Regulation of sympathetic function by infarction

描述（由申请人提供）：冠心病是美国死亡的主要原因，心肌梗死（MI）存活的患者发生心律失常和心源性猝死的风险很高。心肌梗死改变了心脏交感神经纤维的分布和密度、神经递质合成和神经肽的产生，导致交感神经传递的异质性。这些损伤引起的交感神经传递改变可导致梗死后心律失常和心源性猝死。这项研究的长期目标是了解心脏损伤后交感神经可塑性的分子基础，以及神经变化如何促进心律失常易感性的增加。最近的神经损伤研究表明，通过gp130受体起作用的炎症细胞因子对轴突再生很重要。心肌梗死后，几种gp130细胞因子在心脏中升高，影响酪氨酸羟化酶水平和梗死周围交感神经的去甲肾上腺素能传递。新的数据表明细胞因子在轴突再生中也有作用。Aim 1验证了心肌梗死后左心室交感神经再生需要gp130细胞因子的假设，由此导致的神经过度支配增加了心律失常的倾向。进一步的研究将确定所涉及的机制。最近的一项心力衰竭研究发现，gp130细胞因子刺激心脏交感神经元中乙酰胆碱（ACh）的合成，我们的数据表明，急性心肌梗死后，细胞因子刺激心脏交感神经元中乙酰胆碱（ACh）的合成。NE和ACh对心肌细胞具有相反的作用，通常不存在于左心室的同一区域。一些证据表明，NE和乙酰胆碱的共同释放会增加心律失常的风险，降低心肌细胞的收缩力，但交感神经乙酰胆碱释放的功能后果尚不清楚。我们将验证gp130细胞因子诱导急性心肌梗死（Aim 2）后心脏交感神经胆碱能转分化的假设，以及急性心肌梗死（Aim 2）和心力衰竭（Aim 3）后心室ACh增加心律失常倾向和降低心脏收缩力的假设。这些研究将使用遗传策略来改变交感神经再生和交感神经化学特性，并将其与超声心动图、有意识小鼠的心电图遥测和离体光学制图相结合，以确定交感神经传递的变化如何改变心律和功能。一个杰出的专家团队和独特的动物模型将被用于开展这些研究，这将是第一个直接测试操纵心脏神经是否会改变梗死后心律失常的频率、部位和机制。这项工作测试了关于交感神经可塑性的新假设，这可能为心肌梗死后心律失常的增加提供分子基础，并可能最终导致新疗法的发展。

DESCRIPTION (provided by applicant): 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.