Klinik für Innere Medizin III (Kardiologie, Angiologie, Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Kirrberger Strasse, Homburg/Saar D 66421, Germany.
Cardiovasc Res. 2010 Aug 1;87(3):485-93. doi: 10.1093/cvr/cvq079. Epub 2010 Mar 7.
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.
小分子 GTP 酶 Rac1 似乎在心房颤动（AF）的发病机制中起作用。本研究的目的是描述 Rac1 过表达对心房电生理的影响。
在心脏过表达组成型激活 Rac1（RacET）、他汀治疗的 RacET 和野生型对照（6 月龄）的小鼠中，进行心外膜标测右心房（RA）和左心房（LA）的传导。测定心房有效不应期（AERP）并检测心房心律失常的易感性。在分离细胞中记录动作电位。通过压力-容积分析测量左心室功能。在 11 只 RacET 心脏中有 5 只显示自发性或诱发性房性心动过速，而在 9 只对照中无 1 只（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）。RacET 中更常出现局部传导时间延长（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 表现出明显的心房纤维化，但仅有中度收缩性心力衰竭。RacET 和他汀治疗的 RacET 在心房电生理方面没有显著差异。
在 Rac1 过表达的小鼠中，心房颤动的发生基质特征为传导障碍和心房纤维化。电重构（即 AERP 缩短）不起作用。在这种模型中，他汀类药物治疗不能预防明显的 Rac1 过表达的结构和电生理效应。
