OSAS 与动脉粥样硬化

OSAS相关动脉粥样硬化 氧化应激与慢性炎症学说 血管内皮损伤 脂蛋白的氧化修饰 胰岛素抵抗

Evidence of early atherosclerotic development

动脉粥样硬化与炎症 炎症反应在AS的发病机制中起着重要的作用。 C-反应蛋是应答于炎症白由肝脏合成的细胞因子，也是发生糖尿病和心血管疾病危险预测因子。

Activation of inflammatory pathways in OSA Serum levels CRP IL-6 P<0.0001 P<0.0001 mg/dL pg/ml 0.6 3.0 0.5 0.4 2.0 0.3 0.2 1.0 Spontaneous IL-6 production by monocytes. 24h culture 0.1 0.0 0.0 Before nCPAP Before nCPAP Yokoe et al. Circulation 2003;107:1129-34

C-反应蛋白 存在于动脉粥样硬化的斑块中； 促进炎症介导的细胞因子的分泌； 促进内皮细胞黏附因子的表达； 通过巨噬细胞摄取LDL，形成泡沫细胞。

C-反应蛋白在动脉粥样硬化形成中的作用 CRP Entering plaques Activation of complement system Stimulate monocytes Inhibition of iNOs Stimulate MP in plaques Stimulate endothelium Release of cytokin Secretion of inflammatory factor, cellular adhesion factor…… Untake of LDL Endothelial dysfunction 此处是否可以同过不同的颜色来设置某种元素的变化，比如黄色警告，红色出现不好的情况() foam cell Inflammatory effects atherosclerosis

Effects of CPAP on CRP and IL6 in OSA

TNF-α 与 OSAS 促进TNF-α 生成的TNF- α (-308A) 的基因多态性在OSAS患者中更为常见 (Riha, ERJ 2005). OSAS患者存在T淋巴细胞被激活伴有TNF- α 生成增加和对血管内皮的细胞毒性，该作用可被CPAP治疗所缓解。 (Dyugovskaya, Ann NY Acad Sci 2005).

OSAS 患者单核细胞生成 TNF-a 增加 Minoguchi, Chest 2004. CPAP治疗1月后TNF-a 水平下降

Disturbed coagulation TNF-α在动脉粥样硬化形成中的作用 TNF-a NFB Activation of LC, N, Plt, EC Adhesion molecule expression Inducing cellular apoptosis MC MP Inflammatory factors Disturbed coagulation and fibrolysis Uptake of LDL Endothelial dysfunction 此处是否可以同过不同的颜色来设置某种元素的变化，比如黄色警告，红色出现不好的情况() Endothelial damage foam cell atherosclerosis

Serum level of tumour necrosis factor-alpha in controls and OSAS patients. Ryan, Circulation 2005; 112:2660-2667. Controls OSAS OSAS 6 weeks on CPAP 1.00 2.00 3.00 4.00 TNF alpha in pg/ml p<0.001 p=0.002

Effects of CPAP on circulating ICAM-1 and IL-8 levels. *P<0.05 Elevated ICAM-1and IL-8 levels in OSAS and response to CPAP; Ohga JAP 2003. Effects of CPAP on circulating ICAM-1 and IL-8 levels. *P<0.05

OSAS患者血浆 IL-18 与 AHI的相关性 R=0.865 P<0.001

提示 以上资料提示OSAS的间歇性缺氧通过机体对其的适应性途径产生选择性炎症反应，该反应为OSAS患者发生心血管疾病提供了潜在的分子机制，因为这些炎症反应正是产生动脉粥样硬化的前提。

血管内皮功能紊乱 血管内皮功能受以下因素调节： 血管活性或炎症介质 胰岛素抵抗 氧化的脂质 依赖内皮的血管舒张受内皮分泌的NO调节 临床上反映血管内皮功能紊乱的内皮依赖血管舒张功能紊乱往往是动脉粥样硬化的先兆和心血管疾病的预告。

