SDB and Multiple Organ Impairment 睡眠呼吸障碍和多器官损害 Dr. Glenn Richards Chief Medical Officer ResMed

睡眠呼吸障碍疾病在心血管疾病和代谢性疾病中的严重性 Question 问题 Why is Sleep Disordered Breathing (SDB) important in Cardiovascular and Metabolic Diseases? 睡眠呼吸障碍疾病在心血管疾病和代谢性疾病中的严重性 Cardiovascular and metabolic consequences of SDB 睡眠呼吸障碍的心血管和代谢方面的后果

Sleep apnea prevalence 睡眠呼吸暂停患病率 80% Logan et al. J. Hypertension 2001 70% Einhorn et al. Endocrine Prac 2007 50% Javaheri et al. Circulation 1999 耐药性高血压：三种和三种以上类型的服药（不同作用机制药物）收缩压高于130，舒张压高于90 房颤：心房纤颤，心室没跳心房先跳 50% Somers et al. Circulation 2004 Sjostrom et al. Thorax 2002 35% Schafer et al. Cardiology 1999 30% Sanner et al. Clin Cardiology 2001 30%

Physiological consequences of sleep apnea 睡眠呼吸暂停对机体的影响 Increase in blood pressure 血压增加 Plunging blood oxygen Saturation 血氧饱和度下降 Apnea Surge in sympathetic nerve activity 交感神经兴奋性激活 Negative swings in intra-thoracic Pressure 胸内负压 Sudden changes at apnea termination cause an increase in stroke volume, heart rate and cardiac output, under hypoxic conditions, into a constricted arterial system. 呼吸暂停的停止的突然改变会导致在低氧的情况下，心搏量、心率和心输出量的增加，并流入一个收缩的动脉系统。 Cyclical surges of BP.循环系统血压增加 Sleep resumes rapidly and pharyngeal collapse recurs.睡眠很快恢复并且咽部塌陷再次发生 胸腔内压力：食道里测量胸腔压力。吸气动力 SNA交感神经活跃性 随气流减弱，血样饱和度下降延迟。 Morgan et al., 1996 Sleep

Becker hypertension graph Becker et al Circulation 2003;107:74-80. 5 SDB and cardiovascular disease © ResMed 03 09

OSA causes systemic inflammation OSA导致系统的炎症反应

OSA increases sympathetic nervous system activity OSA增加交感神经兴奋型 Narkiewicz et al 1998

SDB and CVD 睡眠呼吸障碍与心血管疾病 血氧不足 胸内压 复氧 觉醒 血碳酸过多症 睡眠剥夺 阻塞性睡眠呼吸暂停 1.相关情况出现 2.交感神经激活：缺氧 3.代谢失调：洋气波动 4左心房增大：胸内呀影响，回心血量增多 5内皮功能紊乱：造成血管内表皮损伤，大分子（葡萄糖）会卡在损伤处，形成血栓。与炎症反应有关 6血凝过快：红细胞增多造成：缺氧，人在缺氧情况下产生更多载氧红细胞。 7高血压：肺部：胸腔内牙压力下，肺部血管受到外力影响。会使肺的渗透性增强 8心衰和心率失常 9肾功能：血流速度增加，血液粘稠，肾过滤频率增大，衰老速度比正常快 10 中锋，心肌梗死：血管阻塞：血管壁变窄，血栓形成（炎症反应） 内皮功能紊乱 交感神经激活 代谢失调 系统性炎症 病发机理 血凝过快 左心房增大 全身性 高血压 肾功能障碍 肺部的 心衰 相关心血管疾病 中风 心律失常 心肌梗死 心脏性猝死 Somers et al., Circulation 2008

Cardiovascular disease continuum 心血管疾病事件链 冠脉血栓形成 心肌梗死 心肌缺血 心率失常/心肌缺损 1高压冲击高分子渗透内壁动脉粥样硬化;左心室射血力量增大左心室肥大 2动脉粥样硬化越硬每次运输血越少，心脏越大越没劲心肌缺血，血栓形成心肌梗死、心律失常、新机缺损 左心室增大，右心室接受血液，变大 心室扩大 动脉粥样硬化/左室肥大 充血性心力衰竭 高血压 Sympathetic activity Inflammation 心脏疾病终末期 Adapted from Dzau et al, 2006 Circulation

Effects of CPAP CPAP的影响 CPAP reverses the hypertension, sympathetic activity and inflammation associated with OSA CPAP治疗可逆转与OSA相关的高血压，交感神经活性和炎症反应

