Development of the myocardium - Its clinical significance -

Professor of Pediatrics, Pharmacology, Physiology and Neuroscience, Director, Pediatric Cardiology,
New York University School of Medicine,
New York, USA
Michael Artman

The developing heart undergoes profound changes in the molecular and cellular pathways involved in the transport of calcium to and from the contractile proteins. Characterization of the changes in calcium transport in the developing heart is necessary in order to formulate strategies for manipulating contraction and relaxation in the immature heart.
  In mature ventricular myocytes, graded control of contraction amplitude is achieved largely by changes in the magnitude of L-type calcium current and triggered release of calcium from the sarcoplasmic reticulum（SR）. Under physiologically relevant conditions, L-type calcium current is regulated by membrane potential and phosphorylation state. The evidence accumulated to date suggests that triggering of SR calcium release by L-type calcium current does not control contraction amplitude in immature myocytes. However, since contraction in immature myocytes is not an all-or-none phenomenon, there must be alternative mechanisms for exerting graded control of contraction amplitude in developing cells. In contrast to adult myocytes, ventricular myocytes from newborn rabbits are much more dependent on the Na⁺/Ca²⁺ exchanger（NCX）, both for calcium influx to generate contractions and for calcium efflux during relaxation. Consequently, conventional approaches for altering contractile function in the mature heart, such as changing L-type calcium current and/or SR calcium release and reuptake, are less likely to be effective in the immature heart. Instead, graded control of intracellular calcium concentration and contraction amplitude is predicted to be achieved in immature myocytes predominantly by factors that modulate NCX activity. NCX activity may be influenced by a number of factors, but the extent and duration of membrane depolarization and the transsarcolemmal gradients of sodium and calcium are the primary determinants of NCX activity. A greater dependency on NCX as the source of activator calcium predicts that graded control of calcium influx（and hence, the force of contraction）can be achieved by subtle changes in action potential duration and/or configuration.
  One of the primary physiological and pharmacological mechanisms for modulation of cardiac contractile function involves β-adrenergic receptor signaling pathways. The overall effects of β-adrenergic stimulation in the mature heart include increases in contractile force generation, enhanced relaxation and increases in heart rate and conduction velocity. The inotropic response is due to increased calcium influx through L-type calcium channels and greater SR calcium release. Enhanced relaxation results from more rapid dissociation of calcium from the contractile proteins and increased reuptake into the SR. It is known that β-adrenergic agonists exert qualitatively similar responses in immature hearts. However, since the primary target proteins and calcium transport pathways affected by β-adrenergic agonists in the adult heart play a diminished role the immature heart, alternative cellular and molecular mechanisms may be involved. Recently, isoproterenol has been shown to enhance NCX currents in adult guinea pig myocytes. Preliminary results suggest that β-adrenergic stimulation has a similar effect on NCX activity in immature ventricular myocytes.
  It is only by gaining a thorough understanding of the basic molecular and cellular processes governing contractile function that we can derive the foundation for developing rational and age-appropriate pharmacological strategies for fetal and neonatal patients.