Abstract
目的
评估心血管并发症出现前老年阻塞性睡眠呼吸暂停综合征（OSA）患者的心脏结构和功能改变及其影响因素。
方法
入选82名无心血管疾病的老年OSA患者，根据睡眠呼吸暂停低通气指数（AHI）分为轻度组（AHI < 15次/h）和中/重度组（AHI ≥ 15次/h）。记录患者人口统计学资料及一般基础资料，PSG监测结束的当天早上空腹状态下抽取静脉血，检测血常规与生化指标。在整夜多导睡眠监测完成1周内完成超声心动图检查，分析两组间心脏结构、功能及血生化指标等的差异。
结果
中重度OSA组患者血小板比积（0.22±0.08 vs 0.17±0.04，P=0.032）、血肌酐水平（70.94±27.88 vs 54.49±34.22，P=0.022）高于轻度OSA组。两组患者的左室射血分数、室间隔厚度、左室后壁厚度、左房内径、左室舒张末内径均无显著差别。两组二尖瓣舒张早期血流速度峰值（E）相似，但中重度OSA组的舒张晚期二尖瓣血流速度峰值（A）高于轻度OSA组（70.35±6.87 vs 64.09±8.31，P= 0.0001)，其E/A比值显著低于轻度OSA组（0.98±0.06 vs 1.08±0.05，P=0.0001）。多元线性回归显示，E/A比值与AHI呈负相关（β=-0.645，P=0.0001）。
结论
在没有高血压和任何其他心血管疾病的情况下，老年中重度OSA患者可出现心脏舒张功能受损，其程度与AHI正相关。
Keywords: 阻塞性睡眠呼吸暂停, 心脏舒张功能, 老年人, 低通气指数
Abstract
Objective
To evaluate the changes of cardiac structure and function and their risk factors in elderly patients with obstructive sleep apnea syndrome (OSA) without cardiovascular complications.
Methods
Eighty-two elderly OSA patients without cardiovascular disease admitted between January, 2015 and October, 2016 were enrolled in this study. According to their apnea-hypopnea index (AHI, calculated as the average number of episodes of apnoea and hypopnoea per hour of sleep), the patients were divided into mild OSA group (AHI < 15) and moderate to severe OSA group (AHI ≥ 15). The demographic data and the general clinical data were recorded and fasting blood samples were collected from the patients on the next morning following polysomnographic monitoring for blood cell analysis and biochemical examination. Echocardiography was performed within one week after overnight polysomnography, and the cardiac structure, cardiac function and biochemical indexes were compared between the two groups.
Results
Compared with those with mild OSA group, the patients with moderate to severe OSA had significantly higher hematocrit (0.22±0.08 vs 0.17±0.04, P=0.032) and serum creatinine level (70.94± 27.88 vs 54.49±34.22 μmol/L, P=0.022). The left ventricular ejection fraction, interventricular septal thickness, left ventricular posterior wall thickness, left atrial diameter and left ventricular end-diastolic diameter were all similar between the two groups. With a similar early diastolic mitral flow velocity (E) between the two groups, the patients with moderate to severe OSA had a significantly higher late diastolic mitral flow velocity (A) (70.35±6.87 vs 64.09±8.31, P=0.0001) and a significantly lower E/A ratio (0.98±0.06 vs 1.08±0.05, P=0.0001) than the patients with mild OSA. Multiple linear regression showed that the E/A ratio was negatively correlated with AHI (β =- 0.645, P=0.0001).
Conclusion
Cardiac diastolic function impairment may occur in elderly patients with moderate or severe OSA who do not have hypertension or other cardiovascular diseases, and the severity of the impairment is positively correlated with AHI.
