Approximately 1% of live births are complicated with some sort of cardiovascular malformation. This accounts for 80 to 90% of pediatric patients under 1 year of age that develop congestive heart failure. It is thus important to understand the physiology of heart failure in the infant and fetus. Cardiac hypertrophy is an important adaptive mechanisms that enables the heart to compensate for overload and is a process that precedes heart failure. This proposal focuses on the cellular abnormalities that occur during hypertrophy of the fetal heart. The purpose of this application is to determine whether the electrical and inotropic properties of the heart are altered in an animal model of fetal sheep left ventricular cardiac hypertrophy.
The Specific Aims of this study are: 1) to determine whether the action potential and inotropic state of the heart are altered in the fetal hypertrophic model; 2) to determine whether potassium channel function is altered in the fetal hypertrophic model; 3) to determine whether Ca2+ channel function is altered in the fetal hypertrophic model; 4) to biochemically determine the number of beta-adrenergic and dihydropyridine (L-type Ca channel) receptor sites in the fetal hypertrophic model; 5) to determine the ontogeny of the ionic currents in the developing sheep heart at 80, 120, 135, 145 and 155 days post- conception.
Aim 1 will provide important information about modulation of the force-interval relationship by beta-adrenergic stimulation in the hypertrophic model and whether the action potential is prolonged as in adult models of hypertrophy.
Aims 2 and 3 will provide information about whether the individual potassium and calcium currents, that underlie the action potential and effect excitation-contraction coupling, are altered in the fetal hypertrophic model.
Aim 4 will determine whether Ca channel and beta-adrenergic receptor densities are altered and provide information on whether desensitization or functional uncoupling of beta-adrenergic receptors has occurred in the hypertrophic model.
Aim 5 will test the hypothesis that load induced hypertrophy of fetal hearts follows a different cellular program than normal development. This study will provide new and valuable information on the plasticity of ion channels in the fetal heart.
