The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart
Key result
Global or cardiomyocyte-selective deletion of HCN4 channels in mice resulted in embryonic death between days 9.5 and 11.5, an 85% reduction in If current, and lack of mature pacemaker potentials.
Population
Mice embryos (wild-type, global HCN4 knockout, and cardiomyocyte-specific HCN4 knockout)
Comparison
Deletion of HCN4 channels vs Wild-type embryos
Design
Preclinical
Authors
Discussion
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Implication
HCN4 is essential for embryonic pacemaker maturation in mice; leaves open its necessity in adult human sinoatrial node function.
Key Points
- To determine the physiological function of the HCN4 channel in the developing cardiac conduction system and pacemaker activity.
- Generated and examined mouse models with either global deletion or cardiomyocyte-specific deletion of the HCN4 channel.
- Assessed embryonic survival, heart contraction rates, cyclic adenosine monophosphate (cAMP) responsiveness, and pacemaker action potentials between embryonic days 9.0 and 11.5.
- Both global and cardiomyocyte-specific HCN4-null mouse embryos died between embryonic days 9.5 and 11.5.
- Cardiomyocytes from HCN4-deficient embryos exhibited an average 85% reduction in hyperpolarization-activated cation currents (If), contracted significantly slower than wild type, and failed to respond to cAMP stimulation.
- While primitive pacemaker action potentials were present in mutant embryos, mature pacemaker action potentials that normally emerge at day 9.0 were completely absent.
Structured PICO
P
Population
Mice embryos (wild-type, global HCN4 knockout, and cardiomyocyte-specific HCN4 knockout)
I
Intervention
Deletion of HCN4 channels (global or cardiomyocyte-specific)
C
Comparator
Wild-type embryos
O
Outcome
Generation of pacemaker action potentials, heart rate, and embryonic survivalsurrogate
HCN4 channels are essential for the generation of mature pacemaker potentials in the emerging sinoatrial node and for embryonic survival.
Cite This Study
Stieber et al. (2003) studied Embryonic heart development. HCN4 channel deletion vs. Wild-type embryos was evaluated on Survival and generation of mature pacemaker potentials. Global or cardiomyocyte-selective deletion of HCN4 channels in mice resulted in embryonic death between days 9.5 and 11.5, an 85% reduction in If current, and lack of mature pacemaker potentials.