Circadian rhythms govern cardiac repolarization and arrhythmogenesis
Open accessAbstract
Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure) or pattern (for example, Brugada's syndrome) of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, krüppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac arrhythmogenesis.
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In mice, the circadian clock controls ionic balance in the heart in a healthy range by regulating rhythms in Kruppel-like factor 15 and thereby kChIP2, with either deficiency or excess increasing susceptibility to serious ventricular arrhythmias.
“In mice, the circadian clock also controls ionic balance in the heart in a healthy range by regulating rhythms in Kruppel-like factor 15 and thereby kChIP2 (a voltage-gated potassium channel), with either deficiency or excess increasing susceptibility to serious ventricular arrhythmias (65).”
From Role of the circadian system in cardiovascular disease (2018) · cites this paper as [65]
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- Authors
- Jeyaraj, D., Haldar, S. M., Wan, X., McCauley, M. D., Ripperger, J. A., Hu, K., Lu, Y., Eapen, B. L., Sharma, N., Ficker, E., Cutler, M. J., Gulick, J., Sanbe, A., Robbins, J., Demolombe, S., Kondratov, R. V., Shea, S. A., Albrecht, U., Wehrens, X. H. T., Rosenbaum, D. S., & Jain, M. K.
- Affiliations
- Case Western Reserve University (US)
- MetroHealth (US)
- Baylor College of Medicine (US)
- University of Fribourg (CH)
- Brigham and Women's Hospital (US)
- Cincinnati Children's Hospital Medical Center (US)
- Centre National de la Recherche Scientifique (FR)
- Cleveland State University (US)
- Corresponding author
- Jeyaraj, Darwin
- Jain, Mukesh K.
- ORCID
- Venue
- Nature
- Published
- 2012-02-22
- Volume
- 483
- Issue
- 7387
- Pages
- 96-99
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3297978
- OpenAlex
- W2066229820
- Cited by
- 343
- References
- 29
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 19 · 2023: 15 · 2022: 16 · 2021: 34 · 2020: 25 · 2019: 18 · 2018: 21 · 2017: 35 · 2016: 21 · 2015: 33 · 2014: 35 · 2013: 31 · 2012: 18
- FWCI
- 23.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- reroDoc Digital Library (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (1k99hl102241-01)
- National Institute on Aging (R01AG039547)
- National Heart, Lung, and Blood Institute (HL 084154, K99-HL102241, R01HL084154, HL76446, HL094660, T32HL066991, HL 086548, K24HL076446, HL054807, HL-076754, R00HL102241, R01HL054807, HL075427, HL-091947, R01HL089598, HL-089598, R01HL110630, K08HL086614, R01HL075427, R01HL086548, HL102241, HL097595, R29HL054807, R01HL097593, R01HL091947, K08HL094660, R01HL076754, HL066991, HL086614)
- National Center for Research Resources (M01RR002635)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- circadian rhythm, cardiac repolarization, ventricular arrhythmias, arrhythmogenesis, KLF15, KChIP2, transient outward potassium current, QT interval, diurnal variation, sudden cardiac death, cardiac ion channels, circadian clock
- MeSH terms
- Animals, Arrhythmias, Cardiac, Cells, Cultured, Circadian Rhythm, DNA-Binding Proteins, Electrocardiography, Gene Expression Regulation, Heart Conduction System, Heart Rate, Heart Ventricles, Male, Mice, Inbred C57BL, Promoter Regions, Genetic, Time Factors, Transcription Factors, Death, Sudden, Cardiac, Muscle Cells, Mice, Rats, Kv Channel-Interacting Proteins, Kruppel-Like Transcription Factors
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