Adenosine-Induced Atrial Fibrillation: Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart.
Adenosine-Induced Atrial Fibrillation: Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart.
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DOI：
10.1161/circulationaha.115.021165
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发表时间：
2016-08-09
期刊：
影响因子：
37.8
通讯作者：
Fedorov VV
中科院分区：
文献类型：
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作者：
Li N;Csepe TA;Hansen BJ;Sul LV;Kalyanasundaram A;Zakharkin SO;Zhao J;Guha A;Van Wagoner DR;Kilic A;Mohler PJ;Janssen PM;Biesiadecki BJ;Hummel JD;Weiss R;Fedorov VV
腺苷在右心房（RA）诱发房颤（AF）的激活频率高于左心房（LA），但其潜在的分子和功能底物尚不清楚。我们检验了腺苷诱导的AF是由腺苷A1受体（A1 R）及其下游GIRK通道（IK，Ado）表达最高的RA区域的局部折返驱动的假设。我们应用双心房光学标测和不同心房区域的免疫印迹标测来揭示腺苷诱导的AF在衰竭和非衰竭人类心脏中的机制（n=37）。冠状动脉灌注的心房光学标测结果显示，腺苷灌注（10-100μM）使RA的动作电位时程（APD_（80））（从290± 45 ms缩短至239± 41 ms，17.3±10.4%; p<0.01）比LA（从307± 24 ms缩短至286± 23 ms，6.7±6.6%; p<0.01）更显著。在10颗心脏中，腺苷诱导了AF（317±116秒），当持续（≥2分钟）时，主要由侧RA中的一个/两个局部折返驱动器维持。Tertiapin（10- 100 nM）是一种选择性GIRK通道阻滞剂，可抵消腺苷诱导的APD缩短并防止AF诱导。免疫印迹显示，RA的上级/中外侧具有比外侧/后LA显著更高的A1 R（2.7±1.7倍; p<0.01）和GIRK 4（1.7±0.8倍; p<0.05）蛋白表达。这项研究揭示了三倍RA-LA A1 R蛋白表达梯度在人类心脏，导致显着更大的RA与LA复极敏感性响应腺苷。持续的腺苷诱导的AF是由位于RA外侧区域的A1 R/GIRK 4表达最高的折返驱动器维持的。选择性心房GIRK通道阻滞可有效治疗内源性腺苷增加条件下的房颤。
Adenosine provokes atrial fibrillation (AF) with a higher activation frequency in right atria (RA) versus left atria (LA) in patients, but the underlying molecular and functional substrates are unclear. We tested the hypothesis that adenosine-induced AF is driven by localized reentry in RA areas with highest expression of adenosine A1 receptor (A1R) and its downstream GIRK channels (IK,Ado). We applied bi-atrial optical mapping and immunoblot mapping of various atrial regions to reveal the mechanism of adenosine-induced AF in explanted failing and non-failing human hearts (n=37). Optical mapping of coronary-perfused atria (n=24) revealed that adenosine perfusion (10–100μM) produced more significant shortening of action potential durations (APD80) in RA (from 290±45ms to 239±41ms, 17.3±10.4%; p<0.01) than LA (from 307±24ms to 286±23ms, 6.7±6.6%; p<0.01). In ten hearts, adenosine induced AF (317±116 sec) that, when sustained (≥2 min), was primarily maintained by one/two localized reentrant drivers in lateral RA. Tertiapin (10–100nM), a selective GIRK channel blocker, counteracted adenosine-induced APD shortening and prevented AF induction. Immunoblotting showed that the superior/middle lateral RA had significantly higher A1R (2.7±1.7 fold; p<0.01) and GIRK4 (1.7±0.8 fold; p<0.05) protein expression than lateral/posterior LA. This study revealed a three-fold RA-to-LA A1R protein expression gradient in the human heart, leading to significantly greater RA vs. LA repolarization sensitivity in response to adenosine. Sustained adenosine-induced AF is maintained by reentrant drivers localized in lateral RA regions with the highest A1R/GIRK4 expression. Selective atrial GIRK channel blockade may effectively treat AF during conditions with increased endogenous adenosine.