CARDIOVASCULAR STRESS OF SLEEP APNEA AND HEART FAILURE

描述(由申请人提供)： 睡眠呼吸暂停是一种常见的疾病，与心血管疾病的风险增加有关，在心力衰竭患者中尤其普遍。在出现心力衰竭的情况下，睡眠呼吸暂停的心血管风险可能会放大，因为每种疾病都会加剧另一种疾病。这项建议研究了睡眠呼吸暂停和心力衰竭之间的相互关系，以及当两者相互作用时导致心血管压力的机制。我们的建议是基于睡眠呼吸暂停会增加心血管压力，并进一步恶化心力衰竭患者的左心功能。我们的主要假设是，睡眠呼吸暂停和心力衰竭之间存在着相互作用，其中与睡眠相关的关键介质的紊乱会导致心血管应激的急性和慢性增加，并使左心功能恶化。为了验证这一假设，在人类和小鼠的睡眠呼吸暂停和心力衰竭模型上进行了实验。在特定的目标1和2中，将对心力衰竭患者进行夜间深入研究，以阐明睡眠呼吸暂停及其相关觉醒和低氧发作急剧增加心血管应激并长期维持心血管应激的机制。在特定的目标3和4中，对慢性间歇性和睡眠诱导低氧的新型小鼠模型的研究将检查睡眠呼吸暂停和心力衰竭在心脏和中枢神经系统水平上相互作用的机制。这种潜在的有害相互作用将通过评估以下方面的反应来探索：(A)心血管应激的新介质(反应氧、细胞因子、瘦素和胰岛素)，(B)急、慢性心血管应激的重要生物标记物(B型利钠肽，BNP)，(C)心脏组织，以及(D)心脏和中枢神经系统的基因表达。该研究计划将阐明导致心力衰竭患者心血管发病率和死亡率过高的新机制，并提供检测、监测和治疗心力衰竭患者睡眠呼吸暂停的新方法。

DESCRIPTION (provided by applicant): Sleep apnea is a common disorder associated with an increased risk of cardiovascular disease, and is particularly prevalent in heart failure patients. The cardiovascular risk of sleep apnea is likely to be amplified in the presence of heart failure since each disorder can aggravate the other. This proposal examines the interrelationship between sleep apnea and heart failure, and the mechanisms leading to cardiovascular stress when the two interact. Our proposal is predicated on the notion that sleep apnea increases cardiovascular stress, and further worsens left ventricular function in heart failure patients. Our major hypothesis is that a reciprocal interaction exists between sleep apnea and heart failure, wherein sleep-related disturbances in key mediators lead to acute and chronic increases in cardiovascular stress and worsening left ventricular function. To test this hypothesis, experiments are proposed in humans and murine models of sleep apnea and heart failure. In Specific Aims 1 and 2, heart failure patients will be intensively studied nocturnally to elucidate the mechanisms by which sleep apnea and its associated arousals and hypoxemic episodes increase cardiovascular stress acutely and perpetuate cardiovascular stress chronically. In Specific Aims 3 and 4, studies in novel murine models of chronic intermittent and sleep-induced hypoxia will examine the mechanisms in which sleep apnea and heart failure interact at the cardiac and central nervous system level. This potentially harmful interaction will be explored by assessing responses in: (a) novel mediators of cardiovascular stress (reactive oxygen species, cytokines, leptin, and insulin), (b) an important biomarker of acute and chronic cardiovascular stress (B-type natriuretic peptide, BNP), (c) cardiac tissue, and in (d) cardiac and CNS gene expression. The research plan will elucidate new mechanisms causing excess cardiovascular morbidity and mortality in heart failure, as well as provide new approaches to detect, monitor and treat sleep apnea in heart failure patients.