title: Circadian rhythms govern cardiac repolarization and arrhythmogenesis.
abstract: 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.
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. darwinjeyaraj@gmail.com
authors.forename: Darwin
authors.initials: D
authors.lastname: Jeyaraj
authors.forename: Saptarsi M
authors.initials: SM
authors.lastname: Haldar
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wan
authors.forename: Mark D
authors.initials: MD
authors.lastname: McCauley
authors.forename: Jürgen A
authors.initials: JA
authors.lastname: Ripperger
authors.forename: Kun
authors.initials: K
authors.lastname: Hu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Betty L
authors.initials: BL
authors.lastname: Eapen
authors.forename: Nikunj
authors.initials: N
authors.lastname: Sharma
authors.forename: Eckhard
authors.initials: E
authors.lastname: Ficker
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cutler
authors.forename: James
authors.initials: J
authors.lastname: Gulick
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Sophie
authors.initials: S
authors.lastname: Demolombe
authors.forename: Roman V
authors.initials: RV
authors.lastname: Kondratov
authors.forename: Steven A
authors.initials: SA
authors.lastname: Shea
authors.forename: Urs
authors.initials: U
authors.lastname: Albrecht
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenbaum
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004562:Electrocardiography; D005786:Gene Expression Regulation; D006329:Heart Conduction System / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology; D051741:Kruppel-Like Transcription Factors; D051605:Kv Channel-Interacting Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C496758:Kcnip2 protein, rat; C467418:Klf15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051605:Kv Channel-Interacting Proteins; D014157:Transcription Factors