Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, CA 95616, USA.
Cardiovasc Res. 2021 Dec 17;117(14):2781-2793. doi: 10.1093/cvr/cvab006.
Diabetic hyperglycaemia is associated with increased arrhythmia risk. We aimed to investigate whether hyperglycaemia alone can be accountable for arrhythmias or whether it requires the presence of additional pathological factors.
Action potentials (APs) and arrhythmogenic spontaneous diastolic activities were measured in isolated murine ventricular, rabbit atrial, and ventricular myocytes acutely exposed to high glucose. Acute hyperglycaemia increased the short-term variability (STV) of action potential duration (APD), enhanced delayed afterdepolarizations, and the inducibility of APD alternans during tachypacing in both murine and rabbit atrial and ventricular myocytes. Hyperglycaemia also prolonged APD in mice and rabbit atrial cells but not in rabbit ventricular myocytes. However, rabbit ventricular APD was more strongly depressed by block of late Na+ current (INaL) during hyperglycaemia, consistent with elevated INaL in hyperglycaemia. All the above proarrhythmic glucose effects were Ca2+-dependent and abolished by CaMKII inhibition. Importantly, when the repolarization reserve was reduced by pharmacological inhibition of K+ channels (either Ito, IKr, IKs, or IK1) or hypokalaemia, acute hyperglycaemia further prolonged APD and further increased STV and alternans in rabbit ventricular myocytes. Likewise, when rabbit ventricular myocytes were pretreated with isoproterenol or angiotensin II, hyperglycaemia significantly prolonged APD, increased STV and promoted alternans. Moreover, acute hyperglycaemia markedly prolonged APD and further enhanced STV in failing rabbit ventricular myocytes.
We conclude that even though hyperglycaemia alone can enhance cellular proarrhythmic mechanisms, a second hit which reduces the repolarization reserve or stimulates G protein-coupled receptor signalling greatly exacerbates cardiac arrhythmogenesis in diabetic hyperglycaemia.
糖尿病高血糖与心律失常风险增加有关。我们旨在研究高血糖本身是否足以导致心律失常，或者是否需要存在其他病理因素。
在急性暴露于高葡萄糖的情况下，测量了分离的鼠心室、兔心房和心室肌细胞中的动作电位 (AP) 和致心律失常性自发性舒张活动。急性高血糖增加了动作电位时程 (APD) 的短期变异性 (STV)，增强了延迟后除极，并在鼠和兔心房和心室肌细胞的快速起搏期间增强了 APD 交替的可诱导性。高血糖还延长了小鼠和兔心房细胞的 APD，但不延长兔心室肌细胞的 APD。然而，在高血糖期间，晚期钠电流 (INaL) 的阻断使兔心室 APD 延长更为明显，这与高血糖时 INaL 升高一致。所有这些致心律失常的葡萄糖作用均依赖于 Ca2+，并被 CaMKII 抑制所消除。重要的是，当通过药理学抑制 K+ 通道 (无论是 Ito、IKr、IKs 还是 IK1) 或低钾血症来减少复极化储备时，急性高血糖会进一步延长兔心室肌细胞的 APD 并进一步增加 STV 和交替。同样，当兔心室肌细胞用异丙肾上腺素或血管紧张素 II 预处理时，高血糖显著延长 APD，增加 STV 并促进交替。此外，急性高血糖可显著延长 APD 并进一步增强衰竭兔心室肌细胞的 STV。
我们的结论是，即使高血糖本身可以增强细胞的致心律失常机制，但当降低复极化储备或刺激 G 蛋白偶联受体信号的第二次打击发生时，它会极大地加剧糖尿病高血糖中的心脏心律失常发生。
