Myocardial Ischemia Remodels the Cardiac Nervous System

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DESCRIPTION (provided by applicant): The overall objective of this proposal is to determine how the cardiac neuronal hierarchy modulates electrical events in the ischemic myocardium. We hypothesize that heterogeneity of reflex responses evoked by neurons at different levels of the cardiac neuronal hierarchy can result in this system becoming overwhelmed by excessive ischemia-induced afferent inputs. The resultant imbalance of information processing between its peripheral and central components induces heterogeneity of catecholamine release within the ventricle to exacerbate the substrate for arrhythmia formation. We hypothesize that subpopulations of CNS (spinal cord) neurons act to stabilize select components of the intrathoracic cardiac neuronal hierarchy to suppress inhomogeneous sympathetic efferent neuronal inputs to the heart, thereby reducing arrhythmia susceptibility. In order to accomplish this objective, we propose to determine: 1) How the milieu of the normal and ischemic myocardium is transduced by afferent neurons to second order neurons throughout the cardiac neuronal hierarchy; 2) How that information impinges on intrathoracic local circuit neurons that ultimately coordinate efferent neuronal outflows to the heart; and 3) How thoracic spinal cord neurons stabilize the processing of such information. Specific aim 1. To determine the relationship of dispersion of regional cardiac electrical events concomitant with differential regional catecholamine release into the cardiac interstitium in reflex response to transient ventricular ischemia, including determining the contribution of central versus peripheral reflex processing of such dispersion. Specific aim 2. To determine how cardiac afferent neurons at different levels' in the cardiac neuronal hierarchy differentially transduce the mechanical and chemical milieu of the normally perfused versus ischemic myocardium to second order neurons and to determine the morphology and neurochemical coding expressed by the different intrathoracic neuronal subtypes (afferent, efferent, and local circuit neurons) involved. Specific aim 3. To determine the capacity of spinal cord neurons to mitigate such myocardial ischemia-induced reflex release of catecholamines into disparate LV regions to thereby blunt any resultant deleterious disparity of cardiac electrophysiological properties. This will include determining the inherent contributions of centrally-induced changes in sympathetic versus vagal descending projections to the intrathoracic nervous system in mitigating untoward cardiac electrical events initiated by such a state.