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急性冠状动脉综合征(ACS)是一组严重的心脏急性缺血综合征[1-2],其病情变化迅速,且对心肌产生不可逆转的缺血损伤。虽然随着现代医学水平的进步,ACS的发病机制已逐渐明确[3-4],治疗方案也日趋完善,但仍有部分病人在接受了系统的药物及介入治疗后会出现不良心血管事件[1-2, 5-6]。因此,积极探索心肌细胞死亡调控通路,保护心脏免受缺血相关损伤,将对临床靶向防治ACS并改善其远期预后有重要的指导价值。
有研究[7]表明,抑制谷胱甘肽过氧化物酶4(GPX4)的功能将导致细胞膜发生脂质过氧化,并可诱导铁死亡。FENG等[8]研究发现,铁死亡抑制剂利普罗斯他汀-1通过增加GPX4活性,减少线粒体脂质活性氧的生成,保护小鼠心肌细胞免受缺血再灌注损伤。我们推测ACS病人可能会因为高水平的GPX4抑制心肌细胞铁死亡而获益。但目前GPX4与ACS之间的相关性仍不明确,血浆GPX4水平与心肌缺血损伤之间的研究大多处于基础研究阶段。本研究采用酶联免疫吸附法(ELISA)对404例病人的血浆GPX4水平进行检测,观测血浆GPX4水平变化与ACS病人临床特征、危险分层及其预后之间的相关性,从而为更精确有效地防治ACS并改善其预后提供新的治疗思路。
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ACS组在年龄、男性病人比例、合并高血压、合并糖尿病、血肌酐、TG、低密度脂蛋白水平上高于对照组,而高密度脂蛋白水平低于对照组(P < 0.05~P < 0.01)(见表 1)。
分组 n 年龄/岁 男 高血压 糖尿病 血糖/(mmol/L) 尿酸/(μmol/L) 肌酐/(μmol/L) ACS组 316 63.33±10.89 201 202 76 5.85(5.51, 6.20) 315.31(304.25, 326.37) 70.55(68.31, 72.79) 对照组 88 57.77±10.34 44 43 6 5.42(5.07, 5.77) 302.96(286.11, 319.81) 63.42(60.94, 65.90) Zc — 4.27* 5.02# 6.54# 12.48# 0.77 1.56 4.05 P — < 0.01 < 0.05 < 0.05 < 0.01 >0.05 >0.05 < 0.01 分组 n 总胆固醇/(mmol/L) 三酰甘油/(mmol/L) 低密度脂蛋白胆固醇/(mmol/L) 高密度脂蛋白胆固醇/(mmol/L) C反应蛋白/(mg/L) D-二聚体/(mg/L) 脂蛋白a/(mg/L) ACS组 316 4.02(3.86, 4.17) 1.74(1.60, 1.88) 2.26(2.16, 2.35) 0.96(0.92, 1.00) 5.46(3.55, 7.37) 0.57(0.39, 0.74) 363.68(327.29, 400.08) 对照组 88 3.96(3.73, 4.18) 1.47(1.25, 1.69) 2.04(2.01, 2.16) 1.01(0.94, 1.07) 4.54(1.92, 7.16) 0.76(0.12, 1.41) 287.57(237.61, 337.53) Zc — 1.98 2.31 3.05 1.88 1.60 0.37 0.37 P — >0.05 < 0.05 < 0.05 < 0.05 >0.05 >0.05 >0.05 *示t值;#示χ2值 表 1 AC组与对照组病人基线资料比较[M(P25, P75)]
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ACS组血浆GPX4水平低于对照组(P < 0.05)。UAP组与AMI组血浆GPX4水平差异无统计学意义(P>0.05)(见表 2)。
分组 n GPX4/(ng/mL) ACS组 316 103.80(101.50,106.11) 对照组 88 131.38(126.31,136.45) Zc — 9.48 P — < 0.05 UAP组 261 105.09(102.67,107.51) AMI组 55 104.23(98.47,109.99) Zc — 0.49 P — >0.05 表 2 不同病人血浆GPX4水平比较
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ROC曲线显示血浆CTPX4水平可以辅助ACS的诊断。ROC曲线下面积(AUC)为0.828(0.778~0.878),其最佳截断点为128.78 ng/mL,特异性为64.8%,敏感性为90.0%(P < 0.05)(见图 1)。
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根据病人TIMI危险评分将ACS组病人分为低危组、中危组和高危组,结果发现,低危组在年龄、合并高血压、C反应蛋白、D-二聚体水平均低于中危组及高危组,在合并糖尿病、Gensini评分水平低于高危组,在男性病人占比上高于高危组(P < 0.05~P < 0.01)。低危组血浆GPX4水平高于中危组和高危组(P < 0.05),高危组病人血浆GPX4水平与中危组差异无统计学意义(P>0.05)(见表 3)。
