Myocardial infarction and mechanisms of impaired sleep and breathing

总结 睡眠和呼吸受损会产生多种全身性和器官特异性影响，包括炎症， 交感神经激活和代谢和心血管风险增加。最近，人们的注意力集中在 心脏事件与睡眠和呼吸中断之间的关系;睡眠呼吸障碍， 与不良的心脏结局相关，心脏病反过来被认为是一个可能的原因， 睡眠呼吸紊乱和睡眠片段。我们认为睡眠质量差可能会影响 心肌梗死（MI）后的主要结局，并有助于前馈机制， 随后的心脏事件和更差的结局。我们已经开发了小鼠模型来检查 实验诱导的心肌梗死与睡眠和呼吸受损之间的关系， 不存在肥胖，这是心血管疾病的主要共病。我们的初步研究表明， 在健康的瘦小鼠中，两天的睡眠片段诱导心脏中的促炎状态， 显著增加心脏功能障碍和随后MI的死亡率。相反，在MI小鼠中， 显著的睡眠障碍，主要特征是（1）总的NREM睡眠时间显著增加， 黑暗/活跃期，模拟人类的“白天嗜睡”;（2）觉醒显著增加 频率，主要是在巩固睡眠的光周期，模拟破碎，睡眠质量差， 人类与心肌梗死后睡眠的这些变化相关，我们观察到心肌梗死后细胞因子表达的增加。 下丘脑依赖于完整的心脏交感神经通路。我们将使用最先进的 生理技术来研究睡眠中断和MI之间的关系， 研究心脏神经和促炎通路在瘦小鼠和肥胖小鼠中的作用。目标1将检查 既往睡眠中断对MI结局恶化的影响，目标2-4将检查MI对以下方面的影响： 随后的睡眠和呼吸中断以及前馈机制的发展进一步 MI结局恶化。我们的目标是： 目的1：确定先前睡眠片段化的影响和心脏交感神经通路的作用， 肥胖对心肌梗死后心功能和死亡率的影响。目的2：确定MI介导的呼吸的作用 不稳定性对睡眠碎片化和“白天嗜睡”的发展。目标3：确定 心脏传入交感神经通路在心肌梗死后碎片化睡眠和增加“白天嗜睡”中的作用。 目的4：确定激活中枢神经系统细胞因子在增加心肌梗死后的“白天嗜睡”中的作用。 这项研究将为了解功能失调的睡眠与呼吸和心脏之间的关系提供见解。 病理学使用离散的干预来定义在临床研究中不可能的机制途径。 此外，我们的长期目标是将我们的发现转化回临床竞技场，改善结果， 治疗方案的选择。

SUMMARY Impaired sleep and breathing has multiple systemic and organ-specific effects including inflammation, sympathetic activation and heightened metabolic and cardiovascular risk. Recently, attention has focused on the relationship between cardiac events and disrupted sleep and breathing; sleep disordered breathing is associated with poor cardiac outcomes, and cardiac disease has, in turn, been identified as a possible cause of sleep disordered breathing and fragmentation of sleep. We propose that poor sleep quality may affect primary outcomes after myocardial infarction (MI), and contribute to a feedforward mechanism leading to subsequent cardiac events and worse outcomes. We have developed murine models to examine the relationship between experimentally-induced MI and impaired sleep and breathing in both the presence and absence of obesity, a major co-morbidity in cardiovascular disease. Our preliminary studies demonstrate that two days of sleep fragmentation in healthy lean mice induces a pro-inflammatory state in the heart and significantly increases cardiac dysfunction and mortality to subsequent MI. Conversely, in mice with MI there are marked sleep disturbances, primarily characterized by (1) a striking increase in total NREM sleep time in the dark/active period, simulating `daytime sleepiness' in humans and (2) a marked increase in arousal frequency, predominantly in the light period of consolidated sleep, simulating fractured, poor sleep quality in humans. Associated with these changes in sleep after MI, we observed an increase in cytokine expression in the hypothalamus that was dependent on intact cardiac sympathetic pathways. We, will use state-of-the-art physiologic techniques to investigate the relationship between sleep disruption and MI and mechanistically examine the role of cardiac neural and pro-inflammatory pathways in lean and obese mice. Aim 1 will examine the effect of prior sleep disruption on worsening MI outcomes and Aims 2-4 will examine the effect of MI on subsequent sleep and breathing disruption and the development of a feedforward mechanism further worsening MI outcomes. Our aims are: Aim 1: To determine the impact of prior sleep fragmentation and the role of cardiac sympathetic pathways and obesity on cardiac function and mortality after MI. Aim 2: To determine the role of MI-mediated breathing instability on the development of sleep fragmentation and `daytime sleepiness.' Aim 3: To determine the role of cardiac afferent sympathetic pathways in fragmenting sleep and increasing `daytime sleepiness' after MI. Aim 4: To determine the role of activation of CNS cytokines in increasing `daytime sleepiness' after MI. This study will provide insights into the relationship between dysfunctional sleep and breathing and cardiac pathology using discrete interventions to define mechanistic pathways that are not possible in clinical studies. Moreover, our long-term goal is to translate our findings back to the clinical arena and improve outcomes and therapeutic options in this vulnerable population.