Differential conditions for early after‐depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits

• Published in: The Journal of physiology 2012-03, Vol.590 (5), p.1171-1180
• Main Authors: Liu, Gong‐Xin, Choi, Bum‐Rak, Ziv, Ohad, Li, Weiyan, de Lange, Enno, Qu, Zhilin, Koren, Gideon
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Adrenergic beta-Agonists - pharmacology; Animals; Animals, Genetically Modified; Calcium - physiology; Cardiac arrhythmia; Cardiomyocytes; Cardiovascular; Computer Simulation; Electrocardiography; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - genetics; In Vitro Techniques; Isoproterenol - pharmacology; KCNQ1 Potassium Channel - genetics; Long QT Syndrome - physiopathology; Models, Biological; Mutation; Myocytes, Cardiac - physiology; Potassium - physiology; Rabbits
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2011.218164

Non‐technical summary  Long QT syndrome (LQTS) is a genetic disorder characterized by recurrent syncope and sudden cardiac death (SCD). Type 1 (LQT1) and Type 2 (LQT2) LQTS account for 90% of the genotyped mutations in patients with this disorder. These syndromes have been associated with different sympathetic modes for initiation of cardiac arrest. Using isolated cardiomyocytes and Langendorff‐perfused hearts from transgenic rabbit models of LQT1 and LQT2, we have identified differential conditions and cellular mechanisms for the generation of early afterdepolarizations (EADs), abnormal depolarizations during the plateau and repolarization phase of action potentials and the hallmark of the arrhythmias in LQTS. These differences explain why different types of increased autonomic nervous system activity, i.e. sympathetic surge vs. high sympathetic tone, are associated with the initiation of polymorphic ventricular tachycardia in LQTS patients with different genetic background.   Early after‐depolarization (EAD), or abnormal depolarization during the plateau phase of action potentials, is a hallmark of long‐QT syndrome (LQTS). More than 13 genes have been identified as responsible for LQTS, and elevated risks for EADs may depend on genotypes, such as exercise in LQT1 vs. sudden arousal in LQT2 patients. We investigated mechanisms underlying different high‐risk conditions that trigger EADs using transgenic rabbit models of LQT1 and LQT2, which lack IKs and IKr (slow and fast components of delayed rectifying K+ current), respectively. Single‐cell patch‐clamp studies show that prolongation of action potential duration (APD) can be further enhanced by lowering extracellular potassium concentration ([K+]o) from 5.4 to 3.6 mm. However, only LQT2 myocytes developed spontaneous EADs following perfusion with lower [K+]o, while there was no EAD formation in littermate control (LMC) or LQT1 myocytes, although APDs were also prolonged in LMC myocytes and LQT1 myocytes. Isoprenaline (ISO) prolonged APDs and triggered EADs in LQT1 myocytes in the presence of lower [K+]o. In contrast, continuous ISO perfusion diminished APD prolongation and reduced the incidence of EADs in LQT2 myocytes. These different effects of ISO on LQT1 and LQT2 were verified by optical mapping of the whole heart, suggesting that ISO‐induced EADs are genotype specific. Further voltage‐clamp studies revealed that ISO increases L‐type calcium current (ICa) faster than IKs (time constant 9.2 s for ICa a