Defects in Cardiac Conduction System Lineages and Malignant Arrhythmias: Developmental Pathways and Disease

  1. Derek J. Chadwick Organizer and
  2. Jamie Goode
  1. Tara R. St. Amand,
  2. Jonathan T. Lu and
  3. Kenneth R. Chien*

Published Online: 7 OCT 2008

DOI: 10.1002/0470868066.ch16

Development of the Cardiac Conduction System: Novartis Foundation Symposium 250

Development of the Cardiac Conduction System: Novartis Foundation Symposium 250

How to Cite

St. Amand, T. R., Lu, J. T. and Chien, K. R. (2003) Defects in Cardiac Conduction System Lineages and Malignant Arrhythmias: Developmental Pathways and Disease, 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.ch16

Author Information

  1. Institute of Molecular Medicine, University of California San Diego, 0613-C, 9500 Gilman Drive, La Jolla, CA 92093, USA

*University of California San Diego, Institute of Molecular Medicine, UCSD School of Medicine, 0613-C, 9500 Gilman Drive, La Jolla, CA 92093, 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

To unravel the complex disease phenotype of heart failure, we are utilizing an integrative approach employing genomics, physiology, and mouse genetics to identify nodal pathways for specific physiological end points such as myocyte stretch activation responses, contractility and electrical conduction. A new class of genetic pathways for cardiac sudden death and associated arrhythmias has been based on transcription factors that control conduction system lineages, including HF1b/SP4 and NKX2.5. Previous studies have established that HF1b plays a critical role in conduction system lineage formation and the loss of HF1b leads to a confused electrophysiological identity in Purkinje and ventricular cell lineages, resulting in cardiac sudden death and marked tachy and brady arrhythmias. Utilizing Hf1b and Nkx2.5 floxed alleles, we now have identified the primary pathways which link these transcription factors with cardiac arrythmogenesis. Mice which harbour a neural crest restricted knockout of HF1b display marked arrhythmogenesis and conduction system defects, implicating neural crest cues in conduction system development and disease. Mice which harbour a ventricular-restricted knockout of Nkx2.5 display completely normal conduction at birth, but a hypoplastic atrioventricular (AV) node. During maturation, progressive complete heart block ensues, associated with a selective dropout of distal AV nodal cell lineages at the boundaries of the penetrating His bundle. Single cell analyses examining individual nodal cells within AV node of ventricular restricted Nkx2.5 knockout mice clearly document a cell autonomous requirement for NKX2.5 within AV nodal lineages per se. Micro-electrophysiological AV nodal mapping indicates a selective conduction defect at the boundary of the distal AV node and His bundle. HF1b and NKX2.5 reflect new cardiac cell non-autonomous and autonomous pathways for conduction system lineage defects and associated cardiac arrythmogenesis.