The Effect of Ivabradine Administration on the Night Drop of Heart Rate in Patients With Inappropriate Sinus Tachycardia

Ptaszyński, Paweł; Kaczmarek, Krzysztof; Cygankiewicz, Iwona; Klingenheben, Thomas; Ruta, Jan; Urbanek, Irmina; Kałowski, Michał; Wranicz, Jerzy Krzysztof

doi:10.1016/s0735-1097(18)30933-1

Cited by 4 publications

(5 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In other words, the effect of ivabradine on heart rate showed a circadian rhythm and was greater when the subjects were awake. This is consistent with the work on the mice (Figure 5C,D) 54 . However, it is known that cardiac-specific knockout of Bmal1 46 or cardiac-specific expression of a dominant negative Clock mutant 56 does not abolish the circadian rhythm in heart rate in vivo (although it does reduce it).…”

Section: Discussionsupporting

confidence: 93%

“…Furthermore, block of HCN4 and I f by ivabradine had a bigger effect on heart rate during the awake period and abolished the circadian rhythm in heart rate in vivo in the mouse (Figure 5C). Data consistent with this have been obtained by Ptaszynski et al 54 and Grigoryan et al 55 who studied the effect of ivabradine on the heart rate of patients either with inappropriate sinus node tachycardia or ischaemic heart disease and heart failure; whereas ivabradine caused a large decrease in heart rate during the day, it caused little decrease at night. In other words, the effect of ivabradine on heart rate showed a circadian rhythm and was greater when the subjects were awake.…”

Section: Discussionsupporting

confidence: 79%

See 1 more Smart Citation

Circadian control of intrinsic heart rate via a sinus node clock and the pacemaker channel

Wang

Olieslagers

Johnsen

et al. 2019

Preprint

View full text Add to dashboard Cite

29In the human, there is a circadian rhythm in the resting heart rate and it is higher during the day in 30 preparation for physical activity. Conversely, slow heart rhythms (bradyarrhythmias) occur primarily 31 at night. Although the lower heart rate at night is widely assumed to be neural in origin (the result 32 of high vagal tone), the objective of the study was to test whether there is an intrinsic change in 33 heart rate driven by a local circadian clock. In the mouse, there was a circadian rhythm in the heart 34 rate in vivo in the conscious telemetrized animal, but there was also a circadian rhythm in the 35 intrinsic heart rate in denervated preparations: the Langendorff-perfused heart and isolated sinus 36 node. In the sinus node, experiments (qPCR and bioluminescence recordings in mice with a Per1 37 luciferase reporter) revealed functioning canonical clock genes, e.g. Bmal1 and Per1. We identified 38 a circadian rhythm in the expression of key ion channels, notably the pacemaker channel Hcn4 39 (mRNA and protein) and the corresponding ionic current (funny current, measured by whole cell 40 patch clamp in isolated sinus node cells). Block of funny current in the isolated sinus node 41 abolished the circadian rhythm in the intrinsic heart rate. Incapacitating the local clock (by cardiac-42 specific knockout of Bmal1) abolished the normal circadian rhythm of Hcn4, funny current and the 43 intrinsic heart rate. Chromatin immunoprecipitation demonstrated that Hcn4 is a transcriptional 44 target of BMAL1 establishing a pathway by which the local clock can regulate heart rate. In 45 conclusion, there is a circadian rhythm in the intrinsic heart rate as a result of a local circadian 46 clock in the sinus node that drives rhythmic expression of Hcn4. The data reveal a novel regulator 47 of heart rate and mechanistic insight into the occurrence of bradyarrhythmias at night. 483 Living things including humans are attuned to the 24 h day-night cycle and many biological 49 processes exhibit an intrinsic ~24 h (i.e. circadian) rhythm. In the human, the resting heart rate (in 50 the absence of physical activity) shows a circadian rhythm and is higher during the day when we 51 are awake 1,2 . The heart is therefore primed, anticipating the increase in demand during the awake 52 period. Conversely, bradyarrhythmias primarily occur at night 1,3 . Previously, the circadian rhythm in 53 heart rate in vivo has been attributed to the autonomic nervous system: to high sympathetic nerve 54 activity accompanying physical activity during the awake period and high vagal tone during the 55 sleep period 4 . This is partly based on heart rate variability as a surrogate measure of autonomic 56 tone 5-7 ; however, we have shown that heart rate variability cannot be used in any simple way as a 57 measure of autonomic tone 8 . Therefore, the mechanism underlying the circadian rhythm in heart 58 rate is still unknown. We asked the question whether there is a circadian rhythm in the intrinsic 59 heart rate set by the pacemaker of the he...

