Key result
Cardiomyocyte Bmal1 deletion exacerbates QT and RR interval prolongation in 1KPQ-Scn5a mutant mice.
Why the study?
Deletion of the circadian clock transcription factor Bmal1 disrupts cardiac ion channel expression, slows heart rate, and prolongs the QT-interval, but its electrophysiological impact in long QT syndrome was unknown.
p-value: p=<0.05
Deletion of the circadian clock gene Bmal1 in cardiomyocytes worsens electrophysiological abnormalities in a mouse model of long QT syndrome.
Bmal1 deletion worsens QT prolongation in LQTS mouse models; leaves open any human translational relevance or therapeutic targeting.
Circadian rhythms are generated by cell autonomous circadian clocks that perform a ubiquitous cellular time-keeping function and cell type-specific functions important for normal physiology. Studies show inducing the deletion of the core circadian clock transcription factor Bmal1 in adult mouse cardiomyocytes disrupts cardiac circadian clock function, cardiac ion channel expression, slows heart rate, and prolongs the QT-interval at slow heart rates. This study determined how inducing the deletion of Bmal1 in adult cardiomyocytes impacted the in vivo electrophysiological phenotype of a knock-in mouse model for the arrhythmogenic long QT syndrome ( Scn5a +/Δ KPQ ). Electrocardiographic telemetry showed inducing the deletion of Bmal1 in the cardiomyocytes of mice with or without the ΔKPQ- Scn5a mutation increased the QT-interval at RR-intervals that were ≥130 ms. Inducing the deletion of Bmal1 in the cardiomyocytes of mice with or without the ΔKPQ- Scn5a mutation also increased the day/night rhythm-adjusted mean in the RR-interval, but it did not change the period, phase or amplitude. Compared to mice without the ΔKPQ- Scn5a mutation, mice with the ΔKPQ- Scn5a mutation had reduced heart rate variability (HRV) during the peak of the day/night rhythm in the RR-interval. Inducing the deletion of Bmal1 in cardiomyocytes did not affect HRV in mice without the ΔKPQ- Scn5a mutation, but it did increase HRV in mice with the ΔKPQ- Scn5a mutation. The data demonstrate that deleting Bmal1 in cardiomyocytes exacerbates QT- and RR-interval prolongation in mice with the ΔKPQ- Scn5a mutation.
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Schroder et al. (2021) studied Long QT syndrome. Cardiomyocyte deletion of Bmal1 vs. Vehicle injection or pre-tamoxifen (iCS1Bmal1+/+) was evaluated on QT-interval prolongation at slow heart rates (p=<0.05). Cardiomyocyte deletion of Bmal1 exacerbates QT- and RR-interval prolongation in mice with the 1KPQ-Scn5a mutation.
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