Circadian rhythm in QT interval is preserved in mice deficient of potassium channel interacting protein 2

Gottlieb, Lisa A.; Lubberding, Anniek F.; Larsen, Allan; Thomsen, Morten B.

doi:10.1080/07420528.2016.1225074

Cited by 11 publications

(19 citation statements)

References 38 publications

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“…We have previously documented the presence of a 24‐h rhythm of the QRS complex in conscious wild‐type mice (Gottlieb et al. ). The control mechanism of such 24‐h rhythm can reside in (1) the endogenous cardiac clock, using a transcription‐based mechanism (Martino and Young ); (2) an endogenous clock of another cell type or organ that provides a neurohumoral signal to the heart; or (3) by the central clock in the suprachiasmatic nucleus of the brain, where environmental cues entrain the master clock controlling all the peripheral organ clocks (Buhr et al.…”

Section: Discussionmentioning

confidence: 97%

“…Radiotransmitter telemetry devices (ETA‐F10, Data Sciences International, St. Paul, MN) were implanted in anesthetized mice (2% isoflurane in 100% O 2 ) subcutaneously on the dorsal area between the scapulae, as previously described (Gottlieb et al. ). Postoperative analgesia included carprofen (10 mg/kg, s.c.), lidocaine, and bupivacain (0.4 and 1.0 mg/kg, respectively, in the s.c. pocket).…”

Section: Methodsmentioning

confidence: 99%

“…Electrocardiograms (ECG) were recorded continuously at 1 kHz for 24 h in freely moving and conscious mice >7 days after surgery using a setup previously described (Gottlieb et al. ). The mice were in their normal 12‐h light/dark schedule, and had access to food and water ad libitum during the recordings.…”

Section: Methodsmentioning

confidence: 99%

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Uremia increases QRS duration afterβ-adrenergic stimulation in mice

et al. 2018

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Chronic kidney disease (CKD) and uremia increase the risk of heart disease and sudden cardiac death. Coronary artery disease can only partly account for this. The remaining mechanistic links between CKD and sudden death are elusive, but may involve cardiac arrhythmias. For the present study, we hypothesized that a thorough electrophysiological study in mice with CKD would provide us valuable information that could aid in the identification of additional underlying causes of sudden cardiac death in patients with kidney disease. Partial (5/6) nephrectomy (NX) in mice induced mild CKD: plasma urea in NX was 24 ± 1 mmol/L (n = 23) versus 12 ± 1 mmol/L (n = 22) in sham‐operated control mice (P < 0.05). Echocardiography did not identify structural or mechanical remodeling in NX mice. Baseline ECG parameters were comparable in conscious NX and control mice; however, the normal 24‐h diurnal rhythm in QRS duration was lost in NX mice. Moreover, β‐adrenergic stimulation (isoprenaline, 200 μg/kg intraperitoneally) prolonged QRS duration in conscious NX mice (from 12 ± 1 to 15 ± 2 msec, P < 0.05), but not in sham‐operated controls (from 13 ± 1 to 13 ± 2 msec, P > 0.05). No spontaneous arrhythmias were observed in conscious NX mice, and intracardiac pacing in anesthetized mice showed a comparable arrhythmia vulnerability in NX and sham‐operated mice. Isoprenaline (2 mg/kg intraperitoneally) changed the duration of the QRS complex from 11.2 ± 0.4 to 11.9 ± 0.5 (P = 0.06) in NX mice and from 10.7 ± 0.6 to 10.6 ± 0.6 (P = 0.50) in sham‐operated mice. Ex vivo measurements of cardiac ventricular conduction velocity were comparable in NX and sham mice. Transcriptional activity of Scn5a, Gja1 and several profibrotic genes was similar in NX and sham mice. We conclude that proper kidney function is necessary to maintain diurnal variation in QRS duration and that sympathetic regulation of the QRS duration is altered in kidney disease.

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Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

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Uremia increases QRS duration afterβ-adrenergic stimulation in mice

et al. 2018

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“…A subcutaneous pocket was created in the mid‐dorsal region and the telemetric device was placed inside. The electrode leads were tunnelled subcutaneously to the right shoulder joint (negative lead) and under the left armpit (positive lead) and secured using non‐absorbable suture (Ethicon), creating a lead‐II ECG with a high signal‐to‐noise ratio . In a subset of db/db mice, blood pressure in the abdominal aorta was recorded simultaneously with the ECG (HD‐X11; DataSciences International) as previously described .…”

