AUTHOR=Schroder Elizabeth A. , Wayland Jennifer L. , Samuels Kaitlyn M. , Shah Syed F. , Burgess Don E. , Seward Tanya , Elayi Claude S. , Esser Karyn A. , Delisle Brian P. 

TITLE=Cardiomyocyte Deletion of Bmal1 Exacerbates QT- and RR-Interval Prolongation in Scn5a+/ΔKPQ Mice

JOURNAL=Frontiers in Physiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.681011

DOI=10.3389/fphys.2021.681011

ISSN=1664-042X

ABSTRACT=<p>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 <italic>Bmal1</italic> 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 <italic>Bmal1</italic> in adult cardiomyocytes impacted the <italic>in vivo</italic> electrophysiological phenotype of a knock-in mouse model for the arrhythmogenic long QT syndrome (<italic>Scn5a</italic><sup>+/Δ<italic>KPQ</italic></sup>). Electrocardiographic telemetry showed inducing the deletion of <italic>Bmal1</italic> in the cardiomyocytes of mice with or without the ΔKPQ-<italic>Scn5a</italic> mutation increased the QT-interval at RR-intervals that were ≥130 ms. Inducing the deletion of <italic>Bmal1</italic> in the cardiomyocytes of mice with or without the ΔKPQ-<italic>Scn5a</italic> 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-<italic>Scn5a</italic> mutation, mice with the ΔKPQ-<italic>Scn5a</italic> mutation had reduced heart rate variability (HRV) during the peak of the day/night rhythm in the RR-interval. Inducing the deletion of <italic>Bmal1</italic> in cardiomyocytes did not affect HRV in mice without the ΔKPQ-<italic>Scn5a</italic> mutation, but it did increase HRV in mice with the ΔKPQ-<italic>Scn5a</italic> mutation. The data demonstrate that deleting <italic>Bmal1</italic> in cardiomyocytes exacerbates QT- and RR-interval prolongation in mice with the ΔKPQ-<italic>Scn5a</italic> mutation.</p>