Impaired ACh-induced dilation was caused by bioavailability  of nitric oxide NORM IH Phillips, et al. Am J Physiol 286:H388-H393, 2004 19

Circulating Nitric Oxide in OSA 20 40 60 80 100 120 OSA Control Serum Nitrites & Nitrates (µM) N= 30 N= 40 P=0.015 10 20 30 40 50 60 70 80 90 Baseline Post CPAP Serum Nitrites & Nitrates (µM) p = 0.01 N=22 Ip M et al. Am J Resp Crit Care Med 2000 Decreased plasma nitrites/ nitrates in 21 OSA patients compared with healthy/ morbidity-matched controls. Increased with CPAP for 2 days & 5.5 months. Schulz et al. Thorax 2000

Chronic IH blunted hypoxic vasodilation PO2=40 mmHg * NORM IH Phillips, et al. Am J Physiol 286:H388-H393, 2004

In vivo allopurinol treatment prevents IH-induced endothelial dysfunction NORMOXIA HYPOXIA NORMOXIA HYPOXIA Veh Allo … therefore, xanthine oxidase is a potential source of superoxide

2 weeks of IH increased the amount of “new” collagen in medial layer NORM * CIH IH

OSAS患者的血管内皮功能紊乱是可逆转的 28 OSA, 12 controls FMD + Doppler, NTG-induced dilatation n.s., CPAP 4w and W-D 1w n=40, r=-0.655, p<=.001 Ip M et al. AJRCCM 2004;169:348

颈动脉内-中膜厚度(IMT)与OSAS程度的关系 Compare with control，**P<0.01; Compare with mild OSAHS group，△△P<0.01

OSAS患者的循环 VEGF 水平增高 Gozal, Sleep 2002. Open circles are adults and closed squares are children. The relationship for both are highly significant; r =0.83 and 0.81 respectively (P<0.001)

nmol O2- / 5x106 PMN, fMLP stimulated 中性粒细胞释放过氧化物 30 P<0.01 P<0.01 P<0.01 20 nmol O2- / 5x106 PMN, fMLP stimulated 10 Superoxide production leads to a rapid destruction of NO presumably due oxidative inactivation. Experimental evidence suggests that this mechanism may be of importance in the development of endothelial dysfunction in hypercholesterolemia and atherosclerosis. For instance the production of NO from hypercholesterolemic rabbit aorta in increased rather than impaired suggesting intact NOS. On the other hand, there is an increased production of superoxide anions in hypercholesterolemia which may account for the reduction of relaxations. SOD constitutes the protective mechanism whereby superoxide is inactivated. Schulz and coworkers investigated superoxide release from polymorphonuclear neutrophils after bacterial tripeptide fMLP before and after follow-up after CPAP (appr. 5/12). Två stimuleringsmedier fMLP och Ca ionophore mer effekt (skillnad) av den senare - antyder en mer ”uppströms förändring i signaleringskaskad” än förändring i själva leucocyte NADPH. This constitutes a mechanism which not only could explain the reduced NO dependent vasodilation but it could also provide a basis for a mechanism for accelerated development of atherosclerotic disease in OSA Control (n=10) OSA (n=18) OSA/CPAP (2 nights) OSA/CPAP (Follow-up) Schulz et al. AJRCCM 2000;162:566

OSA & Insulin Resistance Homeostasis model assessment (HOMA) Fasting glucose & insulin level HOMA-IR was independently associated with BMI /waist (p<0.001), AHI /minimum O2 saturation (p <0.05) Seen in both obese and non-obese subjects Ip et al. Am J Resp Crit Care Med 2001 1 2 3 4 5 6 7 8 9 10 11 12 13 14 AHI < 5 15 ≤AHI > 30 AHI ≥ 30 HOMA IR BMI = 24.4 BMI = 26.9 BMI = 28.4 BMI = 29.5 p < 0.01 5 ≤AHI > 15

OSAS患者的胰岛素抵抗 Vgontzas A. J Clin Endocrinol Metab 2000 OSAS患者的血浆胰岛素和血糖水平高于肥胖对照者 *P < 0.05.

