Respiratory and autonomic plasticity following intermittent hypoxia

间歇性缺氧后的呼吸和自主神经可塑性

• 批准号: 8262642
• 负责人: Jason H. Mateika
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262642
• 关键词: Accidents; Acute; Animals; Antioxidants; Apnea; Arousal; Automobile Driving; Autonomic nervous system; Blood Pressure; Cerebral hemisphere hemorrhage; Congestive Heart Failure; Coronary; Coronary heart disease; Development; Disease; Environmental air flow; Epidemiologic Studies; Event; Excessive Daytime Sleepiness; Experimental Designs; Exposure to; Fatigue; Feedback; Female; Gender; Health; Heart; Heart Rate; Hour; Human; Hypertension; Hypoxia; Individual; Lead; Long-Term Depression; Motor Activity; Neuronal Plasticity; Obstructive Sleep Apnea; Oxidative Stress; Parasympathetic Nervous System; Participant; Performance; Placebos; Population; Prevalence; Severities; Sleep; Sleep Apnea Syndromes; Stroke; Subarachnoid Hemorrhage; Sympathetic Nervous System; System; Time; United States; Vascular Diseases; Ventricular Arrhythmia; Veterans; Wakefulness; Workplace; abstracting; base; blood pressure regulation; experience; indexing; male; novel; prevent; public health relevance; respiratory; response

DESCRIPTION (provided by applicant): Abstract Approximately 8 % of the Veteran population in the United States suffers from sleep apnea. Consequences of untreated sleep apnea include increased daytime fatigue, hypertension and stroke. Thus, sleep apnea is a major health concern. One of the primary hallmarks of sleep apnea is exposure to intermittent hypoxia (IH) which occurs as a consequence of central or obstructive apneas. Exposure to IH may lead to neural plasticity (i.e. a change in system performance based on prior experience) of the respiratory and autonomic nervous system. One adaptation that has been shown to manifest itself in animals following exposure to IH is long-term facilitation (LTF) of ventilation and sympathetic nervous system activity (SNSA). This phenomenon is characterized by a gradual increase in respiratory motor activity and SNSA during successive periods of normoxia that separate hypoxic episodes and by activity that persists above baseline levels for up to 90 minutes following exposure to IH. Although LTF of minute ventilation has been well established in animals it has not been observed consistently in healthy humans or in individuals with obstructive sleep apnea. Similarly, although a few studies have shown that exposure to IH leads to increases in SNSA in healthy individuals the magnitude of the response has varied significantly. Findings from animal studies suggest that the manifestation of LTF in humans might in part be dependent on a variety of factors, including prior exposure to IH, arousal state (wake vs. sleep) and gender. Thus, the initial aim of our proposal will establish whether LTF can be induced in healthy humans and individuals with obstructive sleep apnea and whether the magnitude of the response is dependent on those factors mentioned above. Moreover, the initial aim will explore whether the presence of LTF of minute ventilation promotes apnea severity. Animal studies have also indicated that LTF of respiratory and autonomic activity may in part be induced by increases in oxidative stress. Thus, the second objective of our proposal will explore whether administration of an antioxidant cocktail impacts of respiratory and autonomic nervous system plasticity during wakefulness and sleep following IH. Likewise, the second aim will explore whether administration of an antioxidant cocktail mitigates apnea severity following exposure to IH. Establishing whether LTF of minute ventilation exists in individuals with sleep apnea is important since activation of this phenomenon could impact on apnea severity across the night. Similarly, LTF of SNSA activity and possibly long-term depression (LTD) of parasympathetic nervous system activity (PNSA) could ultimately lead to persistent increases in blood pressure and heart rate abnormalities. Furthermore, given that exposure to IH may lead to long-term plasticity of respiratory and autonomic activity that are physiologically detrimental, exploring mechanisms that ultimately lead to treatments that may mitigate or prevent the manifestation of this phenomenon are important. PUBLIC HEALTH RELEVANCE: Narrative The prevalence of obstructive sleep apnea is high in the Veteran population. If not treated promptly, obstructive sleep apnea may result in daytime fatigue which may lead to increased prevalence of accidents while driving or in the workplace. Recent large scale epidemiological studies have shown that the prevalence of excessive daytime sleepiness increases from 15 % in individuals who do not suffer from obstructive sleep apnea to 39 % in individuals with obstructive sleep apnea. Obstructive sleep apnea may also result in the development of hypertension, cerebral and subarachnoid hemorrhage, and ventricular arrhythmias. Results obtained from the Sleep Heart Health Study revealed that subjects with sleep apnea have 42 % greater odds of prevalent coronary vascular disease (i.e. coronary heart disease, stroke and congestive heart failure) compared to individuals with an apnea/hypopnea index of less than 1 event per hour. Thus, a significant amount of empirical evidence suggests that obstructive sleep apnea is a major health concern in the Veteran population. Consequently, determining the mechanisms that may impact on apnea severity and exacerbate autonomic perturbations associated with this disorder is important, as is discovering novel treatments.