Keywords: obstructive sleep apnea, cardiac diastolic function, elderly, apnea-hypopnea index
阻塞性睡眠呼吸暂停综合征（OSA）以睡眠期间上气道反复出现完全阻塞（呼吸暂停）或部分阻塞（低通气）为特征，伴有间歇低氧、睡眠中反复觉醒和胸腔内压力变化[1]。OSA与高血压、心律失常、冠心病、心力衰竭、肺动脉高压等多种疾病有关，是心血管事件的独立危险因素[2-5]。
持续气道正压通气（CPAP）是公认的治疗OSA的有效方法，理论上治疗OSA可降低心血管疾病风险。已合并缺血性心脑血管疾病的OSA患者，CPAP治疗并未显著降低心脑血管终点事件的发生率[6]。提示对已合并心血管疾病的OSA患者再进行CPAP治疗来降低再发风险可能为时已晚，早期就对OSA进行干预来防止心血管问题可能更加有效[7]。因此，界定能反映OSA患者早期心血管损伤的指标，并根据这些指标对OSA患者进行早期干预显得尤为重要。
研究表明心脏结构和功能改变可预测心肺疾病的预后[8]。超声心动图做为一种无创、便捷的检测手段，可早期评估患者心脏结构和功能，有助于早期发现OSA患者心脏潜在损伤，为尽早开展CPAP治疗提供依据。
既往研究提示OSA患者存在左心室舒张功能异常和障碍[9-12]；在OSA早期尚未出现心血管并发症时，已能观察到左心室的整体纵向应变减少，在疾病进展到晚期出现明显并发症时，左心室射血分数才显著下降[13-14]。但这些研究并未排除合并高血压的患者，考虑到OSA是高血压发生的独立危险因素[2]，而左心室舒张功能不全是高血压伴OSA患者的常见表现，这些患者的心脏结构和功能改变不能完全排除高血压的影响。在高血压和其他心血管并发症出现之前，OSA是否可独立导致心血管损伤，目前研究结果尚存在争议[15-16]。
阻塞性睡眠呼吸暂停综合征是老年患者最常见的睡眠呼吸障碍性疾病[17-18]。关于老年阻塞性睡眠呼吸暂停综合征患者心脏结构和功能变化的数据较少，且研究人群多合并高血压等基础心血管疾病[2, 12, 19-21]，难以直接反映OSA对心脏结构和功能的影响，本研究旨在分析心血管并发症出现前，老年OSA患者的心脏结构和功能改变及其影响因素。
1. 资料和方法
1.1. 研究对象
选择2015年1月~2016年10月，在北京大学国际医院、解放军总医院就诊的417名老年阻塞性睡眠呼吸暂停综合征患者。纳入标准：年龄≥ 65岁；符合阻塞性睡眠呼吸暂停综合征诊断标准；愿意参与本研究并签署知情同意书。排除标准：原发性高血压、继发性高血压；糖尿病；冠心病、肺心病等其他已知的心脏疾病；高脂血症；既往脑卒中诊断史；恶性肿瘤患者。最终，纳入82名阻塞性睡眠呼吸暂停综合征患者进行数据分析。该研究得到解放军总医院伦理委员会批准（伦理号S2019-352-01）。
1.2. 方法
患者分组：参考《成人阻塞性睡眠呼吸暂停多学科诊疗指南》[22]，本研究根据呼吸暂停低通气指数（AHI）将纳入的OSA患者分为轻度OSA组（AHI < 15次/h）和中/重度OSA组（AHI ≥ 15次/h）。记录患者人口统计学资料及一般基础资料如性别、年龄、身高、体质量、血压等，PSG监测结束的当天早上空腹状态下抽取静脉血，检测血常规与生化指标。
睡眠监测：在睡眠试验室使用康迪多导睡眠监测仪对患者进行技术员值守的整夜多导睡眠监测，监测参数包括脑电图、眼电图、下颌肌电图、口鼻气流、胸腹运动、鼾声、脉搏氧饱和度等。监测结果自动分析后由专业睡眠技师人工校准，监测报告包括AHI（呼吸暂停低通气指数）、氧减指数（ODI，睡眠中每小时脉搏血氧饱和度下降 > 4%的总次数）、最低/平均脉氧饱和度（SpO2）等。
超声心动图：所有患者均于PSG完成后1周内完成超声心动图检查。由2名有经验的超声专业医师应用美国通用电气公司Vivid机器（Vivid E9-GE Healthcare, Milwaukee, WI）进行检查。动态图像帧频≥ 50帧/s，测量至少3个心动周期取平均值，M型及多普勒频谱走速为75~100 mm/s。患者平静休息30 min后，取左侧卧位，测量并记录室间隔厚度、左室后壁厚度、左室舒张末期内径、左室收缩末期内径、左室射血分数，左房内径、舒张早期二尖瓣血流速度峰值（E）、舒张晚期二尖瓣血流速度峰值（A），组织多普勒测量舒张早期心肌运动速度峰值（Em）、舒张晚期心肌运动速度峰值（Am），计算E/A、Em/Am值。
1.3. 统计学处理
应用SPSS 22.0软件处理相关数据。正态分布的计量资料用均数±标准差表示，组间比较采用独立样本t 检验，如方差不齐采用非参数Mann-Whitney检验。分类变量以百分率表示，组间比较用χ2检验；两变量相互关系采用Pearson相关性分析法，如非正态分布采用spearman相关性分析；与E/A比值相关性采用多元线性回归分析，P < 0.05为差异有统计学意义。
2. 结果
2.1. 两组一般资料的比较
轻度OSA组共32人，平均AHI 10.47±2.73次/h，中重度OSA组共50人，平均AHI 26.40±10.59次/h（P= 0.0001）。两组患者年龄相当（71.66±6.28岁vs 72.38± 6.04岁，P=0.637），两组患者中女性占比均较少，中重度组女性更少，但两组间女性占比差异无统计学意义（40.6% vs 21.2%），P > 0.05。中重度OSA组平均SpO2低于轻度OSA组，但差异无统计学意义（93.58±5.41 vs 95.61±3.03，P=0.056）。两组在吸烟史、体质量指数（BMI）、血压、血糖、血脂等方面差异无统计学意义（P > 0.05）。中重度OSA组患者血小板比积（0.22±0.08 vs 0.17 ± 0.04，P=0.032）、血肌酐水平（70.94 ± 27.88 vs 54.49±34.22，P=0.022）高于轻度OSA组（表 1）。
1.
