甲亢源性心房颤动与心房交感神经重构相关的发病机制研究
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摘要
目的研究甲亢源性房颤与心房交感神经重构相关的发病机制。方法选取50只成年健康日本大耳兔,按照随机数字表法分为给药2月组(n=20)、给药4月组(n=20)、对照组(n=10)。给药2月组每日腹腔内注射甲状腺素50μg/kg,持续2个月;给药4月组每日腹腔内注射甲状腺素50μg/kg,持续4个月;对照组每日腹腔内注射等剂量生理盐水,持续4个月。制备甲亢房颤易患动物模型,比较三组基础资料、左心房有效不应期(LAERP)、房颤诱发率,以及交感神经激活和重构相关指标的表达情况。结果①实验后,给药2月组和给药4月组体重低于对照组,且给药4月组体重低于给药2月组(P <0.05);给药2月组和给药4月组心率快于对照组(P <0.05)。②给药2月组、给药4月组的LAERP均短于对照组,且给药4月组短于给药2月组(P <0.05)。③给药4月组的房颤诱发率高于给药2月组和对照组(P <0.05)。④给药2月组和给药4月组去甲肾上腺素水平高于对照组(P <0.05)。⑤给药2月组、给药4月组酪氨酸羟化酶(TH)和生长相关蛋白-43(GAP-43)的mRNA相对表达量高于对照组(P <0.05),且给药4月组GAP-43 mRNA相对表达量高于给药2月组(P <0.05)。⑥给药2月组、给药4月组TH和GAP-43蛋白相对表达量高于对照组(P <0.05),且给药4月组GAP-43蛋白相对表达量高于给药2月组(P <0.05)。结论持续高水平甲状腺素暴露下心房交感神经被过度激活、重构,其可能是甲亢源性心房颤动的发病机制之一。
Objective To study the pathogenesis of hyperthyroidism-induced atrial fibrillation and atrial sympathetic nerve remodeling. Methods According to random number table method, 50 adult healthy Japanese big ear rabbits were divided into two month administration group(n = 20), four month administration group(n = 20) and control group(n =10). The two month administration group received intraperitoneal injection of thyroxine 50 μg/kg daily for 2 months, the four month administration group received intraperitoneal injection of thyroxine 50 μg/kg daily for 4 months, and the control group received intraperitoneal injection of equal dose of normal saline for 4 months. Animal models of hyperthyroidism and atrial fibrillation vulnerability were prepared. The basic data, left atrial effective refractory period(LAERP), induced rate of atrial fibrillation, and expression of related indicators of sympathetic nerve activation and remodeling were compared among the three groups. Results ①After the experiment, the body weight of two month administration group and four month administration group were lower than those of control group, and the body weight of four month administration group was lower than that of two month administration group(P < 0.05); the heart rate of two month administration group and four month administration group were faster than those of control group(P < 0.05). ②The LAERP in the two month administration group and four month administration group were shorter than those in the control group, and that in the four month administration group was shorter than that in the two month administration group(P < 0.05). ③The induced rate of atrial fibrillation in the four month administration group was higher than that in the two month administration group and the control group(P < 0.05). ④The level of norepinephrine in the two month administration group and the four month administration group were higher than those in the control group(P < 0.05). ⑤The relative expression of tyrosine hydroxylase(TH) and growth associated proteins-43(GAP-43) mRNA in the two month administration group and four month administration group were higher than those in the control group(P < 0.05), and the relative expression of GAP-43 mRNA in the four month administration group was higher than that in the two month administration group(P < 0.05). ⑥The relative expression of TH and GAP-43 protein in the two month administration group and four month administration group were higher than those in the control group(P < 0.05), and the relative expression of GAP-43 protein in the four month administration group was higher than that in the two month administration group(P < 0.05). Conclusion Atrial sympathetic nerve is overactivated and remodeled under continuous high level of thyroxine exposure, which may be one of the pathogenesis of hyperthyroidisminduced atrial fibrillation.
