Basis of sex-specific therapeutic responses to obstructive sleep apnea: Oxidative stress, inflammation, and vascular function

阻塞性睡眠呼吸暂停的性别特异性治疗反应的基础：氧化应激、炎症和血管功能

• 批准号: 10930195
• 负责人: Rashmi Nisha Aurora
• 金额: $ 75.74万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10930195
• 关键词: Acetylcysteine; Acute; Address; Adherence; Age; Antioxidants; Arousal; Biological Availability; Biological Markers; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Data; Development; Devices; Diabetes Mellitus; Early identification; Elderly; Estrogen decline; Estrogens; Functional disorder; Glutathione; Glutathione Disulfide; Health; Hypertension; Hypoxemia; Inflammation; Inflammatory; Interleukin-6; Isoprostanes; Life; Measures; Monitor; Morbidity - disease rate; Nitrates; Nitric Oxide; Nitrites; Non-Insulin-Dependent Diabetes Mellitus; Obstructive Sleep Apnea; Outcome Measure; Oxidative Stress; Oxidative Stress Induction; Participant; Pathway interactions; Patients; Placebos; Population; Prevalence; Prevention; Public Health; Randomized; Recurrence; Risk; Risk Factors; Sampling; Sex Differences; Sleep; Source; System; TNF gene; Vascular Diseases; Vascular System; Vulnerable Populations; Woman; age related; aged; antioxidant therapy; cardiovascular risk factor; comorbidity; endothelial dysfunction; human old age (65+); improved; improved outcome; men; middle age; modifiable risk; mortality; novel; older women; positive airway pressure; prevent; primary outcome; sex; therapy adherence; treatment effect; treatment response

Project Summary The absolute number of cardiovascular-associated deaths in women exceed those in men. Key modifiable risk factors for cardiovascular disease (CVD) rise as women age, when CVD prevalence becomes higher compared with same-age men. The relatively abrupt, age-related reduction in estrogen — which had previously served as a major antioxidant defense system—may be why. Compared with men (in whom greater early-life, ongoing oxidative stress may serve as a compensatory adaptation as they age), women’s vascular systems may be more vulnerable to this sharp rise in acute oxidative stress. One highly prevalent source of oxidative stress is obstructive sleep apnea (OSA), which is associated with incident hypertension, CVD, and diabetes. OSA’s intermittent hypoxemia and recurrent arousals cause deleterious health effects via oxidative stress, which triggers inflammation-related decreases in nitric oxide bioavailability. Thus, oxidative stress is considered a key intermediary through which OSA promotes vascular dysfunction. Even without OSA, middle-aged and older women have worse vascular function than do age-matched men. Critically, OSA prevalence also rises sharply as women age, suggesting sex-based pathophysiology. Our team’s preliminary data suggest sex-specific differences in oxidative stress and vascular dysfunction in middle-aged and older women with OSA, as evidenced by higher post-sleep nitrate levels and worse endothelial dysfunction compared with men; however, only women have improved glycemic measures after three months of positive airway pressure (PAP) therapy. This may indicate a sex-specific treatment effect on oxidative stress. Although it is the first line OSA treatment, a marked number of OSA patients do not meet minimum PAP therapy adherence requirements. Thus, N-acetylcysteine, a readily available, safe antioxidant may be a valuable, adjunct therapy for patients with OSA. To address these significant issues, we will study women and men (aged 50–75 years) with moderate-to-severe OSA and minimal, well-controlled comorbidities. Our primary objectives are to identify sex-specific differences in: a) the effects of OSA on overnight oxidative stress and inflammatory biomarkers; b) vascular function; and c) effects of PAP therapy plus N-acetylcysteine or placebo. Our overarching hypotheses are: 1) OSA differentially contributes to adverse cardiovascular consequences in middle-aged and older women compared with age-matched men via increased oxidative stress; 2) Women’s greater benefit from PAP therapy is due to their larger decline in overnight oxidative stress; and 3) Adjunctive therapy with a novel supplement helps prevent CVD morbidity from OSA. Given the staggering public health burden of CVD, targeting a treatable risk factor such as OSA in women presents a critical opportunity to markedly improve health in an enormous, vulnerable population. Mitigating OSA-induced oxidative stress with an accessible supplement—N-acetylcysteine—will be especially valuable for those who struggle with PAP use or have only partial improvement in oxidative stress with PAP therapy.

项目摘要 女性心血管相关死亡的绝对数超过男性。关键的可修改风险 心血管疾病(CVD)的因素随着女性年龄的增长而增加，与之相比，心血管疾病的患病率更高 和同龄男人在一起。雌激素的相对突然的、与年龄相关的下降--它以前是 一种主要的抗氧化剂防御系统--可能是原因。与男性相比(在男性中，更大的早期生活，正在进行 随着年龄的增长，氧化应激可能会起到补偿适应的作用)，女性的血管系统可能会 容易受到这种急性氧化应激的急剧上升的影响。氧化应激的一个非常普遍的来源是 阻塞性睡眠呼吸暂停(OSA)，与高血压、心血管疾病和糖尿病相关。OSA‘s 间歇性低氧血症和反复唤醒通过氧化应激导致有害的健康影响，这 引发炎症相关的一氧化氮生物利用度下降。因此，氧化应激被认为是一个关键 阻塞性睡眠呼吸暂停综合征促进血管功能障碍的中介。即使没有OSA，中老年也是如此 女性的血管功能比同龄男性差。关键的是，阻塞性睡眠呼吸暂停综合症的患病率也急剧上升 随着女性年龄的增长，这表明了基于性别的病理生理学。我们团队的初步数据表明 中老年阻塞性睡眠呼吸暂停综合征患者氧化应激和血管功能障碍的差异 与男性相比，睡眠后硝酸盐水平更高，内皮功能障碍更严重；然而，只有女性 在三个月的气道正压(PAP)治疗后，血糖测量有所改善。今年5月 表明针对氧化应激的特定性别的治疗效果。虽然这是一线阻塞性睡眠呼吸暂停治疗，但标志着 OSA患者的数量不符合最低PAP治疗依从性要求。因此，N-乙酰半胱氨酸，a 容易获得的、安全的抗氧化剂可能是阻塞性睡眠呼吸暂停综合征患者的一种有价值的辅助治疗方法。要解决这些问题 重大问题，我们将研究患有中到重度阻塞性睡眠呼吸暂停和轻度阻塞性睡眠呼吸暂停的女性和男性(50-75岁)， 控制良好的合并症。我们的主要目标是在以下方面确定性别差异：a) OSA对过夜氧化应激和炎性生物标志物的影响；b)血管功能；c)PAP的作用 治疗加N-乙酰半胱氨酸或安慰剂。我们的主要假设是：1)阻塞性睡眠呼吸暂停综合征对 与年龄匹配的男性相比，中老年女性的心血管不良后果 氧化应激增加；2)女性从PAP治疗中获得的更大好处是由于她们在 过夜氧化应激；以及3)辅以新的补充剂有助于预防心血管疾病的发病率 奥萨。鉴于心血管疾病令人震惊的公共卫生负担，针对女性OSA等可治疗的风险因素 这是一个重要的机会，可以显著改善庞大脆弱人口的健康状况。减轻 OSA诱导的氧化应激与一种可获得的补充-N-乙酰半胱氨酸-将特别有价值 那些与PAP作斗争的人使用PAP疗法或仅部分改善氧化应激。