分组 n 年龄/岁 男 高血压 糖尿病 血糖/(mmol/L) 尿酸/(μmol/L) 肌酐/(μmol/L) 总胆固醇/(mmol/L) 三酰甘油/(mmol/L) 低危组 53 54.58±7.85 41 24 8 5.18(4.57, 5.79) 342.78(314.89, 370.66) 66.95(63.58, 70.32) 4.04(3.66, 4.42) 1.72(1.33, 2.12) 中危组 227 64.46±10.61* 142 146* 46 5.81(5.43, 6.19) 309.49(296.17, 322.80) 71.10(68.29, 73.91) 4.00(3.80, 4.19) 1.74(1.57, 1.92) 高危组 36 69.03±9.56* 18* 32* 22* 6.77(5.11, 8.42) 302.44(268.93, 335.95) 72.56(63.50, 81.62) 4.20(3.70, 4.71) 1.79(1.50, 2.09) Zc — 27.00 7.41 17.61# 31.50# 5.97 4.60 0.53 1.58 4.11 P — < 0.01 < 0.05 < 0.01 < 0.01 >0.05 >0.05 >0.05 >0.05 >0.05 分组 n 低密度脂蛋白胆固醇/(mmol/L) 高密度脂蛋白胆固醇/(mmol/L) C反应蛋白/(mg/L) D-二聚体/(mg/L) 脂蛋白a/(mg/L) Gensini评分 GPX4 /(ng/mL) 低危组 53 2.30(2.03, 2.57) 0.96(0.90, 1.03) 1.59(1.01, 2.18) 0.26(0.16, 0.37) 363.68(327.29, 400.08) 23.75(16.70, 30.80) 114.63(107.46, 121.79) 中危组 227 2.14(2.02, 2.27) 0.95(0.92, 0.98) 5.91(3.42, 8.41)* 0.57(0.34, 0.79)* 332.72(291.79, 373.65) 33.18(28.54, 37.81) 101.61(99.01, 104.20)* 高危组 36 2.41(2.07, 2.74) 1.06(0.69, 1.43) 8.38(1.23, 15.54)* 0.79(0.35, 1.24)* 378.36(248.47, 508.25) 52.44(37.23, 67.65)* 102.75(96.85, 108.66)* Zc — 3.68 3.53 9.99 16.49 3.67 13.78 14.50 P — >0.05 >0.05 < 0.01 < 0.01 >0.05 < 0.01 < 0.05 与低危组比较*P < 0.05;#示χ2值 表 3 TIMI危险分层低危组、中危组和高危组病人基线资料比较[M(P25, P75)]
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ROC曲线显示血浆GPX4水平可以辅助TIMI危险分层中低危病人的诊断。AUC为0.665(0.577~0.754),敏感度为37.7%,特异性为95.0%,最佳截断值为127.06 ng/mL(P < 0.05)(见图 2)。
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本研究对ACS组病人进行了平均21个月的门诊或电话随访,其中4例(1.3%)失访,共30例(9.5%)发生MACEs事件。根据随访结果中病人是否发生MACEs事件,将ACS组病人分为MACEs组30例和非MACEs组282例,结果发现,MACEs组病人GPX4水平为95.16(90.05,100.26)ng/mL, 低于非MACEs组104.53(102.01,107.06)ng/mL(Zc=2.86, P < 0.05)。
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依据所有ACS病人测得GPX4数值的中位数将研究对象分为GPX4≥101.90 ng/mL组和GPX4 < 101.90 ng/mL组,绘制Kaplan-Meier曲线。在所有ACS病人中,4例失访。GPX4≥101.90 ng/mL 158例,失访2例,共10例发生MACEs事件,平均生存时间为620.06 d;GPX4 < 101.90 ng/mL的病人人数为158例,失访2例,共20例发生MACEs事件,平均生存时间为607.23 d。K-M曲线显示,血浆GPX4 < 101.90 ng/mL的ACS病人预期生存时间与GPX4≥101.90 ng/mL组差异无统计学意义(χ2=3.70,P>0.05)(见图 3)。
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将血浆GPX4水平纳入Cox风险比例回归分析,结果显示,B′为-0.03,SE为0.01,Waldχ2为6.99,OR(95%CI)为0.97(0.95~0.99)。随着ACS病人血浆GPX4水平的升高,ACS病人发生MACEs事件的风险降低,表明血浆GPX4水平升高是MACEs事件发生的保护因素(P < 0.05)。
GPX4水平与急性冠状动脉综合征病人临床特征、危险分层及其预后相关性研究
Study on the correlation between the plasma level of glutathione peroxidase 4 and clinical characteristics, risk stratification and prognosis of patients with acute coronary syndrome
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摘要:
目的探讨血浆谷胱甘肽过氧化物酶4(GPX4)水平与急性冠状动脉综合征(ACS)病人临床特征、危险分层及预后之间的相关性。 方法拟行冠状动脉造影病人404例,依据病史、生化检验指标、影像学检查结果及冠状动脉造影检查结果分为ACS组(n=316)和对照组(CON组,n=88)。并将ACS组病人分为不稳定型心绞痛组(UAP组,n=261)和急性心肌梗死组(AMI组,n=55)。依据TIMI危险分层将ACS组病人分为高危组(n=36)、中危组(n=227)和低危组(n=53)。采用酶联免疫吸附法检测病人血浆GPX4水平。出院后对ACS组病人进行平均21个月的随访,追踪有无主要心血管不良事件(MACEs)的发生,其中4例失访,将病人分为MACEs组(n=30)和非MACEs组(n=282), 依据ACS组病人GPX4水平中位数将病人分为GPX4≥101.90 ng/mL组(n=158)和GPX4 < 101.90 ng/mL组(n=158)。 结果ACS组病人血浆GPX4水平低于对照组(P < 0.05)。