Research progress of hypoxia-inducible factor-1α and obstructive sleep apnea associated hypertension
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摘要:
阻塞性睡眠呼吸暂停（OSA）是一种呼吸障碍性疾病，与顽固性高血压密切相关。OSA可引起缺氧诱导因子-1α（HIF-1α）的水平升高，并且间歇性低氧（IH）会导致HIF-α亚型失调，与OSA相关高血压相关。本研究探讨IH引起HIF-α亚型失调导致活性氧（ROS）的生成增加，进而激活化学反射、减弱压力反射并且导致内皮功能障碍影响血压调节的机制，展望HIF-1α相关抑制性药物用于治疗OSA相关高血压的前景。
Abstract:Obstructive sleep apnea (OSA) is a respiratory disorder that closely associated with refractory hypertension. OSA can lead to increase of hypoxia-inducible factor-1α (HIF-1α), and intermittent hypoxia (IH) can lead to imbalance of HIF-α subtypes, which is related with OSA associated hypertension. In this review, the mechanism of increase in the generation of reactive oxygen species (ROS) due to HIF-α subtypes imbalance caused by IH was explored, which can affect the regulation of blood pressure by activating chemoreflex, weakening baroreflex and causing endothelial dysfunction, and propose the prospect of HIF-1α related inhibitory drugs for the treatment of OSA-related hypertension.
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Keywords:
- hypoxia-inducible factor-1α /
- obstructive sleep apnea /
- hypertension /
- reactive oxygen /
- chemoreflex /
- baroreflex /
- clock genes
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ST段抬高型急性心肌梗死(STEMI)是冠心病的严重类型，病情重、进展快，严重威胁患者的生命安全[1]。经皮冠状动脉介入治疗(PCI)是目前治疗STEMI的主要方法，能有效复通闭塞冠状动脉，恢复心肌灌注，降低患者死亡风险[2]。然而，部分PCI术后患者会发生再梗死、心力衰竭等严重并发症，这与血脂异常密切相关[3-4]。因此，通过药物调节患者血脂水平，对减少PCI术后并发症的发生具有重要意义[5]。阿托伐他汀、瑞舒伐他汀和辛伐他汀均为临床常用的他汀类药物，可显著调节血脂，有效降低血清总胆固醇和低密度脂蛋白胆固醇水平，升高高密度脂蛋白胆固醇水平[6]。本研究探讨不同剂量阿托伐他汀、瑞舒伐他汀和辛伐他汀对老年STEMI患者PCI术后心肌功能、不良反应等的影响，现报告如下。
1. 资料与方法
1.1 一般资料
前瞻性选取2021年7月—2023年7月沧州市中心医院收治的接受PCI的180例STEMI患者为研究对象。纳入标准: ①符合《急性ST段抬高型心肌梗死诊断和治疗指南》[7]中STEMI诊断标准，且经影像学检查确诊者; ②年龄≥60岁者; ③发病12 h内行PCI者; ④本人及家属均知情同意并签署承诺书者。排除标准: ①重要脏器功能不全者; ②心脏结构异常或有严重先天心脏病者; ③凝血功能异常者; ④合并严重出血性疾病、感染性疾病者; ⑤合并恶性肿瘤者; ⑥合并免疫功能疾病者; ⑦有认知障碍、精神疾病不能配合本研究者。采用随机数字表法将患者分为A组、B组、C组、D组、E组、F组，每组30例。6组患者一般资料比较，差异无统计学意义(P>0.05)。见表 1。本研究经医院医学伦理委员会审查批准，审查意见号为2021-144-12(z)。
