帕罗西汀改善AMI伴抑郁症患者心脏功能的作用及对交感神经-GRK2通路的影响
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摘要
目的探究帕罗西汀对急性心肌梗死(AMI)伴抑郁症患者心脏功能的改善作用以及对交感神经-G蛋白-偶联受体激酶2(GRK2)通路的负性调控机制。方法选择2016年7月～2018年5月于平顶山市第二人民医院心内科确诊并住院接受治疗的AMI患者272例,根据焦虑抑郁量表(HAD)和汉密尔顿抑郁量表(HAMD-17)评分,84例为AMI伴抑郁症患者,并将其随机分为帕罗西汀治疗组(n=35,AMID-P),氟西汀治疗组(n=29,AMID-F),未接受任何抗抑郁治疗组(n=20,AMID-N),治疗12周。另外188例未合并抑郁症的AMI患者作为对照组。检测各组患者治疗前后左室射血分数(LVEF)、左室舒张末径(LVEDd)、左心室短轴缩短率(FS)以及心率变异性(HRV)指标,包括高频参数(HF,0.15～0.40 Hz)、低频参数(LF,0.04～0.15 Hz)、全部窦性心搏R-R间期的标准差(SDNN),外周血GRK2、去甲肾上腺素(NE)、肾上腺素(EPI)水平。并采用Spearman相关性分析各指标之间的关系。结果 AMI伴抑郁症患者外周血GRK2水平明显高于单纯AMI患者(P<0.05)。治疗12周后,AMID-P组患者GRK2水平、LVEF、LVEDd、FS、HF、LF、SDNN值均较治疗前有明显改善,且优于AMID-N组和AMID-F组患者(P<0.05)。AMID-P组和AMID-F组患者HAMD-17评分和HAD评分均较治疗前有明显降低(P<0.05),且治疗后两组患者评分未见统计学差异(P>0.05)。经Spearman相关性分析,AMID-P组患者经帕罗西汀治疗后,GRK2水平与SDNN、LF呈负相关性(P<0.05);而与NE、EPI水平以及HAMD-17评分、HAD评分呈正相关性(P<0.05)。结论帕罗西汀可能通过直接或间接抑制GRK2的生成调节交感神经系统的兴奋性,改善急性心肌梗死伴抑郁症患者的心功能。
Objective To study the improving effect of paroxetine on heart function and its negative regulative mechanism to sympathetic nerve-G protein-coupled receptor kinase 2(GRK2) in patients with acute myocardial infarction(AMI) accompanied by depression. Methods AMI patients(n=272) were chosen from Department of Cardiology of the Second People's Hospital of Pingdingshan City from July 2016 to May 2018. All patients were scored according to hospital anxiety and depression scale(HADS) and Hamilton Depression Scale(HAMD-17),and among them there were 84 patients with AMI accompanied by depression, who were divided randomly into paroxetine treatment group(n=35, AMID-P group), fluoxetine treatment group(n=29, AMID-F group) and nonantidepression treatment group(n=20, AMID-N group). All patients were treated for 12 weeks. The patients(n=188) with AMI but without depression were chosen into control group. The indexes of left ventricular ejection fraction(LVEF), left ventricular end-diastolic inner diameter(LVEDd), left ventricular fraction shortening(LVFS)and indexes of heart rate variability(HRV) including high frequency(HF, 0.15 Hz-0.40 Hz), low frequency(LF,0.04 Hz-0.15 Hz), standard deviation of all normal RR interval(SDNN), and levels of peripheral blood GRK2,noradrenalin(NE) and epinephrine(EPI) were detected in all groups before and after treatment. The relationship among all indexes was analyzed by using Spearman correlation analysis. Results The level of peripheral blood GRK2 was significantly higher in patients with AMI accompanied by depression than that in those with only AMI(P<0.05). After treatment for 12 weeks, the level of GRK2 and indexes of LVEF, LVEDd, LVFS, HF, LF and SDNN were all improved significantly in AMID-P group, and were superior to those in AMID-N group and AMID-F group(P<0.05). The scores of HAMD-17 and scores of HADS decreased significantly in AMID-P group and AMID-F group(P<0.05), and there was no statistical difference between these 2 groups(P>0.05) after treatment. The results of Spearman correlation analysis showed that level of GRK2 was negatively correlated to SDNN and LF(P<0.05)and positively correlated to NE, EPI, HAMD-17 scores and HADS scores(P<0.05) in AMID-P group. Conclusion Paroxetine can improve heart function possibly through inhibiting directly or indirectly excitability of sympathetic nervous system induced by GRK2 in patients with AMI accompanied by depression.
