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

Abstract

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+/ΔKPQ). 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.

The role of the cardiomyocyte circadian clocks in ion channel regulation and cardiac electrophysiology

“…The different types of transgenic mice used in these studies include the germline Bmal1 knockout (Bmal1 -/-) mice (Bunger et al, 2000), the cardiomyocyte-specific Bmal1 knockout (CBK) mice (Young et al, 2014) and mice that allow for inducing the cardiomyocyte-specific deletion of Bmal1 (iCS Bmal1) in adult mouse hearts (Schroder et al, 2013). Data from these studies show that the circadian oscillation in Kcnip2 mRNA transcript levels were reduced in Bmal1 -/mice, and the circadian oscillation and mRNA transcript levels in Kcnh2, Kcnq1, Kcnj2, Hcn4 and Scn5a mRNA were lost and reduced in iCS Bmal1 mice after inducing the deletion of Bmal1 (iCS Bmal1 -/-) (Jeyaraj et al, 2012;Schroder et al, 2013Schroder et al, , 2015Schroder, Wayland et al, 2021). These studies confirmed that the core circadian clock mechanism in cardiomyocytes regulates cellular ion channel mRNA levels.…”

“…The studies found that, in mouse hearts, the mRNA transcript levels for Kcnd2, Kcnip2, Kcnh2, Kcnq1, Kcnj2, Hcn4 and Scn5a cycled with a periodicity of 24 h in free-running conditions (Fig. 2A) (Jeyaraj et al, 2012;Schroder et al, 2013Schroder et al, , 2015Schroder, Wayland et al, 2021;Zhang et al, 2014). To investigate the role that the cardiomyocyte circadian clock has on the transcriptional regulation of these ion channels, the circadian oscillation in mRNA transcript levels was studied using transgenic mouse models that disrupt cardiomyocyte circadian clock signalling by Bmal1 knockout or deletion.…”

“…Data show that the difference in the QT‐interval between control and iCSΔ Bmal1 –/– mice increased at slower heart rates (Fig. 3) (Schroder et al., 2015; Schroder, Wayland et al., 2021). In other words, the QT‐interval became disproportionately longer in iCSΔ Bmal1 –/– mice as the heart rate became slower.…”

“…Abnormally long or short QT‐intervals are associated with an increased risk for deadly ventricular arrhythmias (Postema & Wilde, 2014). Several studies show that, compared with control mice, the QT‐interval was longer in CBK and iCSΔ Bmal1 –/– mice independent of the heart rate (Gottlieb et al., 2021; Schroder et al., 2015; Schroder, Wayland et al., 2021). A cellular surrogate of the QT‐interval is the duration of the ventricular AP waveform (Fig.…”

Bmal1 knockdown in the left stellate ganglion inhibits neural activity and prevents ventricular arrhythmias after myocardial ischemia

“…The differentiallyexpressed genes (significantly downregulated genes) involved in ion channels by Bmal1 knockdown were KCNJ14, KCNJ6, and CAMK2B. Bmal1 has been shown to modulate cardiac 10.3389/fcvm.2022.937608 ion channel transcription by binding to the enhancer box (Ebox) elements in the promoters of these genes or altering the expression of other transcription factors that regulate ion channel transcription (24). The differentially-expressed genes involved in receptors for transmitters upregulated by Bmal1 knockdown were GABBR2, GABRE, GABRG1, GABRQ, and HTR5A; and the genes downregulated were DRD2.…”