表 1 各组患者一般资料比较(x±s)[n(%)]组别 n 性别 年龄/岁 体质量指数/(kg/m2) 发病至入院时间/h 病变支数 糖尿病 高血压 男 女 单支 双支 三支 A组 30 19(63.33) 11(36.67) 68.87±3.41 22.02±2.19 4.17±1.09 11(36.67) 13(43.33) 6(20.00) 12(40.00) 14(46.67) B组 30 17(56.67) 13(43.33) 68.53±3.64 22.09±2.25 4.25±1.09 11(36.67) 14(46.67) 5(16.67) 11(36.67) 15(50.00) C组 30 18(60.00) 12(40.00) 68.23±3.58 21.93±2.39 4.30±1.07 12(40.00) 12(40.00) 6(20.00) 10(33.33) 13(43.33) D组 30 18(60.00) 12(40.00) 67.77±3.68 22.25±2.53 4.29±1.08 11(36.67) 11(36.67) 8(26.67) 12(40.00) 14(46.67) E组 30 19(63.33) 11(36.67) 68.07±3.46 22.21±2.42 4.23±1.11 12(40.00) 13(43.33) 5(16.67) 11(36.67) 15(50.00) F组 30 20(66.67) 10(33.33) 67.87±3.858 22.12±2.31 4.21±1.13 10(33.33) 12(40.00) 8(26.67) 11(36.67) 13(43.33) 1.2 方法
A组患者接受术前20 mg/d辛伐他汀口服治疗, B组患者接受术前40 mg/d辛伐他汀口服治疗, C组患者接受术前40 mg/d阿托伐他汀口服治疗, D组患者接受术前80 mg/d阿托伐他汀口服治疗, E组患者接受术前10 mg/d瑞舒伐他汀口服治疗, F组患者接受术前20 mg/d瑞舒伐他汀口服治疗。
1.3 观察指标
① 炎症因子: 分别于术前、术后1 d、术后1个月采集患者清晨空腹静脉血5 mL, 离心分离血清，采用酶联免疫吸附试验(ELISA)检测白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、超敏C反应蛋白(hs-CRP)水平。②心肌损伤标志物和心功能指标: 于术前、术后1 d、术后1个月采集患者清晨空腹静脉血5 mL, 离心分离血清，采用速率法检测肌酸激酶同工酶(CK-MB)水平，采用电化学发光法检测心肌肌钙蛋白T(cTnT)水平，采用ELISA检测N末端脑钠肽前体(NT-proBNP)水平。使用多普勒超声仪(迈瑞DC-N2S彩色多普勒超声仪)检测左心室射血分数(LVEF)、心脏指数(CI)和心排血量(CO)。③ ST段回落情况[8]: 比较各组患者ST段回落情况，即心电图ST段回落>50%。④不良心血管事件: 术后随访3个月，记录并比较各组患者不良心血管事件发生率。⑤不良反应: 术后随访3个月，记录并比较各组患者不良反应发生率。
1.4 统计学分析
采用SPSS 22.0统计学软件分析数据, ST段回落情况、不良心血管事件、不良反应等计数资料以[n(%)]描述，比较行χ2检验，正态分布的计量资料以(x±s)描述，多组间血清炎症因子、心肌损伤标志物、心功能指标比较行单因素ANOVA分析，事后两两比较行LSD-t检验，组内比较行配对样本t检验。P < 0.05为差异有统计学意义。
2. 结果
2.1 血清炎症因子水平比较
各组患者术后1 d时IL-6、hs-CRP、TNF-α水平均高于术前，术后1个月时IL-6、hs-CRP、TNF-α水平均低于术前、术后1 d, 差异有统计学意义(P < 0.05); 术后1 d、术后1个月时, A组、B组、C组、D组、E组、F组的IL-6、hs-CRP、TNF-α水平均依次降低，差异有统计学意义(P < 0.05)。见表 2。
