Cardiac Rac1 overexpression in mice creates a substrate for atrial arrhythmias characterized by structural remodelling
Cardiac Rac1 overexpression in mice creates a substrate for atrial arrhythmias characterized by structural remodelling
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DOI：
10.1093/cvr/cvq079
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发表时间：
2010-08-01
影响因子：
10.8
通讯作者：
Neuberger, Hans-Ruprecht
中科院分区：
文献类型：
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作者：
Reil, Jan-Christian;Hohl, Mathias;Neuberger, Hans-Ruprecht
小GTPase Rac1似乎在房颤（AF）的发病机制中起作用。本研究的目的是表征Rac1过表达对心房电生理的影响。在心脏过表达构成性活性Rac1 （RacET）、他汀类药物治疗的RacET和野生型对照（6个月大）的小鼠中，右心房和左心房（RA和LA）的传导被绘制为心外膜。测定心房有效不应期（AERP），检测心房心律失常的诱发性。在离体细胞中记录动作电位。采用压力-容积法测定左心室功能。11个RacET心脏中有5个出现自发性或诱导性心房性心动过速，对照组9个中0个（P < 0.05）。在RacET中，P波持续时间明显更长（26.8 +/- 2.1 vs. 16.7 +/- 1.1 ms, P = 0.001），总心房激活时间也更长（RA: 13.6 +/- 4.4 vs. 3.2 +/- 0.5 ms; LA: 7.1 +/- 1.2 vs. 2.2 +/- 0.3 ms, P < 0.01）。局部传导时间延长在RacET组更常见（RA: 24.4 +/- 3.8 vs. 2.7 +/- 2.1%; LA: 19.1 +/- 6.3 vs. 1.2 +/- 0.7%, P < 0.01）。两组间AERP和动作电位持续时间无显著差异。RacET显示明显的心房纤维化，但只有中度收缩期心力衰竭。RacET与他汀类药物治疗的RacET在心房电生理方面无显著差异。Rac1过表达小鼠心房心律失常的底物以传导障碍和心房纤维化为特征。电重构（即缩短AERP）不起作用。在该模型中，他汀类药物治疗不能阻止显著的Rac1过表达的结构和电生理效应。
The small GTPase Rac1 seems to play a role in the pathogenesis of atrial fibrillation (AF). The aim of the present study was to characterize the effects of Rac1 overexpression on atrial electrophysiology.In mice with cardiac overexpression of constitutively active Rac1 (RacET), statin-treated RacET, and wild-type controls (age 6 months), conduction in the right and left atrium (RA and LA) was mapped epicardially. The atrial effective refractory period (AERP) was determined and inducibility of atrial arrhythmias was tested. Action potentials were recorded in isolated cells. Left ventricular function was measured by pressure-volume analysis. Five of 11 RacET hearts showed spontaneous or inducible atrial tachyarrhythmias vs. 0 of 9 controls (P < 0.05). In RacET, the P-wave duration was significantly longer (26.8 +/- 2.1 vs. 16.7 +/- 1.1 ms, P = 0.001) as was total atrial activation time (RA: 13.6 +/- 4.4 vs. 3.2 +/- 0.5 ms; LA: 7.1 +/- 1.2 vs. 2.2 +/- 0.3 ms, P < 0.01). Prolonged local conduction times occurred more often in RacET (RA: 24.4 +/- 3.8 vs. 2.7 +/- 2.1%; LA: 19.1 +/- 6.3 vs. 1.2 +/- 0.7%, P < 0.01). The AERP and action potential duration did not differ significantly between both groups. RacET demonstrated significant atrial fibrosis but only moderate systolic heart failure. RacET and statin-treated RacET were not significantly different regarding atrial electrophysiology.The substrate for atrial arrhythmias in mice with Rac1 overexpression is characterized by conduction disturbances and atrial fibrosis. Electrical remodelling (i.e. a shortening of AERP) does not play a role. Statin treatment cannot prevent the structural and electrophysiological effects of pronounced Rac1 overexpression in this model.