Hypothalamic neuron activation to blunt myocardial remodeling during chronic sleep apnea

项目总结 阻塞性睡眠呼吸暂停(OSA)与多种心血管疾病的进展有关，包括 猝死、高血压、心律失常、心肌缺血和心力衰竭。即使这些 合并症是众所周知的，关于阻塞性睡眠呼吸暂停综合征是如何直接增加 心肌损伤和功能障碍。我们的目标是确定慢性间歇性疾病的独立影响 低氧(CIH)是阻塞性睡眠呼吸暂停综合征(OSA)的一种模型，它对大鼠体内心血管和左心室电机械功能障碍的影响。 不幸的是，针对阻塞性睡眠呼吸暂停综合征的有效治疗选择也很少。我们最近确定了一部小说 恢复心脏保护副交感神经张力以减轻心肌损伤的机制 在CIH期间。脑干副交感性心迷走神经元(CVN)接受来自 起源于下丘脑室旁核的催产素(OXT)神经元群。 这些独特的神经元共同释放OXT并增强兴奋性谷氨酸能神经传递给CVN。 尽管我们已经证明，在CIH暴露开始时激活PVN oxt神经元可能有益于 预防高血压的发展，一个基本的和临床相关的问题仍然存在： 激活PVN oxt神经元逆转和/或减轻高血压、心律失常、心脏 发作性脑出血后的炎症和心功能不全？这一最重要的假设 将在两个具体目标上进行测试。目标1是确定长期接触CIH如何改变心脏 组织功能和自主神经张力。使用遥测仪器动物进行的活体研究将测试 假设长期暴露在CIH中的动物运动耐量降低，发病率增加 峰值负荷能力试验期间体内心肌缺血的发生率，以及峰值负荷后心率恢复的减慢 容量。体外灌流心脏研究将测试暴露于CIH的动物的心脏是否减少 收缩功能，需求缺血发生率增加，心律失常发生率增加，并减少 对心脏毒碱刺激的反应。将对炎症和纤维化进行更多评估 功能丧失和心律失常的潜在机制。目标2是确定有效的 治疗窗(S)，通过适当的时机激活PVN oxt神经元可以减缓或 逆转脑出血引起的心脏生理和自主神经张力的不利变化。有效 治疗窗口(S)将通过增加从脑出血发病到 启动PVN oxt神经元的慢性激活。这些研究还将量化发病之间的延迟 PVN催产素神经元的激活和内源性突触释放催产素的量 促进CVN的神经元--从而增加心脏副交感神经张力。我们会进一步评估 PVN oxt神经元激活在钝化或逆转心脏改变中的延迟/奖赏关系 由脑出血引起的生理(体外)和自主神经张力、血压和心率(体内)。

PROJECT SUMMARY Obstructive sleep apnea (OSA) is involved in the progression of multiple cardiovascular diseases including sudden death, hypertension, arrhythmias, myocardial ischemia, and heart failure. Even though these comorbidities are generally known, very little is known about how OSA directly increases the risk for myocardial damage and dysfunction. Our goal is to identify the independent impact of chronic intermittent hypoxia (CIH), a model of OSA, on in-vivo cardiovascular and LV electromechanical dysfunction in rats. Unfortunately, there are also very few effective treatment options for OSA. We have recently identified a novel mechanism for restoring cardio-protective parasympathetic tone to the heart to reduce myocardial damage during CIH. Brainstem parasympathetic cardiac vagal neurons (CVNs) receive powerful excitation from a population of oxytocin (OXT) neurons that originate in the paraventricular nucleus of the hypothalamus (PVN). These unique neurons co-release OXT and enhance excitatory glutamatergic neurotransmission to CVNs. Although we have shown that PVN OXT neuron activation at the onset of CIH exposures can be beneficial in preventing the development of hypertension, an essential and clinically relevant question remains: Can activation of PVN OXT neurons reverse and/or mitigate the hypertension, incidence of arrhythmias, cardiac inflammation, and ventricular dysfunction when initiated after the onset of CIH? This overarching hypothesis will be tested in two Specific Aims. Aim 1 is to determine how chronic exposure to CIH alters cardiac tissue function and autonomic tone. In-vivo studies using telemetry-instrumented animals will test the hypothesis that animals chronically exposed to CIH will have reduced exercise tolerance, increased incidence of in-vivo cardiac ischemia during peak effort capacity tests, and reduced heart rate recovery after peak effort capacity. Ex-vivo perfused heart studies will test whether hearts of animals exposed to CIH have reduced contractile function, increased incidence of demand ischemia, increased incidence of arrhythmia, and reduced responses to cardiac muscarinic stimulation. Additional assessments of inflammation and fibrosis will probe potential mechanisms of loss-of-function and arrhythmogenesis. Aim 2 is to determine the effective treatment window(s) by which appropriately timed activation of PVN OXT neurons could slow or reverse adverse changes in cardiac physiology and autonomic tone that are caused by CIH. Effective treatment window(s) will be identified by increasing the time interval between the onset of CIH and the initiation of chronic activation of PVN OXT neurons. These studies will also quantify the delay between onset of PVN oxytocin neuron activation and the amount of endogenous synaptic release of oxytocin from PVN neurons that facilitates CVNs - thereby increasing cardiac parasympathetic tone. We will further assess the delay/reward relationship of PVN OXT neuron activation in blunting or reversing alterations in cardiac physiology (ex-vivo) and autonomic tone, blood pressure and heart rate (in-vivo) caused by CIH.