Cardiac Conduction and Arrhythmia: Insights from Nkx2.5 Mutations in Mouse and Humans

  1. Derek J. Chadwick Organizer and
  2. Jamie Goode
  1. Patrick Y. Jay1,2,
  2. Charles I. Berul1,
  3. Makoto Tanaka2,3,
  4. Masao Ishii4,
  5. Yoshihisa Kurachi4 and
  6. Seigo Izumo2,*

Published Online: 7 OCT 2008

DOI: 10.1002/0470868066.ch14

Development of the Cardiac Conduction System: Novartis Foundation Symposium 250

Development of the Cardiac Conduction System: Novartis Foundation Symposium 250

How to Cite

Jay, P. Y., Berul, C. I., Tanaka, M., Ishii, M., Kurachi, Y. and Izumo, S. (2003) Cardiac Conduction and Arrhythmia: Insights from Nkx2.5 Mutations in Mouse and Humans, in Development of the Cardiac Conduction System: Novartis Foundation Symposium 250 (eds D. J. Chadwick and J. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/0470868066.ch14

Author Information

  1. 1

    Department of Cardiology, Children's Hospital and Department of Pediatrics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA

  2. 2

    Cardiovascular Division, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, 330 Brookline Avenue, SL-201, Boston, MA 02215, USA

  3. 3

    Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

  4. 4

    Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan

*Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, SL-201, Boston, MA 02215, USA

Publication History

  1. Published Online: 7 OCT 2008
  2. Published Print: 20 JUN 2003

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470850350

Online ISBN: 9780470868065

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Summary

The phenotypes of cardiac conduction and rhythm disorders are very well characterized because of the large numbers of affected patients who seek medical treatment. The few disorders where the genetic basis is known has led to a commonly held notion that the abnormal function of ion pumps, channels and connexins (ICC) causes conduction defects and arrhythmias. Although probably true in general, the ICC-centric model underemphasizes alternative mechanisms involving the organization of cells or mechanisms of gene expression. NKX2.5 was one of the first cardiac transcription factors identified that when mutated causes congenital heart disease and conduction defects in human. We present two hypotheses for the pathogenesis of conduction defects and arrhythmias as caused by transcription factor haploinsufficiency that are alternatives to a strictly ICC-centric model. First, conduction defects may arise from anatomic underdevelopment of the conduction system in utero. Second, the cardiac arrhythmias associated with Nkx2.5 mutation may result from the non-uniform alteration in a population of cardiac myocytes of the levels of channel proteins, leading to increased electrical heterogeneity. We propose that consideration of the two alternative hypotheses, in addition to the traditional ICC-centric model, should lead to a richer understanding of cardiac conduction defects and arrhythmogenesis.