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Updated: Nov 1, 2025
Electrocardiogram Recordings in Anesthetized Mice using Lead II
Published on: June 20, 2020
Prolonged QT intervals in mice with cardiomyocyte-specific deficiency of the molecular clock
Lisa A Gottlieb1,2, Karin Larsen1, Ganesh V Halade3
1Department of Biomedical Sciences, University of Copenhagen, Denmark.
Aim:
Cardiac arrhythmias and sudden deaths have diurnal rhythms in humans. The underlying mechanisms are unknown. Mice with cardiomyocyte-specific disruption of the molecular clock genes have lower heart rate than control. Because changes in the QT interval on the electrocardiogram is a clinically used marker of risk of arrhythmias, we sought to test if the biological rhythms of QT intervals are dependent on heart rate and if this dependency is changed when the molecular clock is disrupted.
Methods:
We implanted radio transmitters in male mice with cardiomyocyte-specific Bmal1 knockout (CBK) and in control mice and recorded 24-h ECGs under diurnal and circadian conditions. We obtained left ventricular monophasic action potentials during pacing in hearts ex vivo.
Results:
Both RR and QT intervals were longer in conscious CBK than control mice (RR: 117 ± 7 vs 110 ± 9 ms, P < .05; and QT: 53 ± 4 vs 48 ± 2 ms, P < .05). The prolonged QT interval was independent of the slow heart rate in CBK mice. The QT interval exhibited diurnal and circadian rhythms in both CBK and control mice. The action potential duration was longer in CBK than in control mice, indicating slower repolarization. Action potential alternans occurred at lower pacing rate in hearts from CBK than control mice (12 ± 3 vs 16 ± 2 Hz, respectively, P < .05).
Conclusion:
The bradycardic CBK mice have prolonged ventricular repolarization independent of the heart rate. Diurnal and circadian rhythms in repolarization are preserved in CBK mice and are not a consequence of the 24-h rhythm in heart rate. Arrhythmia vulnerability appears to be increased when the cardiac clock is disrupted.
Insights
Disrupting the cardiac molecular clock in mice prolongs ventricular repolarization, independent of heart rate. These findings suggest increased arrhythmia vulnerability when the heart
Area of Science:
- Cardiovascular Physiology
- Chronobiology
- Molecular Cardiology
Background:
- Cardiac arrhythmias and sudden cardiac death exhibit diurnal patterns in humans, but the underlying mechanisms remain unclear.
- Disruption of cardiomyocyte-specific molecular clock genes in mice leads to a reduced heart rate.
- The QT interval on electrocardiograms is a recognized clinical marker for arrhythmia risk.
Purpose of the Study:
- To investigate whether biological rhythms of QT intervals are dependent on heart rate.
- To determine if this dependency is altered by the disruption of the cardiac molecular clock.
Main Methods:
- Implantation of radio transmitters in male cardiomyocyte-specific Bmal1 knockout (CBK) mice and control mice for 24-hour electrocardiograms (ECGs).
- Recording of ECGs under both diurnal and circadian conditions.
- Measurement of left ventricular monophasic action potentials ex vivo during cardiac pacing.
Main Results:
- Both RR and QT intervals were significantly longer in conscious CBK mice compared to controls.
- The prolonged QT interval in CBK mice was found to be independent of their slower heart rate.
- QT interval exhibited diurnal and circadian rhythms in both CBK and control groups, with longer action potential duration and slower repolarization in CBK mice.
Conclusions:
- Prolonged ventricular repolarization in bradycardic CBK mice is independent of heart rate.
- Diurnal and circadian rhythms of repolarization are maintained in CBK mice, not solely due to heart rate rhythms.
- Disruption of the cardiac molecular clock appears to increase susceptibility to arrhythmias.
