Coronary heart disease is the leading cause of death in the U.S., and patients who survive a myocardial infarction (MI) have a high risk for cardiac arrhythmias and sudden cardiac death. Myocardial infarction alters the distribution and density of cardiac sympathetic nerve fibers, neurotransmitter synthesis, and neuropeptide production, resulting in heterogeneity of sympathetic transmission. These injury-induced changes in sympathetic transmission contribute to post-infarct arrhythmias and sudden cardiac death. The long term goal of the proposed research is to understand the molecular basis for sympathetic plasticity following cardiac injury, and how neural changes contribute to increased arrhythmia susceptibility. Recent nerve injury studies revealed that inflammatory cytokines that act through the gp130 receptor are important for axon regeneration. Several gp130 cytokines are elevated in the heart after MI, where they impact tyrosine hydroxylase levels and noradrenergic transmission in peri-infarct sympathetic nerves. New data suggest a role for cytokines in axon regeneration as well.
Aim 1 tests the hypothesis that gp130 cytokines are required for sympathetic regeneration in the left ventricle following myocardial infarction, and the resulting hyperinnervation increases arrhythmia propensity. Additional studies will identify the mechanisms involved. A recent heart failure study found that gp130 cytokines stimulate acetylcholine (ACh) synthesis in cardiac sympathetic neurons, and our data suggest that cytokines stimulate ACh synthesis in cardiac sympathetic neurons after acute MI. NE and ACh, which have opposing actions on cardiac myocytes, are not normally present in the same region of the left ventricle. Several lines of evidence suggest that co-release of NE and ACh will increase arrhythmia risk and decrease myocyte contractility, but the functional consequences of sympathetic ACh release are unknown. We will test the hypothesis that gp130-cytokines induce cholinergic transdifferentiation of cardiac sympathetic nerves after acute MI (Aim 2), and that ventricular ACh increases arrhythmia propensity and decreases cardiac contractility after acute MI (Aim 2) and heart failure (Aim 3). These studies will use genetic strategies to alter sympathetic regeneration and sympathetic neurochemical properties, and will combine that with echocardiography, ECG telemetry in conscious mice, and ex vivo optical mapping to determine how changes in sympathetic transmission alter cardiac rhythm and function. An outstanding team of experts along with unique animal models will be used to carry out these studies, which will be the first to directly test if manipulating cardiac nerves will alter the frequency, site, ad mechanism of post-infarct arrhythmias. This work tests novel hypotheses concerning sympathetic neuroplasticity that may provide a molecular basis for increased post-MI arrhythmias, and may ultimately lead to the development of new therapeutics.
Coronary heart disease is the leading cause of death in the U.S, and patients have a high risk for cardiac arrhythmias after surviving a myocardial infarction (heart attack), or developing heart failure. Altered sympathetic neurotransmission is a major contributor to cardiac arrhythmias and sudden cardiac death. These studies will identify factors that control sympathetic nerve regeneration after a heart attack, and will determine if cholinergic transdifferentiation of sympathetic nerves contributes to ventricular arrhythmias and sudden cardiac death.
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