一般临床资料
Clinical characteristics of the patients
| Variables | Mild OSA (n=32) | Moderate/severe OSA (n=50) | χ2/t | P |
| OSA: Obstructive sleep apnea; BMI: Body mass index; AHI: Apnea-hypopnea index; PDW: Platelet distribution width; RDW: Red blood cell distribution width; NLR: Neutrophil to lymphocyte ratio; PLR: Platelet to lymphocyte ratio; HDL: High-density lipoprotein; LDL: Low-density lipoprotein. | ||||
| Age (year, Mean±SD) | 71.66±6.28 | 72.38±6.04 | 0.437 | 0.637 |
| Female [n (%)] | 13(40.6) | 11(21.2) | 3.230 | 0.085 |
| Current smoker [n (%)] | 6(18.8) | 5(10) | 1.270 | 0.325 |
| BMI(kg/m2, Mean±SD) | 23.69±5.07 | 25.03±4.52 | 1.244 | 0.217 |
| AHI (times/h) | 10.47±2.73 | 26.40±10.59 | 8.317 | 0.0001 |
| Average SpO2 (%, Mean±SD) | 95.61±3.03 | 93.58±5.41 | -1.939 | 0.056 |
| Minimum SpO2 (%, Mean±SD) | 81.46±9.66 | 78.18±12.66 | -1.229 | 0.223 |
| Systolic pressure (mmHg, Mean±SD) | 119.06±11.58 | 123.46±13.01 | 1.549 | 0.125 |
| Diastolic pressure (mmHg, Mean±SD) | 71.19±8.02 | 73.32±10.57 | 0.963 | 0.338 |
| Plateletcount (×109, Mean±SD) | 167.22±42.64 | 193.83±80.58 | 1.710 | 0.091 |
| Mean platelet volume (fL, Mean±SD) | 10.95±1.14 | 11.13±1.85 | 0.521 | 0.604 |
| PDW(%, Mean±SD) | 15.46±2.49 | 16.13±1.85 | 1.244 | 0.217 |
| Plateletcrit (%, Mean±SD) | 0.17±0.04 | 0.22±0.08 | 2.188 | 0.032 |
| RDW(%, Mean±SD) | 13.62±1.77 | 14.08±0.51 | 1.615 | 0.111 |
| NLR(Mean±SD) | 2.80±1.48 | 3.14±1.96 | 0.852 | 0.397 |
| PLR(Mean±SD) | 135.74±60.14 | 156.14±77.27 | 0.699 | 0.487 |
| Uric acid (μmol/L, Mean±SD) | 221.10±148.78 | 272.70±124.30 | 0.650 | 0.103 |
| Creatinine (μmol/L, Mean±SD) | 54.49±34.22 | 70.94±27.88 | 2.347 | 0.022 |
| Fasting serum glucose (mmol/L, Mean±SD) | 5.31±0.84 | 5.35±0.90 | 0.290 | 0.977 |
| Total cholesterol (mmol/L, Mean±SD | 4.06±0.73 | 4.29±0.85 | 1.139 | 0.228 |
| Triglyceride (mmol/L, Mean±SD) | 1.22±0.36 | 1.31±0.37 | 1.082 | 0.283 |
| HDL cholesterol (mmol/L, Mean±SD | 1.25±0.54 | 1.32±0.52 | 0.517 | 0.607 |
| LDL cholesterol (mmol/L, Mean±SD) | 2.02±0.89 | 2.28±0.89 | 1.517 | 0.134 |
2.2. 两组患者左室舒张功能参数的比较及相关性分析
心脏结构及功能方面，两组患者的左室射血分数、室间隔厚度、左室后壁厚度、左房内径、左室舒张末内径差异均无统计学意义（P > 0.05）。两组舒张早期二尖瓣血流速度峰值（E）相似，但中重度OSA组的舒张晚期二尖瓣血流速度峰值（A）高于轻度OSA组（70.35± 6.87 vs 64.09±8.31，P=0.0001，表 2），其E/A比值显著低于轻度OSA组（0.98±0.06 vs 1.08±0.05，P=0.0001）。
2.
