Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice
Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice
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DOI：
10.1172/jci44350
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发表时间：
2011-02-01
影响因子：
15.9
通讯作者：
Christoffels, Vincent M.
中科院分区：
文献类型：
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作者：
Aanhaanen, Wim T. J.;Boukens, Bastiaan J. D.;Christoffels, Vincent M.
心室预兴奋是沃尔夫-帕金森-怀特综合征的一个特征，是由绕过纤维环的辅助心肌通路引起的。这种情况会增加房室性心动过速的风险，在房颤存在时，会增加猝死的风险。副通路形成的发育机制尚不清楚，但被认为主要与纤维环畸形有关。在出生前，缓慢传导的房室心肌在纤维环缺失的情况下导致功能性房室激活延迟。这种心肌在出生后仍然存在，表明房室管心肌发育紊乱可能介导了快速传导的副通路的形成。本研究表明，T-box 2 （Tbx2）是房室管形成所必需的转录因子，其心肌特异性失活可导致小鼠快速传导副通路的形成、纤维环畸形和心室预兴奋。辅助通路异位表达快速传导所需的蛋白质（connexin-40 [Cx40]， Cx43和钠通道，电压门控，V型，α [Scn5a]）。Cx30.2（在房室管中表达的低电导间隙连接的亚基，不受Tbx2缺失的影响）的进一步失活不影响副通路的功能。我们的研究结果表明，纤维环畸形和预兴奋是由房室心肌发育紊乱引起的。
Ventricular preexcitation, a feature of Wolff-Parkinson-White syndrome, is caused by accessory myocardial pathways that bypass the annulus fibrosus. This condition increases the risk of atrioventricular tachycardia and, in the presence of atrial fibrillation, sudden death. The developmental mechanisms underlying accessory pathway formation are poorly understood but are thought to primarily involve malformation of the annulus fibrosus. Before birth, slowly conducting atrioventricular myocardium causes a functional atrioventricular activation delay in the absence of the annulus fibrosus. This myocardium remains present after birth, suggesting that the disturbed development of the atrioventricular canal myocardium may mediate the formation of rapidly conducting accessory pathways. Here we show that myocardium-specific inactivation of T-box 2 (Tbx2), a transcription factor essential for atrioventricular canal patterning, leads to the formation of fast-conducting accessory pathways, malformation of the annulus fibrosus, and ventricular preexcitation in mice. The accessory pathways ectopically express proteins required for fast conduction (connexin-40 [Cx40], Cx43, and sodium channel, voltage-gated, type V, alpha [Scn5a]). Additional inactivation of Cx30.2, a subunit for gap junctions with low conductance expressed in the atrioventricular canal and unaffected by the loss of Tbx2, did not affect the functionality of the accessory pathways. Our results suggest that malformation of the annulus fibrosus and preexcitation arise from the disturbed development of the atrioventricular myocardium.