Triggered Firing and Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Induced by Overexpression of TGF-β1

被引：49

作者：

Choi, Eue-Keun ^{[1
,2
]}

Chang, Po-Cheng ^{[1
,2
]}

Lee, Young-Soo ^{[1
,2
]}

Lin, Shien-Fong ^{[1
,2
]}

Zhu, Wuqiang ^{[3
]}

Maruyama, Mitsunori ^{[1
,2
]}

Fishbein, Michael C. ^{[4
]}

Chen, Zhenhui ^{[1
,2
]}

Rubart-von der Lohe, Michael ^{[3
]}

Field, Loren J. ^{[3
]}

Chen, Peng-Sheng ^{[1
,2
]}

机构：

[1] Indiana Univ Sch Med, Krannert Inst Cardiol, Indianapolis, IN USA

[2] Indiana Univ Sch Med, Dept Med, Div Cardiol, Indianapolis, IN USA

[3] Indiana Univ Sch Med, Dept Pediat, Riley Heart Res Ctr, Herman B Wells Ctr Pediat Res, Indianapolis, IN USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Div Anat Pathol, Los Angeles, CA 90095 USA

来源：

CIRCULATION JOURNAL | 2012年 / 76卷 / 06期

基金：

美国国家卫生研究院;

关键词：

Arrhythmia; Atrial fibrillation; Ca2+-triggers; Optical mapping; Transgenic mice models; PULMONARY VEINS; IN-VITRO; HEART; ARRHYTHMIA; MUSCLE; PROPAGATION; TACHYCARDIA; INITIATION; MECHANISM;

D O I：

10.1253/circj.CJ-11-1301

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: Calcium transient triggered firing (CTTF) is induced by large intracellular Calcium (Cai) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early after-depolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor beta 1 (TGF-beta 1). Methods and Results: MHC-TGFcys(33)ser Tx mice develop atrial fibrosis because of elevated levels of TGF-beta 1. We studied membrane potential and Cai transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Cai transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39% vs. 0%, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100%), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Cai(2+)-ATPase 2a. Conclusions: Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Cai transient, EAD and triggered activity. Inhibition of Ca2+ release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-beta 1 Tx atria. (Circ J 2012; 76: 1354-1362)

引用

页码：1354 / 1362

页数：9

共 30 条

[1] Altered right atrial excitation and propagation in Connexin40 knockout mice [J].