超声心动图参数比较
Comparison of echocardiographic parameters of the patients with mild and moderate to severe OSA
| Variables | Mild OSA (n=32) | Moderate/severe OSA (n=50) | χ2/t | P |
| OSA: Obstructive sleep apnea; E: Transmitral early diastolic flow; A: Transmitral late diastolic flow; Em: Early diastolic myocardial velocity from lateral mitral annulus; Am: Late diastolic myocardial velocity from lateral mitral annulus, | ||||
| Ejection fraction (%) | 60.62±5.02 | 59.64±6.06 | -0.360 | 0.720 |
| Intraventricular septum thickness (mm) | 10.03±1.15 | 10.66±1.10 | 1.627 | 0.334 |
| Left ventricle posterior wall thickness (mm) | 9.02±1.12 | 9.59±0.99 | 0.972 | 0.334 |
| Left atrial diameter (mm) | 35.80±6.60 | 36.28±5.57 | 0.319 | 0.751 |
| Left ventricular diastolic diameter (mm) | 47.41±5.53 | 48.22±7.41 | 0.486 | 0.629 |
| E (cm/s) | 68.93±8.87 | 68.38±5.51 | -0.346 | 0.730 |
| A (cm/s) | 64.09±8.31 | 70.35±6.87 | 3.703 | 0.0001 |
| E/A ratio | 1.08±0.05 | 0.98±0.06 | -7.849 | 0.0001 |
| Em (cm/s) | 11.49±1.48 | 11.40±0.92 | -0.346 | 0.755 |
| Am (cm/s) | 9.85±1.32 | 11.89±1.41 | 6.532 | 0.0001 |
| Em/Am ratio | 1.17±0.06 | 0.97±0.11 | -9.812 | 0.0001 |
通过对E/A比值与临床及血液指标的相关分析发现，AHI与E/A比值呈负相关（r=-0.613，P=0.0001），平均氧饱和度与E/A比值呈正相关（r=0.253，P=0.022，图 1）。E/A比值与年龄、BMI、血压、尿酸、血糖、血脂、血小板比积、甘油三酯等均不相关（P > 0.05，表 3）。我们进一步对E/A比值与AHI、平均SpO2、血小板比积、血小板分布宽度、血小板计数进行了多元线性回归，结果显示E/A比值与AHI相关（β=-0.645，P=0.0001，表 4）。
1.
散点图显示AHI与E/A比值呈负相关（A），平均脉氧饱和度与E/A比值呈正相关（B）
Scatter plot showing a negative correlation between AHI and E/A ratio (A) and a positive correlation between mean pulse oxygen saturation and E/A ratio (B) in patients with OSA. AHI: apnea-hypopnea index; E: Transmitral early diastolic flow; A: Transmitral late diastolic flow.
3.
E/A与临床及血液指标的相关性分析
Analysis of the correlation between E/A ratio and the clinical and blood biochemical parameters of the patients with OSA
| Variables | E/A | E/A | |||
| r | P | r | P | ||
| E: Transmitral early diastolic flow; A: Transmitral late diastolic flow; BMI: Body mass index; AHI: Apnea-hypopnea index; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; PDW: Platelet distribution width; RDW: Red cell distribution width; NLR: Neutrophil to lymphocyte ratio; PLR: Platelet to lymphocyte ratio. | |||||
| Age | -0.056 | 0.615 | Average SpO2 | 0.253 | 0.022 |
| BMI | -0.126 | 0.260 | Minimum SpO2 | 0.162 | 0.147 |
| AHI | -0.613 | 0.0001 | Platelet count | -0.195 | 0.084 |
| Systolic pressure | 0.112 | 0.315 | Mean platelet volume | 0.060 | 0.606 |
| Diastolic pressure | 0141 | 0.206 | PDW | 0.219 | 0.053 |
| Creatinine | -0.082 | 0.474 | Plateletcrit | -0.203 | 0.076 |
| Uric acid | -0.069 | 0.551 | RDW | -0.139 | 0.233 |
| Total cholesterol | 0.023 | 0.843 | NLR | 0.062 | 0.595 |
| HDL cholesterol | -0.068 | 0.571 | PLR | 0.005 | 0.962 |
| LDL cholesterol | -0.022 | 0.855 | Triglyceride | 0.098 | 0.408 |
| Fasting serum glucose | -0.033 | 0.776 | - | - | - |
4.
