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