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; 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）： 摘要美国大约8％的退伍军人人口患有睡眠呼吸暂停。未经治疗的睡眠呼吸暂停的后果包括日常疲劳，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标志之一是暴露于间歇性缺氧（IH），这是由于中央或阻塞性呼吸暂停而发生的。接触IH可能会导致呼吸道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的变化）。暴露于IH后的动物中表现出来的一种适应性是通气和交感神经系统活动（SNSA）的长期促进（LTF）。这种现象的特征是，在接触IH后，呼吸运动活动和SNSA的呼吸运动活动和SNSA逐渐增加，而这种现象是分离低氧发作和持续至高于基线水平的活性。尽管在动物中已经很好地确定了微小通风的LTF，但在健康的人或阻塞性睡眠呼吸暂停的个体中尚未观察到。同样，尽管一些研究表明，健康个体的IH暴露会导致SNSA的增加，但反应的大小差异很大。动物研究的发现表明，人类中LTF的表现可能部分取决于多种因素，包括事先暴露于IH，唤醒状态（唤醒与睡眠）和性别。因此，我们提案的最初目的将确定在健康的人类和阻塞性睡眠呼吸暂停的个人中是否可以诱导LTF，以及反应的大小是否取决于上述因素。此外，最初的目标将探索分钟通风的LTF是否会促进呼吸暂停严重程度。动物研究还表明，呼吸道和自主活动的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在IH觉醒和睡眠期间呼吸道和自主神经系统可塑性的抗氧化鸡尾酒的影响。同样，第二个目标将探索抗氧化剂鸡尾酒的给药是否会在暴露于IH后减轻呼吸暂停严重程度。确定睡眠呼吸暂停个体中是否存在微小通风的LTF很重要，因为这种现象的激活可能会影响整个晚上对呼吸暂停的严重程度。同样，SNSA活性的LTF以及副交感神经系统活性（PNSA）的长期抑郁（LTD）最终可能导致血压和心率异常的持续增加。此外，考虑到IH的暴露可能导致生理上有害的呼吸和自主活动的长期可塑性，探索机制最终导致治疗可能会减轻或阻止这种现象的表现。 公共卫生相关性： 叙述性在退伍军人人口中，阻塞性睡眠呼吸暂停的流行率很高。如果未迅速治疗，阻塞性睡眠呼吸暂停可能会导致白天疲劳，这可能导致驾驶或在工作场所中发生事故的患病率增加。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没有阻塞性睡眠呼吸暂停的个体中的15％增加到阻塞性睡眠呼吸暂停患者的39％。阻塞性睡眠呼吸暂停也可能导致高血压，大脑和蛛网膜下腔出血以及心室心律不齐。从睡眠心脏健康研究中获得的结果表明，与患有呼吸暂停/呼吸呼吸症指数少于1个事件的人相比，患有睡眠呼吸暂停的受试者患有患冠状动脉血管疾病的几率（即冠心病，中风和充血性心力衰竭）的几率高42％。因此，大量的经验证据表明，阻塞性睡眠呼吸暂停是退伍军人人口的主要健康问题。因此，确定可能影响呼吸暂停严重程度的机制并加剧与该疾病相关的自主性扰动，发现新的治疗方法也很重要。