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INTRODUCTION

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As described in Chapter 1, the developing mammalian heart undergoes a series of complex and tightly regulated processes during structural organogenesis. Considerable understanding of 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 accompany morphological development of the cardiovascular system. However, compared to our understanding of structural organogenesis, much less is known about the genetic, molecular, and cellular processes that control cardiac contractile function during embryonic development and fetal maturation.

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Although age-related changes occur in the functional cardiac responses to pharmacological or physiological interventions, 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. A thorough understanding of the basic molecular and cellular processes governing contractile function is essential for development of rational and age-appropriate pharmacological strategies for fetal and neonatal patients with impaired cardiac contractile function.

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It should be noted that current concepts of molecular and cellular aspects of myocyte function during cardiac development and maturation are derived mainly from animal models. Limited information is available regarding these processes in the immature human heart. The list of suggested readings at the end of this chapter refers to several monographs that provide a comprehensive and detailed overview of contractile function in the mature heart. In addition, references 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.

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GENERAL OVERVIEW OF CELLULAR ASPECTS OF CARDIAC FUNCTION

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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 [Na/K-ATPase]) 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 opening of sodium channels, which results in a rapid influx of sodium and a brisk rise in membrane potential from negative to positive values. As described in more detail below, 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 re-established, intracellular cytosolic calcium decreases, and calcium dissociates from the contractile protein complex.

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FIGURE 2-1.

Schematic diagram of the major components involved in calcium transport, excitation-contraction coupling, contraction, and relaxation in mature mammalian ventricular myocytes. At rest, a negative membrane potential is maintained largely by the action of the sodium-potassium ...

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