Background Congenital Long QT Syndromes (LQTS) are associated with prolonged ventricular repolarisation and sudden cardiac death. Limitations to existing clinical therapeutic management strategies prompted us to develop a novel human in vitro drug-evaluation system for LQT2 that will complement existing in vitro and in vivo models.

Methods and Results Skin fibroblasts from a patient with a KCNH2 G1681A mutation (encodes I_Kr potassium ion channel) were reprogrammed to human induced pluripotent stem cells (hiPSCs), which were subsequently differentiated to functional cardiomyocytes. Relative to controls (including the patient's mother), multi-electrode array and patch-clamp electrophysiology of LQT2-hiPSC cardiomyocytes showed prolonged field/action potential duration. When LQT2-hiPSC cardiomyocytes were exposed to E4031 (an I_Kr blocker), arrhythmias developed and these presented as early after depolarisations (EADs) in the action potentials. In contrast to control cardiomyocytes, LQT2-hiPSC cardiomyocytes also developed EADs when challenged with the clinically-used stressor, isoprenaline. This effect was reversed by ß-blockers, propranolol and nadolol, the latter being used for the patient's therapy. Treatment of cardiomyocytes with experimental potassium channel enhancers, nicorandil and PD118057, caused action potential shortening. Notably, combined treatment with isoprenaline (enhancers/isoprenaline) caused EADs, but this effect was reversed by nadolol.

Conclusions Findings from this paper demonstrate that patient LQT2-hiPSC cardiomyocytes respond appropriately to clinically-relevant pharmacology and will be a valuable human in vitro model for testing experimental drug combinations.