Objective To study the improving effect of paroxetine on heart function and its negative regulative mechanism to sympathetic nerve-G protein-coupled receptor kinase 2(GRK2) in patients with acute myocardial infarction(AMI) accompanied by depression. Methods AMI patients(n=272) were chosen from Department of Cardiology of the Second People's Hospital of Pingdingshan City from July 2016 to May 2018. All patients were scored according to hospital anxiety and depression scale(HADS) and Hamilton Depression Scale(HAMD-17),and among them there were 84 patients with AMI accompanied by depression, who were divided randomly into paroxetine treatment group(n=35, AMID-P group), fluoxetine treatment group(n=29, AMID-F group) and nonantidepression treatment group(n=20, AMID-N group). All patients were treated for 12 weeks. The patients(n=188) with AMI but without depression were chosen into control group. The indexes of left ventricular ejection fraction(LVEF), left ventricular end-diastolic inner diameter(LVEDd), left ventricular fraction shortening(LVFS)and indexes of heart rate variability(HRV) including high frequency(HF, 0.15 Hz-0.40 Hz), low frequency(LF,0.04 Hz-0.15 Hz), standard deviation of all normal RR interval(SDNN), and levels of peripheral blood GRK2,noradrenalin(NE) and epinephrine(EPI) were detected in all groups before and after treatment. The relationship among all indexes was analyzed by using Spearman correlation analysis. Results The level of peripheral blood GRK2 was significantly higher in patients with AMI accompanied by depression than that in those with only AMI(P<0.05). After treatment for 12 weeks, the level of GRK2 and indexes of LVEF, LVEDd, LVFS, HF, LF and SDNN were all improved significantly in AMID-P group, and were superior to those in AMID-N group and AMID-F group(P<0.05). The scores of HAMD-17 and scores of HADS decreased significantly in AMID-P group and AMID-F group(P<0.05), and there was no statistical difference between these 2 groups(P>0.05) after treatment. The results of Spearman correlation analysis showed that level of GRK2 was negatively correlated to SDNN and LF(P<0.05)and positively correlated to NE, EPI, HAMD-17 scores and HADS scores(P<0.05) in AMID-P group. Conclusion Paroxetine can improve heart function possibly through inhibiting directly or indirectly excitability of sympathetic nervous system induced by GRK2 in patients with AMI accompanied by depression.
引文
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[11]桑城,郝恒剑,许骥,等.心率变异性和QT间期变异性与急性心肌梗死患者室性心律失常的关系研究[J].中国循证心血管医学杂志,2018,11(2):230-2.
[12]Schumacher SM,Koch WJ.Noncanonical roles of G proteincoupled receptor kinases in cardiovascular signaling[J].J Cardiovasc Pharmacol,2017,70(3):129-41.
[13]Lymperopoulos A,Brill A,McCrink KA.GPCRs of adrenal chromaffin cells&catecholamines:The plot thickens[J].Int J Biochem Cell Biol,2016,77(Pt B):213-9.
[14]Tian X,Wang Q,Guo R,et al.Effects of paroxetine-mediated inhibition of GRK2 expression on depression and cardiovascular function in patients with myocardial infarction[J].Neuropsychiatr Dis Treat,2016,12(9):2333-41.
[15]Thal DM,Homan KT,Chen J,et al.Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility[J].ACS Chem Biol,2012,7(11):1830-9.
[2]魏万林,张磊.动脉粥样硬化性心血管疾病与精神心理障碍[J].中国循证心血管医学杂志,2015,8(5):579-82.
[3]Womersley K,Ripullone K,Agius M,et al.What are the risks associated with different Selective Serotonin Re-uptake Inhibitors(SSRIs)to treat depression and anxiety in pregnancy?An evaluation of current evidence[J].Psychiatr Danub,2017,29(Suppl 3):629-44.
[4]Cannavo A,Komici K,Bencivenga L,et al.GRK2 as a therapeutic target for heart failure[J].Expert Opin Ther Targets,2018,22(1):75-83.
[5]中华医学会心血管病学分会,中华心血管病杂志编辑委员会.急性心肌梗死诊断和治疗指南[J].中国循环杂志,2001,16(6):407-22.
[6]王飞,徐晶晶,朱士俊,等.焦虑抑郁对冠心病患者经皮冠状动脉介入治疗预后的影响[J].中国循证心血管医学杂志,2017,10(6):703-4.
[7]Bouley R,Waldschmidt HV,Cato MC,et al.Structural determinants influencing the potency and selectivity of indazole-paroxetine hybrid G protein-coupled receptor kinase 2 inhibitors[J].Mol Pharmacol,2017,92(6):707-17.
[8]Tang J,Dong J,Yang L,et al.Paroxetine alleviates rat limb postischemia induced allodynia through GRK2 upregulation in superior cervical ganglia[J].Int J Clin Exp Med,2015,8(2):2065-76.
[9]Kidwell M,Ellenbroek BA.Heart and soul:heart rate variability and major depression[J].Behav Pharmacol,2018,29(2 and 3-Special Issue):152-64.
[10]翟培彬,马兰,刘星.G蛋白耦联受体信号转导的偏向性调控及其机制研究进展[J].生理学报,2016,53(6):790-8.
[11]桑城,郝恒剑,许骥,等.心率变异性和QT间期变异性与急性心肌梗死患者室性心律失常的关系研究[J].中国循证心血管医学杂志,2018,11(2):230-2.
[12]Schumacher SM,Koch WJ.Noncanonical roles of G proteincoupled receptor kinases in cardiovascular signaling[J].J Cardiovasc Pharmacol,2017,70(3):129-41.
[13]Lymperopoulos A,Brill A,McCrink KA.GPCRs of adrenal chromaffin cells&catecholamines:The plot thickens[J].Int J Biochem Cell Biol,2016,77(Pt B):213-9.
[14]Tian X,Wang Q,Guo R,et al.Effects of paroxetine-mediated inhibition of GRK2 expression on depression and cardiovascular function in patients with myocardial infarction[J].Neuropsychiatr Dis Treat,2016,12(9):2333-41.
[15]Thal DM,Homan KT,Chen J,et al.Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility[J].ACS Chem Biol,2012,7(11):1830-9.