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Defects in cardiac conduction system lineages and malignant arrhythmias: developmental pathways and disease
Tara R St Amand1, Jonathan T Lu, Kenneth R Chien
1Institute of Molecular Medicine, University of California San Diego, 0613-C, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Abstract:
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.
Insights
Transcription factors HF1b and NKX2.5 are key to heart
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Genetics of Heart Disease
Background:
- Understanding heart failure requires integrating genomics, physiology, and mouse genetics.
- Transcription factors HF1b/SP4 and NKX2.5 are implicated in cardiac conduction system development and sudden death.
- Previous studies link HF1b loss to arrhythmias and confused cell identity.
Purpose of the Study:
- Identify nodal pathways linking transcription factors HF1b and NKX2.5 to cardiac arrythmogenesis.
- Investigate the role of neural crest cells in conduction system development.
- Determine the cell-autonomous requirement of NKX2.5 in atrioventricular node lineages.
Main Methods:
- Utilized HF1b and NKX2.5 floxed alleles in mouse models.
- Generated neural crest-restricted and ventricular-restricted knockouts.
- Performed single-cell analyses and micro-electrophysiological mapping of the atrioventricular node.
Main Results:
- Neural crest-restricted HF1b knockout mice showed significant arrhythmogenesis and conduction defects.
- Ventricular-restricted NKX2.5 knockout mice developed progressive heart block and AV node hypoplasia.
- NKX2.5 is cell-autonomously required within AV nodal lineages for proper conduction.
Conclusions:
- HF1b and NKX2.5 represent critical cardiac cell non-autonomous and autonomous pathways in conduction system development.
- Neural crest cues are important for conduction system development and disease.
- These findings elucidate novel pathways for cardiac arrythmogenesis and sudden death.