Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia

Hayter, Edward A; Wehrens, Sophie M T; Dongen, Hans P A Van; Stangherlin, Alessandra; Gaddameedhi, Shobhan; Crooks, Elena; Barron, Nichola J; Venetucci, Luigi; Neill, John S. O’; Brown, T. M.; Skene, Debra J.; Trafford, Andrew W.; Bechtold, David A.

doi:10.1038/s41467-021-22788-8

Cited by 38 publications

(53 citation statements)

References 55 publications

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“…Ex vivo, we find a prolonged action potential duration in CBK hearts when they are paced electrically to maintain constant heart rate (Figure 5C) and an increased vulnerability to AP alternans when pacing frequency is increased (Figure 5E,F). This appears to be in conflict with a recent publication where isolated CBK hearts are reported to be protected against pacing‐induced arrhythmias 20 . There is a day‐night difference in AP alternans susceptibility which is lost at ageing 36 and sinus node arrhythmias and conduction block in inducible CBK mice 18 ; however, this is unlikely a result of compromised repolarization, yet underscores the increased arrhythmia susceptibility when disrupting the cardiac clock.…”

Section: Discussionmentioning

confidence: 89%

“…The cardiac molecular clock can be rendered non‐functional in mice by various means, and to our knowledge, they all produce bradycardia relative to wild‐type controls 17‐20 . Moreover, changing the 24‐h period of the ambient light to 22.5 or 27 hours also slows heart rate significantly in mice but does not change the amplitude of the 24‐h rhythm 21 …”

Section: Introductionmentioning

confidence: 99%

“…13,15,16 The cardiac molecular clock can be rendered nonfunctional in mice by various means, and to our knowledge, they all produce bradycardia relative to wild-type controls. [17][18][19][20] Moreover, changing the 24-h period of the ambient light to 22.5 or 27 hours also slows heart rate significantly in mice but does not change the amplitude of the 24-h rhythm. 21 The QT interval is dependent on heart rate in most species, and in the mouse, it prolongs about 2 ms for every 10 ms prolongation of the RR interval.…”

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confidence: 98%

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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: 89%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 98%

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

et al. 2021

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“…Similar results have been found with other data sets across a variety of studies ( 12 – 14 ). Alternatively, Bowman et al studied the circadian rhythm in heart rate (CRHR), which originates not in the brain but the sino-atrial (SA) node of the heart ( 6 , 15 ). With a Bayesian framework, they isolated the intrinsic circadian phase of heart rate and determined the phase uncertainty of this marker.…”

Section: Introductionmentioning

confidence: 99%

Distinct Circadian Assessments From Wearable Data Reveal Social Distancing Promoted Internal Desynchrony Between Circadian Markers

Huang

Mayer

Walch

et al. 2021

Front. Digit. Health

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Mobile measures of human circadian rhythms (CR) are needed in the age of chronotherapy. Two wearable measures of CR have recently been validated: one that uses heart rate to extract circadian rhythms that originate in the sinoatrial node of the heart, and another that uses activity to predict the laboratory gold standard and central circadian pacemaker marker, dim light melatonin onset (DLMO). We first find that the heart rate markers of normal real-world individuals align with laboratory DLMO measurements when we account for heart rate phase error. Next, we expand upon previous work that has examined sleep patterns or chronotypes during the COVID-19 lockdown by studying the effects of social distancing on circadian rhythms. In particular, using data collected from the Social Rhythms app, a mobile application where individuals upload their wearable data and receive reports on their circadian rhythms, we compared the two circadian phase estimates before and after social distancing. Interestingly, we found that the lockdown had different effects on the two ambulatory measurements. Before the lockdown, the two measures aligned, as predicted by laboratory data. After the lockdown, when circadian timekeeping signals were blunted, these measures diverged in 70% of subjects (with circadian rhythms in heart rate, or CRHR, becoming delayed). Thus, while either approach can measure circadian rhythms, both are needed to understand internal desynchrony. We also argue that interventions may be needed in future lockdowns to better align separate circadian rhythms in the body.

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“…One question of great interest is the circadian mechanisms in SCD, the topic of a recent workshop, “Understanding Circadian Mechanisms of Sudden Cardiac Death”, convened by the National Institutes of Health, USA (accessed on 11 June 2021). Acquired or hereditary heart diseases are the leading cause of SCD, and the primary mechanism leading to SCD is cardiac arrhythmias, particularly ventricular arrhythmias [ 18 , 19 , 20 ]. In the heart, membrane depolarization (sodium and calcium channels) and repolarization (potassium channels) are tightly regulated to maintain normal action potential, and adverse events causing exaggerated depolarization or diminished repolarization can disrupt the balance, increasing the risk of arrhythmias and ultimately SCD [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Clock-Modulating Activities of the Anti-Arrhythmic Drug Moricizine

et al. 2021

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Dysregulated circadian functions contribute to various diseases, including cardiovascular disease. Much progress has been made on chronotherapeutic applications of drugs against cardiovascular disease (CVD); however, the direct effects of various medications on the circadian system are not well characterized. We previously conducted high-throughput chemical screening for clock modulators and identified an off-patent anti-arrhythmic drug, moricizine, as a clock-period lengthening compound. In Per2:LucSV reporter fibroblast cells, we showed that under both dexamethasone and forskolin synchronization, moricizine was able to increase the circadian period length, with greater effects seen with the former. Titration studies revealed a dose-dependent effect of moricizine to lengthen the period. In contrast, flecainide, another Class I anti-arrhythmic, showed no effects on circadian reporter rhythms. Real-time qPCR analysis in fibroblast cells treated with moricizine revealed significant circadian time- and/or treatment-dependent expression changes in core clock genes, consistent with the above period-lengthening effects. Several clock-controlled cardiac channel genes also displayed altered expression patterns. Using tissue explant culture, we showed that moricizine was able to significantly prolong the period length of circadian reporter rhythms in atrial ex vivo cultures. Using wild-type C57BL/6J mice, moricizine treatment was found to promote sleep, alter circadian gene expression in the heart, and show a slight trend of increasing free-running periods. Together, these observations demonstrate novel clock-modulating activities of moricizine, particularly the period-lengthening effects on cellular oscillators, which may have clinical relevance against heart diseases.

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Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia

Cited by 38 publications

References 55 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

Distinct Circadian Assessments From Wearable Data Reveal Social Distancing Promoted Internal Desynchrony Between Circadian Markers

Clock-Modulating Activities of the Anti-Arrhythmic Drug Moricizine

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