胰岛素抵抗是代谢综合征发病的中心环节 胰岛素抵抗 高密度脂蛋白 代谢综合征 高血压 肥胖 高胰岛素血症 糖尿病 高甘油三酯血症 低密度脂蛋白 血液高凝状态 胰岛素抵抗 代谢综合征 Interrelation Between Atherosclerosis and Insulin Resistance Insulin resistance is associated with a panoply of abnormalities, including hypertension, hyperinsulinemia, hypertriglyceridemia with small, dense low-density lipoprotein (LDL) and low high-density lipoprotein (HDL), and hypercoagulability. Of course, insulin resistance is a major risk factor for the development of diabetes. Obesity plays a role both in exacerbating insulin resistance and as an independent risk factor for atherosclerosis. Therefore, any patient with insulin resistance has numerous reasons to be at very high risk for atherosclerosis.

OSAS导致胰岛素抵抗的可能机制 OSAS 睡眠呼吸紊乱 （睡眠暂停 低通气） 细胞因子 （IL-6，TNF-α） 生长激素细胞 功能受损 高碳酸血症 低氧血症 化学感受器 有氧酵解 无氧酵解 生长激素缺乏 胰岛β细胞 内ATP生成 交感神经兴奋 胰岛素抵抗 此处是否可以同过不同的颜色来设置某种元素的变化，比如黄色警告，红色出现不好的情况() 乳酸 胰岛素分泌 儿茶酚胺 肝糖元释放 血 糖

CPAP 治疗改善OSAS患者的胰岛素敏感性 Harsch AJRCCM 2004 Insulin sensitivity index (ISI) at baseline, 2 days, and 3 months after onset of continuous positive airway pressure (CPAP) treatment in 31 patients.

OSAS患者发生脂质过氧化 Lavie L et al. Sleep 2004;27:123 114 participants, 30 controls, 55 OSA – CVD, 59 OSA + CVD TBARS – Thiobarbituric reactive substances (lipid peroxidation) PD – Peroxides (lipid peroxidation) PON1 – Paraxonase-1 (Esterase that protects LDL and HDL against lipid peroxidation) (TBARS and PD reversible by CPAP) Lavie L et al. Sleep 2004;27:123

Statistical comparison adjusted for age, gender, and BMI HDL dysfunction in OSA 2000 4000 6000 8000 10000 12000 OSA Control HDL dysfunction p < 0.01 15 30 45 60 75 Oxidized LDL (µ/L) P < 0.05 N=128 N=82 Statistical comparison adjusted for age, gender, and BMI AHI r = 0.51 p < 0.001 8-isoprostane (Ln) r = 0.22 p < 0.01 CRP r = 0.24 Tan K et al. Atherosclerosis 2006

Obstructive Sleep Apnea Sleep fragmentation/ Sleep Deprivation OSA, Metabolism, Atherosclerosis(AS) and coronary heart disease (CHD) Obstructive Sleep Apnea Type 2 diabetes Intermittent hypoxia Sleep fragmentation/ Sleep Deprivation Obesity Neurohumoral changes Oxidative Stress Insulin Resistance Metabolic syndrome @ Sleep loss in the absence of OSA may promote insulin resistance @ Sleep disruption by frequent arousals, as occurs in OSA, is likely to result in an ever accumulating sleep debt @ Feed forward cascade of negative effects maybe generated by the interaction between OSA and accompanying sleep debt to not only worsen the sleep disorder it self but also contribute to the development of insulin resistance, further weight gain and diabetes. @ Sleep curtailment in western societies…… It is likely that the prevalence and severity of SDB are increased by chronic sleep curtailment ….. Dyslipidemia Inflammation Hypertension AS & CHD Tasali & Ip, Proceedings of Am Thoracic Soc 2008

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