Long term fatal and non-fatal CVS events 长期致死和非致死心血管事件 对照组 打鼾 中度OSAH 重度OSAH CPAP治疗的OSAH 对照组 打鼾 中度OSAH 重度OSAH CPAP治疗的OSAH In men, severe OSAH significantly increases the risk of fatal and non-fatal cardiovascular events (myocardial infarction, stroke, coronary artery bypass surgery, coronary angiography). 在男性中，严重OSA显著增加致死和非致死心血管事件（心肌缺血、中风、冠状动脉搭桥术、冠脉照影术） 累计的发生率 经过治疗的发病率和对照组及打鼾趋势相似 致死性心血管事件累积发病率 非致死性心血管事件累积发病率 Marin et al., 2005 Lancet

Risk factors for co-morbidities 并发症的危险因素 Cardiovascular Disease 心血管疾病 Hyperlipidemia高脂血症 Hypertension高血压 Metabolic Syndrome/ Diabetes 代谢综合征/糖尿病 OSA促进心血管疾病原因之一 Obesity 肥胖 OSA 阻塞性睡眠呼吸暂停综合症

Incidence AF and OSA 房颤的发生率和OSA 房颤的累积频率 随时渐增长，OSA出现房颤增高 年 Gami et al., 2007 J Am Coll Cardiol

Prevalence of OSA in AF OSA患者中房颤的发病率 Prospective study of elective cardioversion for AF (151) vs 312 without AF referred to cardiology practice. OSA diagnosed by Berlin questionnaire. 49% of AF patients vs 32% of general patients. Gami et al Circulation 2004

Type of SDB in stable CHF 稳定期充血性心力衰竭患者的睡眠呼吸障碍类型 表1：在近期（2006-2007）的收缩性心力衰竭前瞻性研究中的睡眠暂停的流行情况 心衰患者出现CSA比OSA多 Levy P et al, Sleep Med Clin 2 (2007) 615–621 Differences in scoring criteria may explain the disparity. 评分标准的差异可能解释不一致性

CSA & Mortality 中枢性睡眠呼吸暂停与病死率 n=32 AHI<5 AHI>=5 存活率 CSA存活率低 n=56 月 Javaheri et. al; JACC 2007

Does treating OSA make a difference?

Effect of CPAP on LV Function CPAP对射血分数的影响 24 patients with stable CHF and OSA randomized to a month of CPAP treatment or medical treatment.No changes in the control group but significant reductions in BP, heart rate, LVESD and increased LVEF (25 vs 33) Kaneko et al NEJM 2003 348; 1233-41 18 SDB and cardiovascular disease © ResMed 03 09

Improved Survival With CPAP CPAP对生存率的改善 n = 64 Sin et al. Circulation 2000 19 SDB and cardiovascular disease © ResMed 03 09

Does treating CSA really make a difference? 治疗中枢性睡眠呼吸暂停会产生不同结果吗？

CANPAP 一项加拿大组织的CPAP治疗CSA和心衰研究 Primary Endpoint: heart transplant-free survival 一项加拿大组织的CPAP治疗CSA和心衰研究 初级研究终点：非心脏移植的生存率 CPAP有收益但并无不同 21 Bradley, T. et al. N Engl J Med 2005;353:2025-2033

CANPAP 加拿大CPAP实验 Arzt M et al. Circulation 2007; 115: 3173-80 Unadjusted P = 0.043 必须有效控制CSA才可以 Arzt M et al. Circulation 2007; 115: 3173-80

Treatment Effects on CSA 中枢性睡眠呼吸暂停治疗效果 H. Teschler et al., AJRCCM 2001;164:614-9

AutoSet CS improves heart failure severity AutoSet CS改善心衰的严重程度 * BNP ASV ASV提高了 CPAP下降 CPAP C. Philippe et al., Heart 2006;92:337 Pepperal et al Am J Respir Crit Care Med 2003 24

SERVE-HF Trial Study completion May 2015 将在1月份完成 Treatment of sleep-disordered breathing with predominant central sleep apnoea by adaptive servo ventilation in patients with heart failure 应用适应性伺服通气（ASV）治疗心衰伴优势中枢性睡眠呼吸暂停的睡眠呼吸紊乱 Randomised, multi-centre, international trial 随机多中心国际研究 Randomised 1:1 to control (optimal medical management) or active treatment (optimal medical treatment + use of adaptive servoventilation) 随机1:1对照（恰当医疗处置）或主动治疗（恰当医疗处置+ASV） Event driven, with 1,350 patients randomised 事件驱动型研究，大约有1,260病人将纳入随机研究 Minimum of 24 months follow-up 至少24个月随访 Enrollment complete 注册已完成 Study completion May 2015 将在1月份完成 25