Objective To study the pathogenesis of hyperthyroidism-induced atrial fibrillation and atrial sympathetic nerve remodeling. Methods According to random number table method, 50 adult healthy Japanese big ear rabbits were divided into two month administration group(n = 20), four month administration group(n = 20) and control group(n =10). The two month administration group received intraperitoneal injection of thyroxine 50 μg/kg daily for 2 months, the four month administration group received intraperitoneal injection of thyroxine 50 μg/kg daily for 4 months, and the control group received intraperitoneal injection of equal dose of normal saline for 4 months. Animal models of hyperthyroidism and atrial fibrillation vulnerability were prepared. The basic data, left atrial effective refractory period(LAERP), induced rate of atrial fibrillation, and expression of related indicators of sympathetic nerve activation and remodeling were compared among the three groups. Results ①After the experiment, the body weight of two month administration group and four month administration group were lower than those of control group, and the body weight of four month administration group was lower than that of two month administration group(P < 0.05); the heart rate of two month administration group and four month administration group were faster than those of control group(P < 0.05). ②The LAERP in the two month administration group and four month administration group were shorter than those in the control group, and that in the four month administration group was shorter than that in the two month administration group(P < 0.05). ③The induced rate of atrial fibrillation in the four month administration group was higher than that in the two month administration group and the control group(P < 0.05). ④The level of norepinephrine in the two month administration group and the four month administration group were higher than those in the control group(P < 0.05). ⑤The relative expression of tyrosine hydroxylase(TH) and growth associated proteins-43(GAP-43) mRNA in the two month administration group and four month administration group were higher than those in the control group(P < 0.05), and the relative expression of GAP-43 mRNA in the four month administration group was higher than that in the two month administration group(P < 0.05). ⑥The relative expression of TH and GAP-43 protein in the two month administration group and four month administration group were higher than those in the control group(P < 0.05), and the relative expression of GAP-43 protein in the four month administration group was higher than that in the two month administration group(P < 0.05). Conclusion Atrial sympathetic nerve is overactivated and remodeled under continuous high level of thyroxine exposure, which may be one of the pathogenesis of hyperthyroidisminduced atrial fibrillation.
引文
[1]李现彪.甲状腺机能亢进症对心血管系统功能的影响及分析[D].长春:吉林大学,2016.
[2]陈海兰,高宇.甲状腺功能亢进症合并心血管疾病研究进展[J].中国老年学,2016,36(16):4122-4124.
[3]Li J,Tan H,Huang J,et al.Case report of recurrent atrial fibrillation induced by thyrotropin-secreting pituitary adenoma with Graves′disease[J].Medicine(Baltimore),2018,97(24):e11047.
[4]黎国兴,李骊华.甲状腺功能亢进与心房颤动相关性的研究进展[J].西部医学,2017,29(7):1023-1027.
[5]王芳.分析探讨甲状腺疾病的临床诊断与治疗[J].中国实用医药,2016,11(4):177-178.
[6]Shen MJ,Zipes DP.Role of the autonomic nervous system in modulating cardiac arrhythmias[J].Circ Res,2014,114(6):1004-1021.
[7]Chen PS,Chen LS,Fishbein MC,et al.Role of the autonomic nervous system in atrial fibrillation:pathophysiology and therapy[J].Circ Res,2014,114(9):1500-1515.
[8]郑甲林,郭涛,张新金.高甲状腺素心房颤动易患模型制作及左心房电生理变化的影响研究[J].中国生化药物杂志,2015,35(4):48-50,54.
[9]宋文荣.疏肝潜阳汤配合普萘洛尔治疗甲状腺功能亢进合并房颤疗效观察[J].现代中西医结合杂志,2018,27(9):969-972.
[10]孟军,孙莉萍,陈涛.甲状腺激素与慢性心力衰竭衰患者心房颤动发生的相关分析[J].岭南心血管病杂志,2017,23(1):67-70.
[11]Reddy V,Taha W,Kundumadam S,et al.Atrial fibrillation and hyperthyroidism:A literature review[J].Indian Heart J,2017,69(4):545-550.
[12]Rosario PW,Carvalho M,Calsolari MR.Symptoms of thyrotoxicosis,bone metabolism and occult atrial fibrillation in older women with mild endogenous subclinical hyperthyroidism[J].Clin Endocrinol(Oxf),2016,85(1):132-136.
[13]Liu L,Yun F,Zhao H,et al.Atrial sympathetic remodeling in experimental hyperthyroidism and hypothyroidism rats[J].Int J Cardiol,2015,187(1):148-150.
[14]Hammond HK,White FC,Buxton IL,et al.Increased myocardial beta-receptors and adrenergic responses in hyperthyroid pigs[J].Am J Physiol,1987,252(2):H283-H290.
[15]Nammas W,Airaksinen JK,Paana T,et al.Renal sympathetic denervation for treatment of patients with atrial fibrillation:Reappraisal of the available evidence[J].Heart Rhythm,2016,13(12):2388-2394.
[16]Kiuchi MG,Chen S,E Silva GR,et al.Pulmonary vein isolation alone and combined with renal sympathetic denervation in chronic kidney disease patients with refractory atrial fibrillation[J].Kidney Res Clin Pract,2016,35(4):237-244.
[17]Oliveira M,Postolache G,Geraldes V,et al.Acute electrophysiological modulation of the atria and pulmonary veins:effects of sympathetic and parasympathetic interaction on atrial fibrillation inducibility[J].Rev Port Cardiol,2012,31(3):215-223.
[18]陈思,周忠.CT引导下胸交感神经阻滞治疗甲亢所致心力衰竭的价值探讨[J].中国现代医生,2017,55(7):12-15.
