A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate

D’Souza, Alicia; Wang, Yanwen; Anderson, Cali; Bucchi, Annalisa; Baruscotti, Mirko; Olieslagers, Servé; Mesirca, Pietro; Johnsen, Anne Berit; Mastitskaya, Svetlana; Ni, Haibo; Zhang, Yu; Black, Nicholas; Cox, Charlotte; Wegner, Sven; Baño-Otálora, Beatriz; Petit, Cheryl; Gill, E. K.; Logantha, Sunil Jit R. J.; Dobrzynski, Halina; Ashton, Nicholas J.; Hart, George; Zhang, Rai; Zhang, Henggui; Cartwright, Elizabeth J.; Wisløff, Ulrik; Mangoni, Matteo E.; Martins, Paula; Piggins, Hugh D.; DiFrancesco, Dario; Boyett, Mark R.

doi:10.1016/j.hrthm.2020.11.026

Cited by 57 publications

(78 citation statements)

References 24 publications

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“…Heart rate is determined by the cardiac sinus node and is orchestrated by the combined action of i) proteins involved in calcium cycling across sarcoplasmic reticulum and sarcolemma membranes, ii) ion channels and iii) the autonomic nervous system. There is a day‐night difference in the expression of Hcn4 encoding the primary ion channel for pacemaking and a larger HCN4‐governed depolarizing current in sinus‐node cells acutely isolated from control mice at the beginning of the dark phase compared to the beginning of the light phase 23 . This is very likely a key underlying mechanism of the 24‐h variation in heart rate; however, the preservation of this 24‐h cycle in CBK mice in the present study suggests that other mechanisms compensate for HCN4 when the cardiac molecular clock is eliminated.…”

Section: Discussionmentioning

confidence: 99%

Prolonged QT intervals in mice with cardiomyocyte‐specific deficiency of the molecular clock

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Prolonged QT intervals in mice with cardiomyocyte‐specific deficiency of the molecular clock

et al. 2021

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“…Studies suggest that Bmal1 directly and indirectly contributes to the transcription of cardiac ion channel genes Scn5a , Kcnh2 , Hcn4 , and Kchip2 ( Jeyaraj et al, 2012 ; Schroder et al, 2013 , 2015 ; D’Souza et al, 2020 ). Bmal1 may regulate cardiac ion channel transcription by binding to enhancer box (E-box) elements in the promoters of ion channel genes, or Bmal1 can modify the expression of other transcription factors that regulate ion channel transcription.…”

Section: Resultsmentioning

confidence: 99%

“…In mice and humans, the cardiac Na + current (I Na ) generates the rapid upstroke of the action potential in the working myocardium and the funny current (I F ) initiates depolarization in the autorhythmic myocardium. Scn5a and Hcn4 encode the major pore-forming proteins that conduct I Na and I F ( Abriel, 2007 ; Kozasa et al, 2018 ; D’Souza et al, 2020 ). Also similar to humans, the inward rectifier K + current (I K 1 ) in the mouse working myocardium is responsible for stabilizing the resting membrane potential.…”

Section: Resultsmentioning

confidence: 99%

“…The increase in HRV normally seen at slower heart rates might explain why HRV increased in the iCSΔ Bmal1 –/– /Scn5a +/Δ KPQ mice ( Figures 3 , 4 ). Another possible explanation for the effect on HRV is the recent observation that the loss of Bmal1 in the heart alters the intrinsic beating rate of sinoatrial node preparations ( D’Souza et al, 2020 ). The time of day changes in sinoatrial node intrinsic beating rate were suggested to be secondary to a reduction in the functional expression of the Hcn4 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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“…Non-dipping, i.e., blunted BP or HR decline overnight (by <10% of the daytime mean), is coupled with an adverse cardiovascular prognosis (5). Although sustained relative sympathetic over-activation at night is considered to be pivotal in the pathophysiology of non-dipping HR, other factors may also participate, such as the disrupted endogenous circadian rhythmicity of the central clock in the suprachiasmatic nucleus, the cardiac clock in the sinoatrial node, or circulating neurohumoral factors, including catecholamines and glucocorticoids (6)(7)(8). Non-dipping HR is rather neglected during cardiovascular risk assessment and is thus omitted from risk management strategies (5).…”

Section: Introductionmentioning

confidence: 99%

Monitoring Non-dipping Heart Rate by Consumer-Grade Wrist-Worn Devices: An Avenue for Cardiovascular Risk Assessment in Hypertension

Baka

Šimko

2021

Front. Cardiovasc. Med.

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A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate

Abstract: BACKGROUND Heart rate follows a diurnal variation, and slow heart rhythms occur primarily at night.

Cited by 57 publications

References 24 publications

Prolonged QT intervals in mice with cardiomyocyte‐specific deficiency of the molecular clock

Prolonged QT intervals in mice with cardiomyocyte‐specific deficiency of the molecular clock

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

Monitoring Non-dipping Heart Rate by Consumer-Grade Wrist-Worn Devices: An Avenue for Cardiovascular Risk Assessment in Hypertension

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