Chronic angiotensin II stimulation in the heart produces an acquired long QT syndrome associated with IK1 potassium current downregulation
Chronic angiotensin II stimulation in the heart produces an acquired long QT syndrome associated with IK1 potassium current downregulation
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DOI：
10.1016/j.yjmcc.2006.09.019
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发表时间：
2007-01-01
影响因子：
5
通讯作者：
Pedrazzini, Thierry
中科院分区：
文献类型：
--
作者：
Domenighetti, Andrea A.;Boixel, Christophe;Pedrazzini, Thierry
心脏肥厚是心血管疾病发病率和死亡率的独立预测因子。它使患者易患心力衰竭、QT间期延长和室性心律失常。血管紧张素II （angii）直接作用于心肌组织，诱导心肌细胞肥大和机电功能障碍。然而，Ang II与心肌细胞电重构之间的直接关联尚未得到证实。转基因TG1306/1R （TG）小鼠心脏特异性Ang II分泌过量，表现出血压不依赖型心脏肥厚，并表现出与机械功能障碍相关的猝死显著增加。本研究利用TG小鼠来评价高水平的心内angii对心脏电生理的直接影响。记录50至60周龄TG和野生型（WT）小鼠的体表肢体心电图测量。与WT相比，TG小鼠QT间期明显延长（+20%）。TG小鼠室性心律失常的发生率也增加。QT延长与90%复极心肌细胞动作电位（APD90）延长相关。APD90的变化与TG与WT心肌细胞IK1钾电流密度的降低相关（-70 mV: 0.3 +/- 0.1 pA/pF vs. 0.8 +/- 0.2 pA/pF, P < 0.05）。在TG小鼠中，IK1的减少与IK1相关的KCNJ2和KCNJ12钾通道Kir2.1和Kir2.2亚基mRNA的显著减少（-50%）相关。这些数据表明，心脏angii的过量产生导致长QT综合征的出现，这是由于ik1依赖性的动作电位持续时间的延长，通过通道亚基表达的调节。(c) 2006爱思唯尔公司版权所有。
Cardiac hypertrophy is an independent predictor of cardiovascular morbidity and mortality. It predisposes patients to heart failure, QT interval prolongation and ventricular arrhythmias. Angiotensin II (Ang II) exerts direct actions on cardiac tissue inducing cardiomyocyte hypertrophy and electro-mechanical dysfunction. However, a direct association between Ang II and cardiomyocyte electrical remodeling has yet to be demonstrated. Transgenic TG1306/1R (TG) mice with cardiac-specific Ang II overproduction demonstrate blood pressure-independent cardiac hypertrophy and exhibit significant increase in sudden death associated with mechanical dysfunction. The present study makes use of TG mice to evaluate the direct effects of high levels of intracardiac Ang II on cardiac electrophysiology. Surface-limb ECG measurements were recorded on 50- to 60-week-old TG and wild-type (WT) mice. QT interval was significantly prolonged (+20%) in TG mice relative to WT. TG mice also showed an increased incidence of ventricular arrhythmias. QT prolongation was associated with prolongation of cardiomyocyte action potential at 90% repolarization (APD90). The change in APD90 correlated with a reduction in IK1 potassium current density in TG vs. WT cardiomyocytes (at -70 mV: 0.3 +/- 0.1 pA/pF vs. 0.8 +/- 0.2 pA/pF, P < 0.05). In TG mice, reduction in IK1 was associated with a significant reduction (-50%) of the mRNA encoding Kir2.1 and Kir2.2 subunits of IK1-related KCNJ2 and KCNJ12 potassium channels. These data suggest that cardiac Ang II overproduction leads to the emergence of a long QT syndrome resulting from an IK1-dependent prolongation of the action potential duration through modulation of channel subunit expression. (c) 2006 Elsevier Inc. All rights reserved.