Patient Demographics and Clinical Characteristics 患者的人口学和临床特征 5605 Age years 年龄 67 ± 11 BMI kg/m2 28.5 ± 5.1 Male gender 男性(%) 4416 (78.8) LVEF 左室射血分数 % 33.4 ± 8.1 NYHA 纽约心脏病分级 ≥ III (%) 3852 (68.7) Atrial fibrillation 房颤 (%) 1382 (24.9) Ischemic etiology 缺血性心衰 (%) 2893 (51.6) AHI 1/h 18.0 ± 15.8 ODI 1/h 16.5 ± 23.2 Mean SpO2 % 92.5 ± 5.1 Min SpO2 % 81.3 ± 7.5

Demographic and Clinical Characteristics 患者的人口学和临床特征 AHI <15/h AHI ≥15/h N (%) 2977 (53) 2628 (47) Age years年龄 65 ± 12 68 ± 10 * BMI kg/m2 28.1 ± 4.9 29.0 ± 5.2 * Male gender (%)男性 2231 (75) 2185 (83) * LVEF %左心室射血分数 33.7 ± 8.0 33.0 ± 8.2 * NYHA ≥ III (%)纽约心脏病 分级 1977 (66) 1875 (71) * Atrial fibrillation (%)房颤 616 (21) 766 (29) * Ischemic etiology (%)缺 血性心衰 1513 (51) 1380 (53) AHI 1/h 6.5 ± 4.0 31.1 ± 13.8 * ODI 1/h 8.4 ± 19.7 25.7 ± 23.5 * Mean SpO2 % 92.8 ± 5.0 92.1 ± 5.2 * Min SpO2 % 82.9 ± 7.1 79.4 ± 7.4 * *p<0.05

SDB Prevalence by Gender and Age SBD的性别和年龄流行病学 Age-dependence of SDB, adjusted for all risk factors in the model. 年龄相关SDB，调整为所有危险因子的模型

CSA prevalence increases with worsening systolic function SchlaHF registry: PSG data CSA prevalence increases with worsening systolic function and increasing NYHA

Gheorghiardi 说：改善出院后的结果（死亡率和再入院率）是AHFS 治疗最重要的目标 Acute Heart Failure- Readmission rate and late mortality 急性心衰再住院率和晚期死亡率 Mortality at 90 days 5-15% 90天死亡率 5-15% Readmission at 90 days 30% 90天再住院率 30% No change in recent times 无变化 Poor correlation with effective treatment of “congestion” 与有效治疗“充血”的关联差 “Improving post discharge outcomes (mortality and readmission) is the most important goal in AHFS.” Gheorghiardi Gheorghiardi 说：改善出院后的结果（死亡率和再入院率）是AHFS 治疗最重要的目标

80% had SDB (AHI>15), of whom 75% had CSA SDB in AHF 急性心衰患者的SDB 急性左心室功能衰竭和治疗超过2月患者睡眠暂停的高流行和持续 80% had SDB (AHI>15), of whom 75% had CSA 80%患有SDB（ AHI>15 ），其中75%患有中枢性睡眠呼吸暂停

Does SDB resolve in 3 months SDB能在3个月内解决吗 No – there is remarkably little change despite considerable clinical improvement in HF 不 – 尽管心衰的临床状况有相当改善，但是SDB显然变化很小

失代偿心衰住院患者在院内的睡眠障碍呼吸测试：报告流行和病例特征 SDB in AHF 急性心衰患者的SDB 临床调查 失代偿心衰住院患者在院内的睡眠障碍呼吸测试：报告流行和病例特征

Study flow and results 研究流程和结果 LVEF mean 33% 左室射血分数平均33% SDB defined as AHI > 15 SDB定义为AHI > 15

Khayat R, J Card Fail. 2012 Jul;18(7):534-40. CONCLUSION: Central sleep apnea is a predictor of cardiac readmission in hospitalized patients with systolic heart failure. 中枢性睡眠呼吸暂停收缩性心衰住院患者因心脏病再住院的预测因子 Khayat R, J Card Fail. 2012 Jul;18(7):534-40. CONCLUSION: In this first evaluation of the impact of SDB on cardiac readmissions in heart failure, CSA was an independent risk factor for 6 months‘ cardiac readmissions. The effect size of CSA exceeded that of all known predictors of heart failure readmissions. 结论： 在这个首次评价SDB对心衰患者因心脏病再入院的影响研究中，CSA是6个月因心脏病再入院率的独立危险因子。CSA的影响作用超过了所有已知的心衰再入院预测因子。

AutoSet CS in Acute Heart Failure AutoSet CS治疗急性心力衰竭 RCT of AutoSet CS applied during an acute admission with CHF AutoSet CS在心衰急性发作时应用的随机控制试验 Any form of SDB (OSA,CSA or mixed) 所有类型的SDB Primary endpoints are readmission and exercise tolerance at 6 months 6个月内再入院率和运动耐受是研究初级终点 International multicentre trial of 200 patients 200例患者的国际多中心试验 Completion 2016 完成