Section: Methodsmentioning

confidence: 99%

Aberrant sinus node firing during β‐adrenergic stimulation leads to cardiac arrhythmias in diabetic mice

et al. 2020

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Aim: Cardiovascular complications, including cardiac arrhythmias, result in high morbidity and mortality in patients with type-2 diabetes mellitus (T2DM). Clinical and experimental data suggest electrophysiological impairment of the natural pacemaker of the diabetic heart. The present study examined sinoatrial node (SAN) arrhythmias in a mouse model of T2DM and physiologically probed their underlying cause. Methods: Electrocardiograms were obtained from conscious diabetic db/db and lean control db/+ mice. In vivo SAN function was probed through pharmacological autonomic modulation with isoprenaline, atropine and carbachol. Blood pressure stability and heart rate variability (HRV) were evaluated. Intrinsic SAN function was evaluated through ex vivo imaging of spontaneous Ca 2+ transients in isolated SAN preparations. Results: While lean control mice showed constant RR intervals during isoprenaline challenge, the diabetic mice experienced SAN arrhythmias with large RR fluctuations in a dose-dependent manner. These arrhythmias were completely abolished by atropine pre-treatment, while carbachol pretreatment significantly increased SAN arrhythmia frequency in the diabetic mice. Blood pressure and HRV were comparable in db/db and db/+ mice, suggesting that neither augmented baroreceptor feedback nor autonomic neuropathy is a likely arrhythmia mechanism. Cycle length response to isoprenaline was comparable in isolated SAN preparations from db/db and db/+ mice; however, Ca 2+ spark frequency was significantly increased in db/db mice compared to db/+ at baseline and after isoprenaline. Conclusion: Our results demonstrate a dysfunction of cardiac pacemaking in an animal model of T2DM upon challenge with a β-adrenergic agonist. Ex vivo, higher Ca 2+ spark frequency is present in diabetic mice, which may be directly linked to in vivo arrhythmias. K E Y W O R D Sautonomic nervous system, baroreflex, calcium, electrophysiology, isoprenaline, type-2 diabetes

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“…Jeyaraj et al [29] showed that Kruppel-like factor 15 (Klf15) is a CCG that directly regulates KChIP2 expression, and that deletion of Klf15 abolishes the circadian rhythm in QT interval and increases suspectibility of mice to ventricular arrhythmias. However, Gottlieb et al [23] concluded that KChIP2 is not a mechanistic link between the cardiac circadian clock and ventricular repolarization and arrhythmogenesis, based on their finding that KChIP2-deficient mice still have a circadian rhythm in QT interval. Rather, they suggest that Klf15 expression controls the transcription of other genes responsible for the circadian rhythm in repolarization and susceptibility to arrhythmias.…”

Section: Circadian Transcription Of Cardiac Ion Channelsmentioning

confidence: 99%

Circadian rhythms of early afterdepolarizations and ventricular arrhythmias in a cardiomyocyte model

Diekman

Wei

2020

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Sudden cardiac arrest is a malfunction of the heart's electrical system, typically caused by ventricular arrhythmias, that can lead to sudden cardiac death (SCD) within minutes. Epidemiological studies have shown that SCD and ventricular arrhythmias are more likely to occur in the morning than in the evening, and laboratory studies indicate that these daily rhythms in adverse cardiovascular events are at least partially under the control of the endogenous circadian timekeeping system. However, the biophysical mechanisms linking molecular circadian clocks to cardiac arrhythmogenesis are not fully understood. Recent experiments have shown that L-type calcium channels exhibit circadian rhythms in both expression and function in guinea pig ventricular cardiomyocytes. We developed an electrophysiological model of these cells to simulate the effect of circadian variation in L-type calcium conductance. We found that there is a circadian pattern in the occurrence of early afterdepolarizations (EADs), which are abnormal depolarizations during the repolarization phase of a cardiac action potential that can trigger fatal ventricular arrhythmias. Specifically, the model produces EADs in the morning but not at other times of day. We show that the model exhibits a codimension-2 Takens-Bogdanov bifurcation that serves as an organizing center for different types of EAD dynamics. We also simulated a 2-D spatial version of this model across a circadian cycle. We found that there is a circadian pattern in the breakup of spiral waves, which represents ventricular fibrillation in cardiac tissue. Specifically, the model produces spiral wave breakup in the morning but not in the evening. Our study is the first to propose a link between circadian rhythms and EAD formation and suggests that the efficacy of drugs targeting EAD-mediated arrhythmias may depend on the time of day that they are administered.

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Circadian rhythm in QT interval is preserved in mice deficient of potassium channel interacting protein 2

Cited by 11 publications

References 38 publications

Uremia increases QRS duration afterβ-adrenergic stimulation in mice

Uremia increases QRS duration afterβ-adrenergic stimulation in mice

Aberrant sinus node firing during β‐adrenergic stimulation leads to cardiac arrhythmias in diabetic mice

Circadian rhythms of early afterdepolarizations and ventricular arrhythmias in a cardiomyocyte model

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