[19]Jayachandran JV,Sih HJ,Winkle W,et al.Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation[J].Circulation,2000,101(10):1185-1191.
[20]Gould PA,Yii M,McLean C,et al.Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation[J].Pacing Clin Electrophysiol,2006,29(8):821-829.
[21]de Jong MR,Hoogerwaard AF,Adiyaman A,et al.Treatment of atrial fibrillation in patients with enhanced sympathetic tone by pulmonary vein isolation or pulmonary vein isolation and renal artery denervation:clinical background and study design:The ASAF trial:ablation of sympathetic atrial fibrillation[J].Clin Res Cardiol,2018,107(7):539-547.
[2]陈海兰,高宇.甲状腺功能亢进症合并心血管疾病研究进展[J].中国老年学,2016,36(16):4122-4124.
[3]Li J,Tan H,Huang J,et al.Case report of recurrent atrial fibrillation induced by thyrotropin-secreting pituitary adenoma with Graves′disease[J].Medicine(Baltimore),2018,97(24):e11047.
[4]黎国兴,李骊华.甲状腺功能亢进与心房颤动相关性的研究进展[J].西部医学,2017,29(7):1023-1027.
[5]王芳.分析探讨甲状腺疾病的临床诊断与治疗[J].中国实用医药,2016,11(4):177-178.
[6]Shen MJ,Zipes DP.Role of the autonomic nervous system in modulating cardiac arrhythmias[J].Circ Res,2014,114(6):1004-1021.
[7]Chen PS,Chen LS,Fishbein MC,et al.Role of the autonomic nervous system in atrial fibrillation:pathophysiology and therapy[J].Circ Res,2014,114(9):1500-1515.
[8]郑甲林,郭涛,张新金.高甲状腺素心房颤动易患模型制作及左心房电生理变化的影响研究[J].中国生化药物杂志,2015,35(4):48-50,54.
[9]宋文荣.疏肝潜阳汤配合普萘洛尔治疗甲状腺功能亢进合并房颤疗效观察[J].现代中西医结合杂志,2018,27(9):969-972.
[10]孟军,孙莉萍,陈涛.甲状腺激素与慢性心力衰竭衰患者心房颤动发生的相关分析[J].岭南心血管病杂志,2017,23(1):67-70.
[11]Reddy V,Taha W,Kundumadam S,et al.Atrial fibrillation and hyperthyroidism:A literature review[J].Indian Heart J,2017,69(4):545-550.
[12]Rosario PW,Carvalho M,Calsolari MR.Symptoms of thyrotoxicosis,bone metabolism and occult atrial fibrillation in older women with mild endogenous subclinical hyperthyroidism[J].Clin Endocrinol(Oxf),2016,85(1):132-136.
[13]Liu L,Yun F,Zhao H,et al.Atrial sympathetic remodeling in experimental hyperthyroidism and hypothyroidism rats[J].Int J Cardiol,2015,187(1):148-150.
[14]Hammond HK,White FC,Buxton IL,et al.Increased myocardial beta-receptors and adrenergic responses in hyperthyroid pigs[J].Am J Physiol,1987,252(2):H283-H290.
[15]Nammas W,Airaksinen JK,Paana T,et al.Renal sympathetic denervation for treatment of patients with atrial fibrillation:Reappraisal of the available evidence[J].Heart Rhythm,2016,13(12):2388-2394.
[16]Kiuchi MG,Chen S,E Silva GR,et al.Pulmonary vein isolation alone and combined with renal sympathetic denervation in chronic kidney disease patients with refractory atrial fibrillation[J].Kidney Res Clin Pract,2016,35(4):237-244.
[17]Oliveira M,Postolache G,Geraldes V,et al.Acute electrophysiological modulation of the atria and pulmonary veins:effects of sympathetic and parasympathetic interaction on atrial fibrillation inducibility[J].Rev Port Cardiol,2012,31(3):215-223.
[18]陈思,周忠.CT引导下胸交感神经阻滞治疗甲亢所致心力衰竭的价值探讨[J].中国现代医生,2017,55(7):12-15.
[19]Jayachandran JV,Sih HJ,Winkle W,et al.Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation[J].Circulation,2000,101(10):1185-1191.
[20]Gould PA,Yii M,McLean C,et al.Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation[J].Pacing Clin Electrophysiol,2006,29(8):821-829.
[21]de Jong MR,Hoogerwaard AF,Adiyaman A,et al.Treatment of atrial fibrillation in patients with enhanced sympathetic tone by pulmonary vein isolation or pulmonary vein isolation and renal artery denervation:clinical background and study design:The ASAF trial:ablation of sympathetic atrial fibrillation[J].Clin Res Cardiol,2018,107(7):539-547.