描述（由申请人提供）： 摘要 在美国，大约 8% 的退伍军人患有睡眠呼吸暂停。未经治疗的睡眠呼吸暂停的后果包括增加日间疲劳、高血压和中风。因此，睡眠呼吸暂停是一个主要的健康问题。睡眠呼吸暂停的主要特征之一是间歇性缺氧 (IH)，这是中枢性或阻塞性呼吸暂停的结果。暴露于 IH 可能会导致呼吸和自主神经系统的神经可塑性（即基于先前经验的系统性能变化）。动物暴露于 IH 后表现出的一种适应是通气和交感神经系统活动 (SNSA) 的长期促进 (LTF)。这种现象的特点是，在连续的含氧量正常期间（分隔缺氧事件），呼吸运动活动和 SNSA 逐渐增加，并且在暴露于 IH 后的活动持续高于基线水平长达 90 分钟。尽管每分钟通气量的 LTF 已在动物中得到很好的证实，但在健康人类或患有阻塞性睡眠呼吸暂停的个体中尚未一致观察到。同样，尽管一些研究表明接触 IH 会导致健康个体 SNSA 增加，但反应的程度却存在显着差异。动物研究结果表明，人类 LTF 的表现可能部分取决于多种因素，包括之前接触过 IH、觉醒状态（清醒与睡眠）和性别。因此，我们提案的最初目的是确定是否可以在健康人和患有阻塞性睡眠呼吸暂停的个体中诱导 LTF，以及反应的程度是否取决于上述因素。此外，最初的目标是探讨每分钟通气量 LTF 的存在是否会加剧呼吸暂停的严重程度。动物研究还表明，呼吸和自主活动的 LTF 可能部分是由氧化应激的增加引起的。因此，我们提案的第二个目标将探讨服用抗氧化剂鸡尾酒是否会影响 IH 后清醒和睡眠期间呼吸和自主神经系统的可塑性。同样，第二个目标将探讨服用抗氧化剂鸡尾酒是否可以减轻暴露于 IH 后呼吸暂停的严重程度。确定患有睡眠呼吸暂停的个体是否存在每分钟通气量 LTF 非常重要，因为这种现象的激活可能会影响整个夜间呼吸暂停的严重程度。同样，SNSA 活动的 LTF 和副交感神经系统活动 (PNSA) 可能的长期抑制 (LTD) 最终可能导致血压持续升高和心率异常。此外，考虑到暴露于 IH 可能导致呼吸和自主活动的长期可塑性，这在生理上是有害的，因此探索最终导致可以减轻或预防这种现象的治疗的机制非常重要。 公共卫生相关性： 叙述 退伍军人中阻塞性睡眠呼吸暂停的患病率很高。如果不及时治疗，阻塞性睡眠呼吸暂停可能会导致白天疲劳，从而导致驾驶或工作场所发生事故的几率增加。最近的大规模流行病学研究表明，白天过度嗜睡的患病率从未患有阻塞性睡眠呼吸暂停的个体的 15% 增加到患有阻塞性睡眠呼吸暂停的个体的 39%。阻塞性睡眠呼吸暂停还可能导致高血压、脑出血和蛛网膜下腔出血以及室性心律失常。睡眠心脏健康研究的结果显示，与呼吸暂停/呼吸不足指数每小时少于 1 次的个体相比，患有睡眠呼吸暂停的受试者患流行冠脉血管疾病（即冠心病、中风和充血性心力衰竭）的几率要高 42%。因此，大量经验证据表明，阻塞性睡眠呼吸暂停是退伍军人群体的一个主要健康问题。因此，确定可能影响呼吸暂停严重程度并加剧与这种疾病相关的自主神经紊乱的机制很重要，发现新的治疗方法也很重要。