Cardiac-specific overexpression of the human type 1 angiotensin II receptor causes delayed repolarization
Cardiac-specific overexpression of the human type 1 angiotensin II receptor causes delayed repolarization
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DOI：
10.1093/cvr/cvn020
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发表时间：
2008-04-01
影响因子：
10.8
通讯作者：
Fiset, Celine
中科院分区：
文献类型：
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作者：
Rivard, Katy;Paradis, Pierre;Fiset, Celine
心脏特异性过表达人血管紧张素II 1型受体（AT1R）的小鼠经历心脏重塑并因猝死而过早死亡。由于QT间期过度延长是室性心律失常和猝死的主要危险因素，我们假设慢性刺激AT1R可能通过促进延迟复极和室性心律失常而导致猝死。在AT1R小鼠中进行心室复极参数的详细分析。与同窝对照组（CTL）相比，8个月的AT1R交配小鼠的Ca2+非依赖性瞬时外向（I-to）、超快速延迟整流（I-Kur）和内向整流（IK1）K+电流显著降低。在AT1R心室中，基础K+通道的表达也减少。此外，在AT1R小鼠中，It.的再激活较慢。与这些发现一致，AT1R小鼠表现出较长的动作电位时程（APD（90），CTL：19.0 +/-1.8 ms; AT1R：39.1 +/-4.7 ms，P = 0.0001）和QTc间期（CTL：53.6 +/-1.5 ms，AT1R：64.2 +/-1.4 ms，P = 0.0005）。此外，在AT1R小鼠中报告了自发性室性心律失常。重要的是，心律失常和复极缺陷的发病率增加也发生在年轻得多的AT1R小鼠，不存在肥大的迹象，证实这些致心律失常的变化是不是继发于心脏remodeling.Conclusion这些结果强烈表明，慢性刺激AT1R直接导致心律失常的发病率增加与延迟复极。
Aims Mice with cardiac-specific overexpression of human angiotensin II type 1 receptor (AT1R) undergo cardiac remodelling and die prematurely of sudden death. Since excessive QT prolongation is a major risk factor for ventricular arrhythmias and sudden death, we hypothesize that chronic stimulation of AT1R might contribute to sudden death by promoting delayed repolarization and ventricular arrhythmias.Methods In the present study, a detailed analysis of ventricular repolarization parameters was undertaken in AT1R mice.Results Measurement of K+ currents in ventricular myocytes isolated from 6-8 months AT1R mate mice revealed a significant reduction of the Ca2+-independent transient outward (I-to), the ultra-rapid delayed rectifier (I-Kur), and the inward rectifier (IK1) K+ currents compared with littermate controls (CTL). The expression of the underlying K+ channels was also decreased in AT1R ventricles. Moreover, reactivation of It. was slower in AT1R mice. Consistent with these findings, AT1R mice presented a longer action potential duration (APD(90), CTL: 19.0 +/- 1.8 ms; AT1R: 39.1 +/- 4.7 ms, P = 0.0001) and QTc interval (CTL: 53.6 +/- 1.5 ms, AT1R: 64.2 +/- 1.4 ms, P = 0.0005). In addition, spontaneous ventricular arrhythmias were reported in the AT1R mice. Importantly, the increased incidence of arrhythmia and the repolarization defects also occurred in much younger AT1R mice that do not present signs of hypertrophy, confirming that these arrhythmogenic changes are not secondary to cardiac remodelling.Conclusion These results strongly suggest that chronic stimulation of AT1R directly leads to an increased incidence of cardiac arrhythmia associated with delayed repolarization.