Obesity and the Metabolic Syndrome 肥胖症与代谢综合征

“Diabetes is a public health emergency in slow motion” The Diabetes Epidemic “Diabetes is a public health emergency in slow motion” 糖尿病是缓慢发展的影响公共健康的非常问题 Ban Ki-Moon, UN Secretary-General

Diabetes prevalence: 2010 糖尿病发病率2010年

Diabetes prevalence: 2030 糖尿病患病率2030年

OSA and T2DM: Wisconsin sleep cohort study OSA和II型糖尿病：维斯康星睡眠队列研究 Odd Ratios for Incident Type 2 Diabetes 伴发糖尿病的比值比 Odds Ratio 95% Confidence Interval可信区间 p-value P值 Adjusted for sex and age 校正性别和年龄 AHI 5 – 15 vs AHI < 5 AHI > 15 vs AHI < 5 2.81 4.06 1.51 – 5.23 1.86 – 8.85 0.001 0.0004 Reichmuth et al., 2005 AJRCCM

Potential mechanisms 可能的机理 睡眠呼吸暂停 间断低氧血症 睡眠片段化 皮质性激素导致儿茶酚胺增加 活性氧导致衰老 白介素6增加细胞坏死的几率 瘦素：来自胰岛，会感觉饥饿，岁饭量的摄入，瘦素迅速下降脂肪因子上升饱腹感 缺氧本身导致胰岛损伤；化学刺激抵抗 交感神经活性增强 儿茶酚安增加 肾上腺轴改变 皮质醇增加 氧化应激 活性氧增加 脂类因子改变 瘦素增加 脂肪因子下降 炎性通路激活 白介素-6 肿瘤坏死因子增加 胰岛素抵抗/胰腺B细胞功能失常 葡萄糖耐受不良/II型糖尿病 Adapted from Punjabi et al, 2005 J Appl Physiol

OSA and Insulin Resistance OSA和胰岛素抵抗 Hui et al 2002

CPAP improves insulin sensitivity CPAP提高胰岛素敏感性 Improvement of insulin sensitivity index (ISI) after onset CPAP treatment in 31 patients 31例患者在使用CPAP治疗后改善胰岛素敏感指数 胰岛素敏感性越高越好 Insulin resistance is when more insulin than normal is required to get the same response in lowering blood glucose. Insulin resistance is a pre-diabetic state. When pancreas can’t produce enough insulin to get normal response, blood glucose then rises and you have type 2 diabetes. 胰岛素抵抗就是要到达相同的降低血糖水平效果需要更多的胰岛素，是糖尿病之前的阶段。当胰腺不能生成足够的胰岛素来获得正常的效果时，血糖升高，II糖尿病产生。 Harsh et al, 2004 AJRCCM

GLYCOSA Trial 糖尿病和OSA有关的试验 Multicentre randomised study of CPAP vs standard medical care in Type 2 diabetics with OSA 合并OSA的二型糖尿病患者CPAP的多中心随机研究对比标准的医疗护理的研究 Australia and USA at 9 sites with 230 patients randomised 澳大利亚和美国9个中心230位患者随机研究 6 months follow up 6个月的随访时间 Primary outcomes are HbA1c and 24 hour BP 主要研究目标为糖化血红蛋白和24小时血压 Publication results 2014 结果将于2014年发表

Diabetic retinopathy 糖尿病视网膜病变 Retinal cells are very susceptible to hypoxia 视网膜细胞极易受低氧影响 OSA causes recurrent hypoxia OSA导致反复低氧 High prevalence of OSA in diabetics with retinopathy 糖尿病伴视网膜病变人群OSA发病率高 Retinopathy significantly worse with OSA 伴有OSA 时视网膜病变明显恶化 OSA independent predictor of retinopathy OSA是视网膜病变独立预警因素 West et al 2010 showed retinopathy significantly worse in diabetics with OSA and that OSA was an independent significant predictor of retinopathy. West et al., 2010 Diabetic Med.

Conclusions 结论 CARDIOVASCULAR 心血管病 SDB is very common in cardiovascular diseases SDB在心血管疾病中非常普遍 Assessment of SDB is becoming routine part of the management cardiology patients 评估SDB-快速成为常规的管理心血管病患者的一部分 DIABETES 糖尿病 OSA and type 2 diabetes frequently coexist OSA和II型糖尿病常共存 Accumulating evidence that OSA impairs glucose metabolism 越来越多证据表明OSA严重影响糖代谢 Increasing awareness of the relationships between OSA and metabolic syndrome 增加OSA和代谢综合征之间关系的意识 SDB management is becoming part of the treatment of common chronic diseases.