What question did this study set out to answer?

To determine the role of cardiac HCN4 pacemaker channels in adult heart rate generation and impulse conduction using a targeted, inducible knockout model.

January 10, 2011Proceedings of the National Academy of SciencesOpen Access

Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4

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Population

Adult tamoxifen-inducible, cardiac-specific HCN4 knockout (ciHCN4-KO) mice (n=14) and control mice (n=14)

Comparison

Cardiac-specific ablation of HCN4 induced by… vs Control mice receiving the same tamoxifen…

Design

Preclinical

Follow-up

up to 10 days

Authors

MBMirko BaruscottiUniversity of Milan ABAnnalisa BucchiUniversity of Milan CVCarlo ViscomiUniversity of Padua

Discussion

Member takes

Implication

HCN4 is indispensable for adult murine pacemaking and conduction; leaves open its relevance as a therapeutic target in human bradyarrhythmias.

Key Points

To determine the role of cardiac HCN4 pacemaker channels in adult heart rate generation and impulse conduction using a targeted, inducible knockout model.
Generated an inducible, cardiac-specific HCN4 knockout (ciHCN4-KO) adult mouse model.
Assessed in vivo cardiac function, survival, and response to beta-adrenergic receptor stimulation.
Isolated sinoatrial node (SAN) myocytes to measure spontaneous firing rates, I(f) current density, and HCN4 protein expression via Western blot and immunofluorescence.
Ablation of HCN4 induced severe progressive bradycardia (~50% reduction in heart rate), high-grade AV block, and fatal cardiac arrest within approximately 5 days.
Isolated SAN myocytes displayed a ~70% reduction in I(f) current and a ~60% reduction in spontaneous firing rate, with preserved sensitivity to beta-adrenergic stimulation.

Structured PICO

Population

Adult tamoxifen-inducible, cardiac-specific HCN4 knockout (ciHCN4-KO) mice (n=14) and control mice (n=14)

Intervention

Cardiac-specific ablation of HCN4 induced by daily tamoxifen injections

Comparator

Control mice receiving the same tamoxifen treatment

Outcome

Heart rate, AV conduction (AV block), and survivalsurrogate

Cardiac-specific knockout of HCN4 in adult mice demonstrates that HCN4 channels are essential for normal heart impulse generation and conduction, as their ablation causes lethal bradycardia and AV block.

Cite This Study

Baruscotti et al. (2011) studied this question.

synapsesocial.com/papers/6a70b48fc92390ac2d07d251 https://doi.org/10.1073/pnas.1010122108

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Implication

HCN4 is indispensable for adult murine pacemaking and conduction; leaves open its relevance as a therapeutic target in human bradyarrhythmias.

Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

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