This study proposes to investigate the dynamic interrelationship between the ontogenesis of adrenergic innervation and the developing ventricular myocardium rat heart in order to delineate possible pathogenetic mechanisms leading to hypertrophic obstructive cardiomyopathy (HCM). We shall test the hypothesis that ventricular hypertrophy results from abnormalities in cardiac autonomic innervation, and if this is the case, to investigate the mechanism. That this hypothesis is true is suggested by the observation that a syndrome similar to HCM can be observed in neonatal rats following administration of nerve growth factor (NGF) or triiodothyroacetate (TRIAC). These unique models will be characterized with regard to (1) their relationship to human congenital HCM and (2) the mechanism of their induction. The relative ventricular and septal volume and contractile protein isoform composition will be determined throughout pre- and postnatal development in control and treated rats. The effects of these interventions on the ontogenesis of cardiac innervation will be determined in parallel observations. We have also observed neuronal induction of cardiac myocyte hypertrophy in vitro, providing a powerful model system for determination of biochemical mechanism. The effects of innervation in the presence or absence of NGF or TRIAC on myocyte volume, sarcomere organization, and protein composition will be determined. Factors released by sympathetic neurons that regulate these aspects of cardiac myocyte development will be isolated and characterized. Should these studies demonstrate a lack of involvement of cardiac innervation in NGF or TRIAC induced HCM, the possibility that cardiac myocytes respond directly to NGF or TRIAC will be investigated in vitro, and cellular localization of NGF receptors will be performed in vivo and in vitro. These studies will identify factors related to myocardial hypertrophy and may suggest possible causes of such ventricular abnormalities in individuals with congenital HCM.
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| Atkins, D L; Rosenthal, J K; Krumm, P A et al. (1991) Application of stereological analysis of cell volume to isolated myocytes in culture with and without adrenergic innervation. Anat Rec 231:209-17 |