ROC曲线显示血浆GPX4水平可以辅助ACS的诊断,曲线下面积(AUC)为0.828(0.778~0.878),其最佳截断点为128.78 ng/mL,特异性为64.8%,敏感性为90.0%。在TIMI危险分层中,与高危组和中危组相比,低危组血浆GPX4水平升高(P < 0.05),ROC曲线显示血浆GPX4水平可以辅助判断ACS病人是否处于TIMI危险分层中的低危状态AUC为0.665(0.577~0.754),最佳截断值为127.06 ng/mL,敏感度为37.7%,特异性为95.0%(P < 0.05)。MACEs组病人血清GPX4水平低于非MACEs组(P < 0.05)。Kaplan-Meier曲线中GPX4 < 101.90 ng/mL组和GPX4≥101.90 ng/mL组中生存时间的差异无统计学意义(P < 0.05)。血浆GPX4水平升高是MACEs发生的保护因素(P < 0.05)。 结论血浆GPX4水平对ACS病人临床诊断、TIMI危险分层及远期预后的判断均有参考价值。 -
关键词:
- 急性冠状动脉综合征 /
- 谷胱甘肽过氧化物酶4 /
- TIMI危险分层 /
- 临床预后
Abstract:ObjectiveTo explore the correlation between the plasma level of glutathione peroxidase 4(GPX4) and clinical characteristics, risk stratification and prognosis of patients with acute coronary syndrome(ACS). MethodsA total of 404 patients scheduled by coronary angiography were divided into the ACS group(n=316) and control group(n=88) according to the medical history, biochemical examination, results of imaging examination and coronary angiography.The ACS group was subdivided into the unstable angina pectoris group(UAP group, n=261) and acute myocardial infarction group(AMI group, n=55).According to TIMI risk stratification, the ACS patients were divided into the high-risk group(n=36), medium-risk group(n=227) and low-risk group(n=53).The plasma levels of GPX4 in all cases were determined by enzyme linked immunosorbent assay.The ACS group was followed up for an average of 21 months after discharge for major adverse cardiovascular events(MACEs), 4 cases were lost to follow-up, and the other patients were divided into the MACEs group(n=30) and non-MACEs group(n=282).The ACS group were divided into the GPX4≥101.90 ng/mL group(n=158) and GPX4 < 101.90 ng/mL group(n=158) according to the median GPX4 level of pateints. ResultsThe serum levels of GPX4 in ACS group were lower than that in control group(P < 0.05).The results of ROC curve showed that serum level of GPX4 could assist the diagnosis of ACS.The area under curve(AUC) was 0.828(0.778-0.878), the optimal cut-off value was 128.78 ng/mL, the specificity was 64.8%, and the sensitivity was 90.0%.In TIMI risk stratification, the serum level of GPX4 in low-risk group was higher than that in high-risk and medium-risk groups(P < 0.05).The results of ROC curve showed that the serum level of GPX4 could assist in determining whether ACS patients were in low-risk state in TIMI risk stratification, and the AUC was 0.665(0.577-0.754).The optimal cut-off value was 127.06 ng/mL, the sensitivity was 37.7%, and the specificity was 95.0%(P < 0.05).The level of GPX4 in MACEs group was lower than that in non-MACEs group(P < 0.05).There was no statistical significance in the survival time between GPX4 < 101.90 ng/mL group and GPX4≥101.90 ng/mL group in Kaplan-Meier curve.The serum level of GPX4 increasing was a protective factor for MACEs(P < 0.05). ConclusionsThe serum level of GPX4 has reference value in the clinical diagnosis, TIMI risk stratification and long-term prognosis of ACS patients. -