E/A与连续变量的多元线性回归分析
Multiple linear regression analysis of E/A ratio and continuous variables
| Variables | Beta | t | P |
| AHI | -0.645 | -6.045 | 0.0001 |
| Average SpO2 | -0.099 | -0.948 | 0.346 |
| Plateletcrit | 0.244 | 0.234 | 0.816 |
| PDW | 0.131 | 1.291 | 0.201 |
| Platelet count | -0.273 | -0.260 | 0.796 |
3. 讨论
本研究在入选患者时，排除了高血压、冠心病、肺心病等各种已知的心脏疾病，结果发现在没有高血压和任何其他心血管疾病的情况下，与轻度OSA患者相比，中重度OSA患者心脏舒张功能受损，E/A比值显著低于轻度患者。提示OSA或可独立导致心脏功能受损。
OSA导致心血管损伤的可能机制在于：慢性间歇性低氧激活交感神经，增加活性氧生成，促进氧化应激，诱导血管炎症，引起内皮功能障碍，介导胰岛素抵抗及瘦素抵抗引起代谢紊乱，进而导致心血管疾病及其他脏器损害。反复觉醒引起交感神经激活，导致血压升高和代谢紊乱。呼吸事件期间胸腔内负压增大、静脉回流增加、右心室前负荷及左心室后负荷增加、左心室壁应力急剧增加诱导交感神经兴奋，加速OSA相关心血管疾病的进程[1, 23-24]。
既往有研究还发现中重度OSA患者室间隔厚度和左房内径增加[25-26]。本研究提示中重度OSA患者室间隔厚度、左房内径相比轻度患者有增加趋势，但未显示出统计学差异，可能与本研究重度患者不多，两组间AHI差别不大有关，增大样本量后，或能显示出统计学差异。另一方面也反映了心脏舒张功能受损早于心脏结构改变，提示相较于其他指标，E/A比值在评估OSA患者早期心功能受损方面敏感性更高。
既往研究发现吸烟量与OSA严重程度有关[27]，与非吸烟者相比，吸烟者的夜间平均血氧饱和度更低，有吸烟史的OSA患者患高血压的风险增加[28]。本研究中，轻度OSA组与中重度OSA组在吸烟率上无显著差异。可能与本研究入选人群总体吸烟率不高及整体样本量较小有关，可在今后的研究中进一步扩展样本量进行分析。
高血压、肥胖、年龄、胆固醇水平、胰岛素抵抗、糖尿病和甲状腺功能减退与阻塞性睡眠呼吸暂停综合征患者心血管疾病的发生有关[29-32]。本研究就E/A比值与临床及血液指标进行相关性分析，未发现E/A比值与年龄、BMI、血压、血糖、血脂等存在相关性，E/A比值与AHI和平均SpO2相关。经多元线性回归进一步分析，E/A与AHI存在负相关。提示AHI为年龄、肥胖等因素之外的OSA患者心脏舒张功能不全的独立预测指标。
综上所述，在没有高血压和任何其他心血管疾病的情况下，中重度老年OSA患者可出现心脏舒张功能受损，且舒张功能受损早于心脏结构受损出现，其程度与AHI正相关。对尚未出现心血管合并症的OSA患者，我们应关注其心脏功能，并对已经出现心脏舒张功能受损的OSA患者给予更积极的干预。
Biography
高莹卉，博士，主治医师，E-mail: ashley_gao@163.com
Funding Statement
军队保健专项科研基金（19BJZ34、16BJZ25）；国家老年疾病临床研究中心2018开放课题（NCRCG-PLAGH-2018008）；解放军总医院军事医学青年项目（QNC19054）
Contributor Information
高 莹卉 (Yinghui GAO), Email: ashley_gao@163.com.
刘 霖 (Lin LIU), Email: liulin715@qq.com.
References
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