and neonatal patients.

This chapter will present current concepts of developmental aspects of myocyte contraction, relaxation, and excitation-contraction coupling that have been derived from animal models. Where appropriate, relevant data from human studies will be presented. In this manner, we can begin to form the scientific foundation for understanding the regulation of myocardial contractile function in infants and children. The list of suggested readings at the end of this chapter refers to several excellent monographs that provide a comprehensive and detailed overview of contractile function in the mature heart. In addition, several recent reviews are listed that provide additional information regarding developmental changes in cardiac ultrastructure, metabolism, electrophysiology, and responses to pathophysiological states. Integration of these myocellular changes into a larger perspective of developmental physiology and cardiac mechanics is presented in Chapter 3.

Excitation, contraction, and relaxation of myocardial cells are mediated by complex ion transport processes and coordination of calcium delivery to and from the contractile proteins (Figure 2-1). At rest, active transport processes (mainly the sodium-potassium pump) maintain electrochemical gradients across the sarcolemmal membrane. Consequently, a resting membrane potential is established with the cell interior being negative relative to the extracellular space. Depolarization of the cardiac sarcolemmal membrane occurs largely due to the opening of sodium channels, which results in an influx of sodium and a rapid rise in membrane potential from negative to positive values. As described in more detail in the following discussion, this change in membrane potential is ultimately translated into an increase in intracellular cytosolic calcium, binding of calcium to the contractile protein complex in the myofibrils, and cell shortening (contraction). Relaxation occurs as the resting sarcolemmal membrane potential is reestablished, intracellular cytosolic calcium decreases, and calcium dissociates from the contractile protein complex.

###### Figure 2-1.

Schematic diagram of the major components involved in calcium transport, excitation-contraction coupling, contraction, and relaxation in mature mammalian ventricular ...

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