Abstract 18040: Directed Screen of Drugs Using Human Cardiomyocytes Derived From Induced Pluripotent Stem Cells with Timothy Syndrome, Lethal Arrhythmia
L-type voltage gated calcium channels (LTCs) play essential roles in the generation of cardiac rhythms and in the contraction of the atrial and ventricular myocytes. A de novo missence mutation in the LTC, CaV1.2, results in Timothy syndrome (TS), a multisystem disorder characterized by QT prolongation, lethal arrhythmia and congenital heart disease. To explore the effect of the TS mutation on the electrical activity and contraction of human cardiomyocytes (CMs), we have generated induced pluripotent stem cells (iPSCs) from two TS patients, and differentiated these cells into CMs. Electrophysiological recording and calcium imaging studies of these cells revealed irregular contraction, excess calcium influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells. To rescue the cardiac phenotypes, we tested calcium channel blockers (roscovitine, nimodipine and verapamil), beta-blocker (metoprolol), calmodulin kinase II inhibitor (KN-93) and late sodium current blocker (ranolazine) using patch clamp recording and calcium imaging in TS CMs. We found that roscovitine restored the electrical and Ca2+ signaling properties of CMs from TS patients while the other drugs didn’t rescue the phenotypes in TS CMs. This approach using iPSC-derived CMs would be a useful platform to provide a robust assay for developing new drugs to treat human cardiac diseases.
- © 2011 by American Heart Association, Inc.