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 79%

Circadian control of intrinsic heart rate via a sinus node clock and the pacemaker channel

Wang

Olieslagers

Johnsen

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The circadian variations of these humoral factors appear to be under the control of the SCN which uses vasoactive intestinal peptide (VIP) to directly and indirectly modulate the release of adrenocorticotropic hormone (ACTH; Buijs et al, 2003 ; Boudreau et al, 2012 ; Morris et al, 2012 ). On the other hand, previous studies have concluded that circadian HR fluctuations arise from daily changes in the intrinsic properties of the SA node (i.e., local circadian cardiac clock; Wang et al, 2021 ), arising from changes in the expression of HCN4-based pace-maker channels ( Oosting et al, 1997 ; Ptaszynski et al, 2018 ; D'Souza et al, 2020 ) or other channels including Kv4.2 ( Yamashita et al, 2003 ) and Kv1.5 ( Durgan et al, 2005 ). While these variations can clearly contribute to the daily HR variations seen in the absence of ANS activity, our studies establish that the ANS plays a necessary and dominant role in controlling basal circadian daily HR fluctuations in anesthetized mice.…”

Section: Discussionmentioning

confidence: 97%

Dissecting the Roles of the Autonomic Nervous System and Physical Activity on Circadian Heart Rate Fluctuations in Mice

et al. 2021

View full text Add to dashboard Cite

Heart rate (HR) and blood pressure as well as adverse cardiovascular events show clear circadian patterns, which are linked to interdependent daily variations in physical activity and cardiac autonomic nerve system (ANS) activity. We set out to assess the relative contributions of the ANS (alone) and physical activity to circadian HR fluctuations. To do so, we measured HR (beats per minute, bpm) in mice that were either immobilized using isoflurane anesthesia or free-moving. Nonlinear fits of HR data to sine functions revealed that anesthetized mice display brisk circadian HR fluctuations with amplitudes of 47.1±7.4bpm with the highest HRs in middle of the dark (active) period (ZT 18: 589±46bpm) and lowest HRs in the middle of the light (rest) period (ZT 6: 497±54bpm). The circadian HR fluctuations were reduced by ~70% following blockade of cardiac parasympathetic nervous activity (PNA) with atropine while declining by <15% following cardiac sympathetic nerve activity (SNA) blockade with propranolol. Small HR fluctuation amplitudes (11.6±5.9bpm) remained after complete cardiac ANS blockade. Remarkably, circadian HR fluctuation amplitudes in freely moving, telemetrized mice were only ~32% larger than in anesthetized mice. However, after gaining access to running wheels for 1week, circadian HR fluctuations increase to 102.9±12.1bpm and this is linked directly to increased O2 consumption during running. We conclude that, independent of physical activity, the ANS is a major determinant of circadian HR variations with PNA playing a dominant role compared to SNA. The effects of physical activity to the daily HR variations are remarkably small unless mice get access to running wheels.

show abstract

“…Data consistent with the time-of-day dependence of HCN4 block have been obtained from patients: in patients with inappropriate sinus tachycardia or ischemic heart disease and heart failure, ivabradine causes a large decrease in heart rate during the day and a slight decrease at night. 25,26 Nevertheless, I f may not be the only mechanism involved: there was a daynight difference in calcium/calmodulin dependent protein kinase II delta (Camk2d/CaMKIId) expression and various K 1 channels, particularly ether-a-go-go related gene (ERG; Kcnh2) (Figure 2A). Further study is warranted on the relative importance of these alterations in controlling SN pacemaking.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

show abstract

The Effect of Ivabradine Administration on the Night Drop of Heart Rate in Patients With Inappropriate Sinus Tachycardia

Cited by 4 publications

References 0 publications

Circadian control of intrinsic heart rate via a sinus node clock and the pacemaker channel

Circadian control of intrinsic heart rate via a sinus node clock and the pacemaker channel

Dissecting the Roles of the Autonomic Nervous System and Physical Activity on Circadian Heart Rate Fluctuations in Mice

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

Contact Info

Product

Resources

About