Cardiovascular Responses to Sleep Apnea in Tetraplegia: A Pilot Study

描述(由申请人提供)： 筛查研究表明，中重度阻塞性睡眠呼吸暂停(OSA)在四肢瘫痪患者中的患病率从22%到36%不等，大大超过了一般人群中男性9.1%和女性4%的患病率估计。最近的证据表明，未经治疗的OSA会增加患高血压、心肌梗死和中风的风险。认为阻塞性睡眠呼吸暂停与不良心血管后遗症之间的联系的主要机制是由于重复的呼吸暂停事件引起的交感神经系统活动增加，尽管伴随着较大的胸腔内压负波动的心输出量下降，以及与氧化应激和内皮功能障碍相关的反复缺氧/复氧也被认为是相关的。与神经功能正常的人相比，四肢瘫痪患者表现为交感神经丧失的模式，其特征是相对心动过缓和低静息血压。目前尚不清楚阻塞性睡眠呼吸暂停是否会增加这些人的心血管疾病风险，尽管心血管疾病的患病率和归因性死亡率似乎比一般人群更高。我们怀疑阻塞性睡眠呼吸暂停合并四肢瘫痪由于呼吸暂停期间心输出量的下降而施加显著的血流动力学压力，儿茶酚胺诱导的变时性、变力性和血管升压性作用并不能阻止这种作用。四肢瘫痪患者的肌肉瘫痪和迟钝的高碳酸血症呼吸反应也是正常的快速眼动(REM)睡眠现象，可能会导致更严重的呼吸暂停，并加剧心输出量的下降，与健康人在REM睡眠中观察到的情况相似，但无论处于哪个睡眠阶段都可能发生。我们还预计，心输出量下降和肾脏低灌流将导致肾素-血管紧张素系统的激活，而肾素-血管紧张素系统的慢性上调与心血管死亡率的增加有关。因此，这项先导性研究的目的是确定在呼吸肌麻痹和交感心血管控制受损的人类模型中，被诊断为OSA的四肢瘫痪患者在窒息事件期间的心输出量是否比神经功能正常的OSA患者表现出更大的下降。在这两组与OSA相关的急性血流动力学变化的背景下，并与第三组无OSA的四肢瘫痪患者进行比较，我们还将检查尿儿茶酚胺释放标志物(香草扁桃酸、去甲肾上腺素和去甲肾上腺素)以及血浆心房利钠因子水平的差异，心房利钠因子是心房拉伸的标志。这项先导性研究的第二个目标将是调查四肢瘫痪和阻塞性睡眠呼吸暂停综合征患者与无阻塞性睡眠呼吸暂停综合征患者相比，夜间血浆肾素和血清醛固酮浓度是否存在差异。一项探索性的目标将是确定与没有OSA的人相比，反复呼吸暂停引起的低氧血症是否会导致OSA患者血管炎症标记物，特别是高敏C反应蛋白和白细胞介素6的升高。 公共卫生相关性： 拟议工作与退伍军人患者护理任务的相关性促进更好地了解困扰脊髓损伤退伍军人的常见医疗条件以及如何最好地治疗他们，最终目标是改善这些人的生活质量，这与退伍军人患者护理任务高度相关。调查四肢瘫痪患者睡眠期间与反复阻塞性呼吸暂停相关的急性心血管事件是了解OSA在这一人群中的血流动力学和潜在有害后果的必要的第一步。基于这一试点调查的初步数据的后续调查是全面功绩审查的基础，将着眼于在初步观察的基础上扩大调查范围并评估治疗效果，这方面的情况知之甚少[10，35，79，79]。

DESCRIPTION (provided by applicant): Screening studies suggest that the prevalence of moderate to severe obstructive sleep apnea (OSA) in persons with tetraplegia ranges from 22% to 36%, thus greatly exceeding prevalence estimates of 9.1% in men and 4% in women encountered in the general population. Recent evidence indicates that untreated OSA carries increased risk for the development of hypertension, myocardial infarction, and stroke. The prevailing mechanism felt to underlie the association between OSA and adverse cardiovascular sequellae is heightened sympathetic nervous system activity stemming from repetitive apneic events, although falls in cardiac output that accompany large negative intrathoracic pressure swings, and repetitive hypoxia/reoxygenation associated with oxidative stress and endothelial dysfunction have also been implicated. In contrast to neurologically intact persons, individuals with tetraplegia represent a model of sympathetic denervation characterized by relative bradycardia and low resting blood pressure. It is unknown whether OSA confers increased cardiovascular disease risk in these individuals, although the prevalence of cardiovascular disease and attributable mortality appear to be greater than that encountered in the general population. We suspect that obstructive sleep apnea complicating tetraplegia imposes significant hemodynamic stress due to falls in cardiac output during apneic events not arrested by catecholamine-induced chronotropic, inotropic, and vasopressor effects. Muscle paralysis and blunted hypercapnic ventilatory responsiveness in persons with tetraplegia, which are also normal rapid eye movement (REM) sleep phenomena, could predispose to greater apnea severity and potentiate falls in cardiac output similar to that observed during REM sleep in able-bodied persons, but will likely occur regardless of sleep stage. We also anticipate that falls in cardiac output and renal hypoperfusion will lead to activation of the renin-angiotensin system, the chronic up- regulation of which has been associated with increased cardiovascular mortality. The purpose of this pilot investigation is therefore to determine in a human model of respiratory muscle paralysis and impaired sympathetic cardiovascular control whether persons with tetraplegia diagnosed with OSA manifest greater decreases in cardiac output during apneic events than that witnessed in neurologically intact individuals with OSA. In the context of the acute hemodynamic changes associated with OSA in these two groups, and in comparison to a third group of subjects with tetraplegia without OSA, we will also examine differences in urinary markers of catecholamine release (vanillyl mandelic acid, metanephrines and normetanephrine), and in plasma levels of atrial natriuretic factor, a marker of atrial stretch. A secondary objective of this pilot investigation will be to investigate whether nocturnal plasma renin and serum aldosterone concentrations differ among individuals with tetraplegia and OSA compared to their counterparts without OSA. An exploratory aim will be to determine if hypoxemia stemming from repetitive apneas leads to elevation in markers of vascular inflammation, specifically high sensitivity C-reactive protein and interleukin-6, in individuals with OSA compared to those without OSA. PUBLIC HEALTH RELEVANCE: Relevance of the Proposed Work to the VA Patient Care Mission Fostering a better understanding of the common medical conditions that beset veterans with SCI and how best to treat them, with the ultimate goal of improving quality of life for these individuals is highly relevant to the VA Patient Care Mission. Investigation of the acute cardiovascular events associated with repetitive obstructive apneas during sleep in persons with tetraplegia is a necessary first step toward gaining an understanding of the hemodynamic and potentially deleterious consequences of OSA in this population. Subsequent investigations based upon preliminary data from this pilot investigation, forming the basis for a full Merit Review, would be geared toward expanding upon initial observations and evaluating treatment effects, of which little is known [10, 35, 79, 79].