表 2 各组患者血清炎症因子水平比较(x±s)组别 n 时点 IL-6/(ng/L) hs-CRP/(mg/L) TNF-α/(ng/L) A组 30 术前 4.38±1.26 4.27±1.18 20.23±3.23 术后1 d 13.47±2.12* 25.54±2.57* 33.84±2.21* 术后1个月 3.62±0.49*# 3.58±0.43*# 14.31±1.52*# B组 30 术前 4.36±1.36 4.25±1.23 20.27±3.31 术后1 d 11.29±2.09*△ 22.27±2.64*△ 31.79±2.12*△ 术后1个月 3.02±0.44*#△ 2.89±0.38*#△ 12.19±1.41*#△ C组 30 术前 4.39±1.30 4.33±1.18 20.25±3.23 术后1 d 8.37±1.43*△▲ 19.26±2.61*△▲ 29.85±2.13*△▲ 术后1个月 2.77±0.36*#△▲ 2.33±0.38*#△▲ 11.16±1.28*#△▲ D组 30 术前 4.37±0.31 4.33±1.25 20.24±3.31 术后1 d 7.41±1.26*△▲▽ 16.60±2.58*△▲▽ 27.76±2.09*△▲▽ 术后1个月 2.34±0.32*#△▲▽ 1.96±0.33*#△▲▽ 9.88±1.23*#△▲▽ E组 30 术前 4.34±0.33 4.30±1.21 20.26±3.21 术后1 d 5.28±1.08*△▲▽▼ 13.30±2.61*△▲▽▼ 25.88±2.14*△▲▽▼ 术后1个月 1.93±0.34*#△▲▽▼ 1.72±0.35*#△▲▽▼ 8.56±1.24*#△▲▽▼ F组 30 术前 4.33±1.35 4.28±1.18 20.26±3.23 术后1 d 3.60±1.15*△▲▽▼⊿ 11.27±2.67*△▲▽▼⊿ 23.83±2.17*△▲▽▼⊿ 术后1个月 1.17±0.26*#△▲▽▼⊿ 1.29±0.31*#△▲▽▼⊿ 7.20±1.11*#△▲▽▼⊿ IL-6: 白细胞介素-6; TNF-α: 肿瘤坏死因子-α; hs-CRP: 超敏C反应蛋白。
与术前比较, * P < 0.05; 与术后1 d比较，#P < 0.05; 与A组比较, △P < 0.05; 与B组比较, ▲P < 0.05; 与C组比较, ▽P < 0.05; 与D组比较, ▼P < 0.05; 与E组比较, ⊿P < 0.05。2.2 心肌损伤标志物和NT-proBNP水平比较
各组患者术后1 d、术后1个月时cTnT、CK-MB、NT-proBNP水平均低于术前，且术后1个月时cTnT、CK-MB、NT-proBNP水平均低于术后1 d时，差异有统计学意义(P < 0.05); 术后1 d、术后1个月时，A组、B组、C组、D组、E组、F组的cTnT、CK-MB、NT-proBNP水平均依次降低，差异有统计学意义(P < 0.05)。见表 3。
表 3 各组患者心肌损伤标志物和NT-proBNP水平比较(x±s)组别 n 时点 cTnT/(μg/L) CK-MB/(U/L) NT-proBNP/(ng/mL) A组 30 术前 3.24±0.42 88.25±25.63 587.69±35.49 术后1 d 2.08±0.35* 61.35±9.75* 505.25±26.25* 术后1个月 0.15±0.03*# 4.29±0.90*# 340.25±16.25*# B组 30 术前 3.32±0.49 89.28±25.81 590.12±33.52 术后1 d 1.89±0.26*△ 53.58±8.83*△ 485.25±23.25*△ 术后1个月 0.13±0.03*#△ 3.52±0.79*#△ 328.25±15.25*#△ C组 30 术前 3.31±0.40 88.65±25.71 588.35±34.25 术后1 d 1.68±0.25*△▲ 45.36±7.27*△▲ 470.25±25.25*△▲ 术后1个月 0.11±0.02*#△▲ 2.74±0.65*#△▲ 319.25±15.25*#△▲ D组 30 术前 3.37±0.47 90.17±26.17 589.12±35.12 术后1 d 1.47±0.26*△▲▽ 37.24±6.80*△▲▽ 452.25±20.25*△▲▽ 术后1个月 0.08±0.02*#△▲▽ 2.34±0.51*#△▲▽ 308.25±15.26*#△▲▽ E组 30 术前 3.34±0.40 90.28±25.98 588.25±33.22 术后1 d 1.33±0.21*△▲▽▼ 29.30±5.37*△▲▽▼ 432.25±19.25*△▲▽▼ 术后1个月 0.06±0.01*#△▲▽▼ 1.87±0.40*#△▲▽▼ 295.25±15.25*#△▲▽▼ F组 30 术前 3.28±0.50 89.62±26.51 587.25±32.15 术后1 d 1.11±0.2*△▲▽▼⊿ 23.30±5.04*△▲▽▼⊿ 395.25±18.56*△▲▽▼⊿ 术后1个月 0.04±0.01*#△▲▽▼⊿ 1.23±0.33*#△▲▽▼⊿ 283.14±15.25*#△▲▽▼⊿ CK-MB: 肌酸激酶同工酶; cTnT: 心肌肌钙蛋白T; NT-proBNP: N末端脑钠肽前体。
