螺内酯对持续性心房起搏犬心房颤动模型心房结构重构的影响。
Effects of spironolactone on atrial structural remodelling in a canine model of atrial fibrillation produced by prolonged atrial pacing.
机构信息
Department of Cardiology, The First Affiliated Hospital, Harbin Medical University, Heilongjiang, China.
出版信息
Br J Pharmacol. 2010 Apr;159(8):1584-94. doi: 10.1111/j.1476-5381.2009.00551.x. Epub 2010 Jan 15.
BACKGROUND AND PURPOSE
Suppression of the renin-angiotensin-aldosterone system can prevent atrial fibrillation (AF) by attenuating atrial structural remodelling but the role of aldosterone in AF prevention has not been investigated thoroughly. We explored whether the aldosterone antagonist, spironolactone, could improve atrial structural remodelling in long-term rapid pacing-induced AF.
EXPERIMENTAL APPROACH
Three groups of dogs were used, sham-operated, control and spironolactone-treated groups. Dogs in the control and spironolactone groups had right atrial pacing for 6 weeks. The spironolactone group was given spironolactone 1 week before and during the atrial pacing. After 6 weeks of pacing, atrial structural and functional changes were assessed by echocardiography, haemodynamic parameters by cardiac catheterization, histopathological changes by light and electron microscopy and cardiomyocyte apoptosis by TUNEL. Caspase-3, Bcl-2, bax, calpain I, calpastatin, matrix metalloproteinase (MMP)-9 and tissue inhibitors of metalloproteinase (TIMP)-1 were analysed by immunohistochemistry and Western blotting. The inducibility and duration of AF were measured by atrial burst pacing.
KEY RESULTS
After atrial pacing, the proportion of TUNEL positive cells, myolysis, atrial fibrosis and dilatation were all significantly increased and these changes were inhibited by spironolactone. Spironolactone treatment reversed the increased expression of caspase-3, bax, calpain I and MMP-9 and the decreased level of Bcl-2, calpastatin and TIMP-1, induced by chronic atrial pacing. Also spironolactone prevented the increased inducibility and duration of AF, induced by tachypacing.
CONCLUSIONS AND IMPLICATIONS
Treatment with spironolactone prevented myocardial apoptosis, myolysis, atrial fibrosis and dilatation, suggesting a possible beneficial effect of aldosterone antagonism on atrial structural remodelling in AF.
背景与目的
抑制肾素-血管紧张素-醛固酮系统可以通过减轻心房结构重塑来预防心房颤动（AF），但醛固酮在预防 AF 中的作用尚未得到充分研究。我们探讨了醛固酮拮抗剂螺内酯是否能改善长期快速起搏诱导的 AF 中的心房结构重塑。
实验方法
使用三组狗，假手术组、对照组和螺内酯治疗组。对照组和螺内酯组的狗接受右心房起搏 6 周。螺内酯组在心房起搏前 1 周和期间给予螺内酯。起搏 6 周后，通过超声心动图评估心房结构和功能变化，通过心导管术评估血流动力学参数，通过光镜和电镜评估组织学变化，通过 TUNEL 评估心肌细胞凋亡。通过免疫组织化学和 Western blot 分析半胱天冬酶-3、Bcl-2、Bax、钙蛋白酶 I、钙蛋白酶抑制剂、基质金属蛋白酶（MMP）-9 和组织金属蛋白酶抑制剂（TIMP）-1。通过心房爆发起搏测量 AF 的可诱导性和持续时间。
主要结果
起搏后，TUNEL 阳性细胞、肌溶解、心房纤维化和扩张的比例均显著增加，螺内酯抑制了这些变化。螺内酯治疗逆转了慢性心房起搏诱导的 caspase-3、Bax、钙蛋白酶 I 和 MMP-9 表达增加，Bcl-2、钙蛋白酶抑制剂和 TIMP-1 表达降低。螺内酯还预防了快速起搏诱导的 AF 可诱导性和持续时间的增加。
结论和意义
螺内酯治疗预防了心肌细胞凋亡、肌溶解、心房纤维化和扩张，表明醛固酮拮抗在 AF 中的心房结构重塑中可能具有有益作用。
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