Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand.
Heart Rhythm. 2019 May;16(5):765-772. doi: 10.1016/j.hrthm.2018.11.001. Epub 2018 Nov 7.
Type 2 diabetes (T2D) increases arrhythmia risk through incompletely elucidated mechanisms. Ventricular arrhythmias could be initiated by delayed afterdepolarizations (DADs) resulting from elevated spontaneous sarcoplasmic reticulum (SR) Ca release (SR Ca leak).
The purpose of this study was to test the role of DADs and SR Ca leak in triggering arrhythmias in T2D hearts.
We compared rats with late-onset T2D that display pancreatic and cardiac phenotypes similar to those in humans with T2D (HIP rats) and their nondiabetic littermates (wild type [WT]).
HIP rats showed higher propensity for premature ventricular complexes and ventricular tachyarrhythmias, whereas HIP myocytes displayed more frequent DADs and had lower SR Ca content than WT. However, the threshold SR Ca at which depolarizing transient inward currents (Is) are generated was also significantly decreased in HIP myocytes and was below the actual SR Ca load, which explains the increased DAD incidence despite reduced Ca in SR. In agreement with these findings, Ca spark frequency was augmented in myocytes from HIP vs WT rats, which suggests activation of ryanodine receptors (RyRs) in HIP hearts. Indeed, RyR phosphorylation (by CaMKII and protein kinase A) and oxidation are enhanced in HIP hearts, whereas there is no RyR O-GlcNAcylation in either HIP or control hearts. CaMKII inhibition dissipated the difference in Ca spark frequency between HIP and WT myocytes.
The threshold SR Ca for generating depolarizing Is is lower in T2D because of RyR activation after hyperphosphorylation and oxidation, which favors the occurrence of DADs despite low SR Ca loads.
2 型糖尿病（T2D）通过尚未完全阐明的机制增加心律失常的风险。室性心律失常可能由自发性肌浆网（SR）Ca 释放（SR Ca 渗漏）增加引起的延迟后去极化（DAD）引发。
本研究旨在测试 DAD 和 SR Ca 渗漏在引发 T2D 心脏心律失常中的作用。
我们比较了具有晚期 T2D 表型的大鼠，这些大鼠表现出与人类 T2D（HIP 大鼠）相似的胰腺和心脏表型，以及它们的非糖尿病同窝仔鼠（野生型[WT]）。
HIP 大鼠表现出更高的室性早搏和室性心动过速倾向，而 HIP 心肌细胞显示出更频繁的 DAD，并且比 WT 具有更低的 SR Ca 含量。然而，在 HIP 心肌细胞中，引起去极化内向电流（Is）的 SR Ca 阈值也显著降低，并且低于实际的 SR Ca 负荷，这解释了尽管 SR 中的 Ca 减少，但 DAD 发生率增加的原因。与这些发现一致，来自 HIP 与 WT 大鼠的心肌细胞中的 Ca 火花频率增加，这表明 HIP 心脏中的 RyR 被激活。事实上，HIP 心脏中的 RyR 磷酸化（由 CaMKII 和蛋白激酶 A 介导）和氧化增强，而在 HIP 或对照心脏中均不存在 RyR O-GlcNAcylation。CaMKII 抑制消除了 HIP 和 WT 心肌细胞之间 Ca 火花频率差异。
由于 RyR 超磷酸化和氧化后的激活，导致在 T2D 中产生去极化 Is 的 SR Ca 阈值降低，尽管 SR Ca 负荷较低，但仍有利于 DAD 的发生。