与术前比较, * P < 0.05; 与术后1 d比较, #P < 0.05; 与A组比较, △P < 0.05; 与B组比较, ▲P < 0.05; 与C组比较, ▽P < 0.05; 与D组比较, ▼P < 0.05; 与E组比较, ⊿P < 0.05。2.3 心功能指标比较
术后1个月时，各组患者LVEF、CO、CI均高于术前，差异有统计学意义(P < 0.05); 术后1个月时, A组、B组、C组、D组、E组、F组的LVEF、CO、CI均依次升高，差异有统计学意义(P < 0.05)。见表 4。
表 4 各组患者心功能指标比较(x±s)组别 n LVEF/% CO/(L/min) CI/[L/(min·m2)] 术前 术后1个月 术前 术后1个月 术前 术后1个月 A组 30 42.61±4.40 50.32±1.32* 3.36±0.47 3.85±0.17* 2.78±0.38 3.26±0.16* B组 30 42.87±5.02 52.01±1.35*△ 3.33±0.48 4.05±0.28*△ 2.79±0.35 3.40±0.21*△ C组 30 42.63±4.16 53.33±1.47*△▲ 3.34±0.43 4.20±0.32*△▲ 2.74±0.34 3.60±0.18*△▲ D组 30 42.62±4.26 54.33±1.46*△▲▽ 3.30±0.46 4.37±0.25*△▲▽ 2.74±0.38 3.79±0.15*△▲▽ E组 30 42.72±4.24 56.15±1.58*△▲▽▼ 3.33±0.50 4.54±0.29*△▲▽▼ 2.80±0.39 4.01±0.21*△▲▽▼ F组 30 42.76±4.29 59.75±1.44*△▲▽▼⊿ 3.37±0.41 4.79±0.20*△▲▽▼⊿ 2.79±0.33 4.22±0.22*△▲▽▼⊿ LVEF: 左心室射血分数; CO: 心排血量; CI: 心脏指数。
与术前比较, * P < 0.05; 与A组比较, △P < 0.05; 与B组比较, ▲P < 0.05; 与C组比较, ▽P < 0.05; 与D组比较, ▼P < 0.05; 与E组比较, ⊿P < 0.05。2.4 ST段回落情况比较
A组ST段回落者16例(53.33%), B组、C组、D组、E组、F组则分别为19例(63.33%)、21例(70.00%)、24例(80.00%)、26例(86.67%)、28例(93.33%)。6组ST段回落情况比较，差异有统计学意义(χ2=17.656, P < 0.05)。
2.5 不良心血管事件比较
6组患者不良心血管事件总发生率比较，差异无统计学意义(P>0.05), 见表 5。
表 5 各组患者不良心血管事件比较[n(%)]组别 n 再发心肌梗死 充血性心力衰竭 恶性心律失常 心源性休克 再发心绞痛 合计 A组 30 1(3.33) 2(6.67) 2(6.67) 0 3(10.0) 8(26.67) B组 30 1(3.33) 2(6.67) 2(6.67) 1(3.33) 2(6.67) 8(26.67) C组 30 1(3.33) 2(6.67) 2(6.67) 0 2(6.67) 7(23.33) D组 30 1(3.33) 1(3.33) 1(3.33) 1(3.33) 2(6.67) 6(20.00) E组 30 0 1(3.33) 1(3.33) 1(3.33) 2(6.67) 5(16.67) F组 30 0 1(3.33) 1(3.33) 0 1(3.33) 3(10.00) 2.6 不良反应发生情况比较
各组患者不良反应总发生率比较，差异无统计学意义(P>0.05), 见表 6。
