The Classically Cardioprotective Agent Diazoxide Elicits Arrhythmias in Type 2 Diabetes Mellitus.
The Classically Cardioprotective Agent Diazoxide Elicits Arrhythmias in Type 2 Diabetes Mellitus.
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DOI：
10.1016/j.jacc.2015.06.1329
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发表时间：
2015-09-08
影响因子：
24
通讯作者：
Akar FG
中科院分区：
文献类型：
--
作者：
Xie C;Hu J;Motloch LJ;Karam BS;Akar FG
2型糖尿病（t2DM）与代谢需求条件下室性心动过速（VT）倾向增加相关。低剂量二氮氧化物（DZX）激活线粒体atp敏感钾（KATP）通道可改善低血糖相关并发症、代谢功能、甘油三酯和游离脂肪酸水平，并逆转t2DM患者体重增加。我们假设DZX可以预防缺血介导的t2DM心律失常，这是由于其假定的心脏保护和抗糖尿病特性。研究2型糖尿病（t2DM） zucker - obesity - diabetes - fatty （ZO）大鼠（N = 43）。对照组为Zucker-Lean大鼠（ZL, N = 13）和正常Sprague-Dawley大鼠（SprD, N = 30）。在无血流缺血12分钟之前和期间进行高分辨率光学动作电位（AP）测绘。t2DM心脏的电生理特性在基线时相对稳定。相比之下，缺血揭示了两组之间的主要差异，因为t2DM的动作电位持续时间（APD）未能对缺血挑战进行进行性适应。DZX促进心律失常的发生，因为所有DZX治疗的t2DM心脏都表现出缺血诱导的室性心动过速（VT），并在再灌注后持续存在。相比之下，未经治疗的t2DM和对照组在缺血期间没有出现VT。与DZX不同，pinacidil促进了对照组和t2DM心脏缺血介导的心律失常。快速且空间异质性的APD缩短先于t2DM患者心律失常的发生。dzx介导的t2DM心律失常与Kir6.1、Kir6.2、SUR1A、SUR1B、SUR2A、SUR2B或ROMK的mRNA表达变化无关。缺血揭示了t2DM心脏对APD适应的矛盾抵抗。DZX逆转了这一特性，导致APD快速且不均匀缩短。这促进了缺血时的可重入性室速。有缺血性事件风险的糖尿病患者应避免使用DZX。
Type 2 diabetes mellitus (t2DM) is associated with enhanced propensity for ventricular tachyarrhythmias (VT) under conditions of metabolic demand. Activation of mitochondrial ATP-sensitive potassium (KATP) channels by low-dose diazoxide (DZX) improves hypoglycemia-related complications, metabolic function, triglyceride and free fatty acid levels, and reverses weight gain in t2DM. We hypothesized that DZX prevents ischemia-mediated arrhythmias in t2DM owing to its putative cardioprotective and antidiabetic property. Zucker-Obese-Diabetic-Fatty (ZO) rats (N = 43) with t2DM were studied. Controls consisted of Zucker-Lean (ZL, N = 13) and normal Sprague-Dawley (SprD, N = 30) rats. High-resolution optical action potential (AP) mapping was performed before and during challenge with no-flow ischemia for 12 min. Electrophysiological properties were relatively stable in t2DM hearts at baseline. In contrast, ischemia uncovered major differences between groups, as action potential duration (APD) in t2DM failed to undergo progressive adaptation to ischemic challenge. DZX promoted the incidence of arrhythmias as all DZX-treated t2DM hearts exhibited ischemia-induced ventricular tachyarrhythmias (VT) that persisted upon reperfusion. In contrast, untreated t2DM and controls did not exhibit VT during ischemia. Unlike DZX, pinacidil promoted ischemia-mediated arrhythmias in both control and t2DM hearts. Rapid and spatially heterogeneous shortening of APD preceded the onset of arrhythmias in t2DM. DZX-mediated proarrhythmia in t2DM was not related to changes in the messenger ribonucleic acid (mRNA) expression of Kir6.1, Kir6.2, SUR1A, SUR1B, SUR2A, SUR2B, or ROMK. Ischemia uncovers a paradoxical resistance of t2DM hearts to APD adaptation. DZX reverses this property resulting in rapid and heterogeneous APD shortening. This promotes reentrant VT during ischemia. DZX should be avoided in diabetic patients at risk of ischemic events.