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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.08.004 Byline: Danny L. Costantini (1)(2)(4)(5), Eric P. Arruda (1)(2)(4)(6), Pooja Agarwal (1)(2)(4)(6), Kyoung-Han Kim (4)(5), Yonghong Zhu (1)(4), Wei Zhu (1), Melanie Lebel (2)(6), Chi Wa Cheng (2)(10), Chong Y. Park (11), Stephanie A. Pierce (11), Alejandra Guerchicoff (12), Guido D. Pollevick (12), Toby Y. Chan (13), M. Golam Kabir (4)(13), Shuk Han Cheng (10), Mansoor Husain (4)(5)(7)(9)(13), Charles Antzelevitch (12), Deepak Srivastava (11), Gil J. Gross (1)(3)(4)(8), Chi-chung Hui (2)(6), Peter H. Backx (4)(5)(7)(14), Benoit G. Bruneau (1)(2)(4)(6) Abstract: Rhythmic cardiac contractions depend on the organized propagation of depolarizing and repolarizing wavefronts. Repolarization is spatially heterogeneous and depends largely on gradients of potassium currents. Gradient disruption in heart disease may underlie susceptibility to fatal arrhythmias, but it is not known how this gradient is established. We show that, in mice lacking the homeodomain transcription factor Irx5, the cardiac repolarization gradient is abolished due to increased K.sub.v4.2 potassium-channel expression in endocardial myocardium, resulting in a selective increase of the major cardiac repolarization current, I.sub.to,f, and increased susceptibility to arrhythmias. Myocardial Irx5 is expressed in a gradient opposite that of K.sub.v4.2, and Irx5 represses K.sub.v4.2 expression by recruiting mBop, a cardiac transcriptional repressor. Thus, an Irx5 repressor gradient negatively regulates potassium-channel-gene expression in the heart, forming an inverse I.sub.to,f gradient that ensures coordinated cardiac repolarization while also preventing arrhythmias. Author Affiliation: (1) Program in Cardiovascular Research, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada (2) Program in Developmental Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada (3) Cardiology Division, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada (4) The Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario M5S 1A8, Canada (5) Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada (6) Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada (7) Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada (8) Department of Pediatrics, University of Toronto, Toronto, Ontario M5S 1A8, Canada (9) McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada (10) Department of Biology and Chemistry, City University of Hong Kong, Hong Kong, China (11) Departments of Pediatrics and Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 (12) Masonic Medical Research Laboratory, Utica, New York 13501 (13) Division of Cellular and Molecular Biology, The Toronto General Hospital Research Institute, Toronto, Ontario M5G 2C4, Canada (14) Division of Cardiology, University Health Network, Toronto, Ontario M5G 2C4, Canada Article History: Received 14 February 2005; Revised 4 July 2005; Accepted 1 August 2005 Article Note: (miscellaneous) Published: October 20, 2005