表 6 各组患者不良反应发生情况比较[n(%)]组别 n 便秘 腹痛 胃肠胀气 肌酶升高 乏力 转氨酶升高 合计 A组 30 5(16.67) 3(10.00) 3(10.00) 1(3.33) 3(10.00) 2(6.67) 17(56.67) B组 30 4(13.33) 3(10.00) 3(10.00) 1(3.33) 2(6.67) 2(6.67) 15(50.00) C组 30 3(10.00) 2(6.67) 3(10.00) 1(3.33) 3(10.00) 2(6.67) 14(46.67) D组 30 3(10.00) 2(6.67) 2(6.67) 1(3.33) 2(6.67) 2(6.67) 12(40.00) E组 30 2(6.67) 2(6.67) 2(6.67) 1(3.33) 2(6.67) 1(3.33) 10(33.33) F组 30 2(6.67) 2(6.67) 2(6.67) 1(3.33) 2(6.67) 1(3.33) 10(33.33) 3. 讨论
STEMI通常由冠状动脉完全闭塞所致，好发于老年人群[9-10], 主要治疗措施为再灌注治疗(包括PCI和溶栓)。PCI通过向冠状动脉中植入支架或球囊而扩张狭窄的血管，可改善心脏供血状况[11-12]。值得注意的是, PCI术后患者应控制血脂水平，以减少并发症的发生。
葛广豪等[13]指出，老年STEMI患者PCI术前应用负荷剂量他汀类药物，可显著降低氧化应激水平，减少心肌细胞坏死，改善短期预后。阿托伐他汀、瑞舒伐他汀、辛伐他汀均为他汀类药物，可抑制胆固醇合成的关键酶3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶，减少胆固醇合成，还可增加肝细胞表面低密度脂蛋白受体表达，加速低密度脂蛋白的清除，进而降低血胆固醇和低密度脂蛋白水平[14]。本研究结果显示，术后1 d、术后1个月时，A组、B组、C组、D组、E组、F组的IL-6、hs-CRP、TNF-α水平均依次降低，差异有统计学意义(P < 0.05), 提示瑞舒伐他汀降低炎症因子水平的作用优于辛伐他汀、阿托伐他汀，且高剂量的效果优于低剂量。分析原因为：高剂量他汀类药物能更有效地抑制HMG-CoA还原酶活性，且可能具有更强的抗炎作用，从而可显著降低胆固醇、低密度脂蛋白及炎症因子水平; 与辛伐他汀、阿托伐他汀相比，瑞舒伐他汀对HMG-CoA还原酶的抑制能力更强，抗炎作用更佳，生物利用度更高，从而可更有效地降低胆固醇水平，减轻炎性反应[15]; 瑞舒伐他汀半衰期较长，可长时间保持稳定的血药浓度，从而更好地控制胆固醇水平[16]。总之，瑞舒伐他汀具有强效的降胆固醇、抗炎、抗血栓形成作用，且具有良好的生物利用度和稳定性，是急性心肌梗死患者的首选治疗药物之一。
本研究结果显示，术后1 d、术后1个月时, A组、B组、C组、D组、E组、F组的cTnT、CK-MB、NT-proBNP水平均依次降低，差异有统计学意义(P < 0.05); 术后1个月时, A组、B组、C组、D组、E组、F组的LVEF、CO、CI均依次升高，差异有统计学意义(P < 0.05)。由此提示，阿托伐他汀、瑞舒伐他汀和辛伐他汀均能改善老年STEMI患者PCI后的心肌功能，其中大剂量瑞舒伐他汀的效果最佳。阿托伐他汀、瑞舒伐他汀和辛伐他汀均可降低胆固醇、低密度脂蛋白水平，减少血管壁脂质沉积，改善血管内皮功能，减轻炎症反应，减少动脉粥样硬化斑块形成，从而改善心肌功能，且高剂量药物效果更佳。研究[17]显示，瑞舒伐他汀能够显著降低老年STEMI患者PCI后血清炎症因子水平，有效改善心肌功能，抑制血小板聚集，减轻氧化应激反应，促进心肌功能恢复。
瑞舒伐他汀、辛伐他汀和阿托伐他汀均为HMG-CoA还原酶抑制剂，能够抑制胆固醇合成[18], 但其降脂疗效存在差异。相较于辛伐他汀、阿托伐他汀，瑞舒伐他汀能够更显著地降低低密度脂蛋白胆固醇、总胆固醇水平，升高高密度脂蛋白胆固醇水平，且具有更强的抗炎作用。研究[19]表明，瑞舒伐他汀可抑制炎症反应，降低动脉粥样硬化和血栓形成风险。此外，不同他汀类药物的生物利用度和半衰期存在差异，其中瑞舒伐他汀的生物利用度较高且半衰期较长，可更好地发挥疗效，而辛伐他汀和阿托伐他汀的生物利用度相对较低，半衰期相对较短，需频繁给药才能维持稳定疗效。本研究中，各组患者不良心血管事件发生率、不良反应发生率均较低，表明不同剂量阿托伐他汀、瑞舒伐他汀、辛伐他汀均具有良好的安全性。
综上所述，低剂量、高剂量的阿托伐他汀、瑞舒伐他汀、辛伐他汀应用于PCI术后STEMI患者，均可有效减轻炎症反应，改善心肌功能，促进ST段回落，其中高剂量瑞舒伐他汀的效果最佳。本研究不足之处为纳入样本量较少，且未观察长期疗效，有待进一步深入研究加以验证。
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