We recently demonstrated heterogeneous myocardial sympathetic innervation in a colony of German shepherd dogs with ventricular arrhythmia and sudden cardiac death. The proposed research will apply scintigraphic methods to study the development of sympathetic nerves in these arrhythmic animals, and determine the effects of altered nerve development on adrenergic receptors, gap junctions, and repolarization responses.
In Aim 1, we will study the postnatal development of myocardial innervation and perfusion and compare the results to the postnatal development of ventricular arrhythmias. The hypothesis to be tested is that postnatal maturation of sympathetic innervation is delayed in this colony of animals, and this delayed maturation is a primary determinant of ventricular arrhythmia.
In Aim 2, we will study the effects of modulation of sympathetic nerve growth on the expression of ventricular arrhythmias. We will test the hypothesis that modulation of sympathetic nerve growth, or induced homogeneity of innervation will decrease the frequency and severity of arrhythmias.
In Aim 3, we will study effects of regional denervation on the distribution of sympathetic nerve histology, myocyte gap junctions, and alpha and beta adrenergic receptor density and affinity. We will test the hypothsosis that heterogeneous spatial gradients of sympathic innervation result in associated gradients in adrenergic receptors and gap junctions.
Aim 4 will study the developmental effects of sympathetic innervation on local myocardial repolarization. The hypothesis to be tested is that heterogeneous innervation results in local abnormalities of myocardial repolarization during the basal state and during sympathetic stimulation. The unique opportunity to investigate the development of cardiac sympathetic innervation and compare functional abnormalities of the sympathetic nerves to myocardial perfusion, signal transduction, intercellular communication and cardiacarrhythmia. These studies may provide a more comprehensive understanding of the interaction of the sympathetic nervous system and arrhythmogenesis.
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