表 1 AC组与对照组病人基线资料比较[M(P25, P75)]
分组 n 年龄/岁 男 高血压 糖尿病 血糖/(mmol/L) 尿酸/(μmol/L) 肌酐/(μmol/L) ACS组 316 63.33±10.89 201 202 76 5.85(5.51, 6.20) 315.31(304.25, 326.37) 70.55(68.31, 72.79) 对照组 88 57.77±10.34 44 43 6 5.42(5.07, 5.77) 302.96(286.11, 319.81) 63.42(60.94, 65.90) Zc — 4.27* 5.02# 6.54# 12.48# 0.77 1.56 4.05 P — < 0.01 < 0.05 < 0.05 < 0.01 >0.05 >0.05 < 0.01 分组 n 总胆固醇/(mmol/L) 三酰甘油/(mmol/L) 低密度脂蛋白胆固醇/(mmol/L) 高密度脂蛋白胆固醇/(mmol/L) C反应蛋白/(mg/L) D-二聚体/(mg/L) 脂蛋白a/(mg/L) ACS组 316 4.02(3.86, 4.17) 1.74(1.60, 1.88) 2.26(2.16, 2.35) 0.96(0.92, 1.00) 5.46(3.55, 7.37) 0.57(0.39, 0.74) 363.68(327.29, 400.08) 对照组 88 3.96(3.73, 4.18) 1.47(1.25, 1.69) 2.04(2.01, 2.16) 1.01(0.94, 1.07) 4.54(1.92, 7.16) 0.76(0.12, 1.41) 287.57(237.61, 337.53) Zc — 1.98 2.31 3.05 1.88 1.60 0.37 0.37 P — >0.05 < 0.05 < 0.05 < 0.05 >0.05 >0.05 >0.05 *示t值;#示χ2值 表 2 不同病人血浆GPX4水平比较
分组 n GPX4/(ng/mL) ACS组 316 103.80(101.50,106.11) 对照组 88 131.38(126.31,136.45) Zc — 9.48 P — < 0.05 UAP组 261 105.09(102.67,107.51) AMI组 55 104.23(98.47,109.99) Zc — 0.49 P — >0.05 表 3 TIMI危险分层低危组、中危组和高危组病人基线资料比较[M(P25, P75)]
分组 n 年龄/岁 男 高血压 糖尿病 血糖/(mmol/L) 尿酸/(μmol/L) 肌酐/(μmol/L) 总胆固醇/(mmol/L) 三酰甘油/(mmol/L) 低危组 53 54.58±7.85 41 24 8 5.18(4.57, 5.79) 342.78(314.89, 370.66) 66.95(63.58, 70.32) 4.04(3.66, 4.42) 1.72(1.33, 2.12) 中危组 227 64.46±10.61* 142 146* 46 5.81(5.43, 6.19) 309.49(296.17, 322.80) 71.10(68.29, 73.91) 4.00(3.80, 4.19) 1.74(1.57, 1.92) 高危组 36 69.03±9.56* 18* 32* 22* 6.77(5.11, 8.42) 302.44(268.93, 335.95) 72.56(63.50, 81.62) 4.20(3.70, 4.71) 1.79(1.50, 2.09) Zc — 27.00 7.41 17.61# 31.50# 5.97 4.60 0.53 1.58 4.11 P — < 0.01 < 0.05 < 0.01 < 0.01 >0.05 >0.05 >0.05 >0.05 >0.05 分组 n 低密度脂蛋白胆固醇/(mmol/L) 高密度脂蛋白胆固醇/(mmol/L) C反应蛋白/(mg/L) D-二聚体/(mg/L) 脂蛋白a/(mg/L) Gensini评分 GPX4 /(ng/mL) 低危组 53 2.30(2.03, 2.57) 0.96(0.90, 1.03) 1.59(1.01, 2.18) 0.26(0.16, 0.37) 363.68(327.29, 400.08) 23.75(16.70, 30.80) 114.63(107.46, 121.79) 中危组 227 2.14(2.02, 2.27) 0.95(0.92, 0.98) 5.91(3.42, 8.41)* 0.57(0.34, 0.79)* 332.72(291.79, 373.65) 33.18(28.54, 37.81) 101.61(99.01, 104.20)* 高危组 36 2.41(2.07, 2.74) 1.06(0.69, 1.43) 8.38(1.23, 15.54)* 0.79(0.35, 1.24)* 378.36(248.47, 508.25) 52.44(37.23, 67.65)* 102.75(96.85, 108.66)* Zc — 3.68 3.53 9.99 16.49 3.67 13.78 14.50 P — >0.05 >0.05 < 0.01 < 0.01 >0.05 < 0.01 < 0.05 与低危组比较*P < 0.05;#示χ2值 -
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