The objective of this research project is to test the hypothesis that the interaction between neural remodeling (nerve sprouting) and electrical remodeling underlie the mechanisms of ventricular arrhythmogenesis after myocardial infarction (MI). We recently reported a positive correlation between the nerve density of native hearts of transplant recipients and a clinical history of ventricular arrhythmia. We also demonstrated in dogs that nerve growth factor (NGF) infusion to the left stellate ganglion could facilitate the development of ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death (SCD). Based on these findings, we propose Nerve Sprouting Hypothesis of ventricular arrhythmia and SCD. The hypothesis states that MI results in nerve injury followed by sympathetic nerve sprouting and regional myocardial hyperinnervation. The coupling between augmented sympathetic nerve sprouting with electrically remodeled ventricular myocardium results in VT, VF and SCD. Modification of nerve sprouting after MI may provide a novel opportunity for arrhythmia control. To test this hypothesis, we plan to pursue the following specific aims: (1) Mechanisms of cardiac nerve sprouting. We will use in-situ hybridization and immunocytochemical staining to detect NGF mRNA and the tenascin proteins in a canine model of MI. (2) Anatomical distribution and functional asymmeta of left and right stellate ganglia. We will study the differential electrophysiological effects of nerve sprouting of the left and right stellate ganglia. We will also use immunocytochemical techniques to demonstrate a differential anatomical distribution of nerves from these two ganglia. (3) Origin of nerves that sprout after MI. We will use recombinant lentivirus vectors (rLVs) to transfer fluorescent protein genes into the stellate ganglia. The cardiac nerve distribution will be determined by the location of positive immunocytochemical staining and fluorescent protein expression. (4) Induction of right stellate ganglion nerve sprouting by electrical current. We will use electrical current to induce cardiac nerve sprouting from the right stellate ganglion and to reduce the incidence of ventricular arrhythmia and SCD. These studies may lead to novel insights into the mechanisms of ventricular arrhythmogenesis after MI and may help develop new methods for arrhythmia control.
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