Circadian rhythms govern cardiac repolarization and arrhythmogenesis

• Published in: Nature (London) 2012-02, Vol.483 (7387), p.96-99
• Main Authors: Jeyaraj, Darwin, Haldar, Saptarsi M., Wan, Xiaoping, McCauley, Mark D., Ripperger, Jürgen A., Hu, Kun, Lu, Yuan, Eapen, Betty L., Sharma, Nikunj, Ficker, Eckhard, Cutler, Michael J., Gulick, James, Sanbe, Atsushi, Robbins, Jeffrey, Demolombe, Sophie, Kondratov, Roman V., Shea, Steven A., Albrecht, Urs, Wehrens, Xander H. T., Rosenbaum, David S., Jain, Mukesh K.
• Format: Article
• Language: English
• Subjects: 631/337/572; 631/45/269; 631/80/105; 692/699/75/29; Animals; Arrhythmias, Cardiac - complications; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - physiopathology; Binding sites; Biological and medical sciences; Cardiac dysrhythmias; Cardiology. Vascular system; Cells, Cultured; Circadian rhythm; Circadian Rhythm - genetics; Circadian Rhythm - physiology; Circadian rhythms; Congenital diseases; Death, Sudden, Cardiac - etiology; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Electrocardiography; Gene expression; Gene Expression Regulation; Heart; Heart Conduction System - physiology; Heart rate; Heart Rate - physiology; Heart Ventricles - cytology; Humanities and Social Sciences; Kruppel-Like Transcription Factors; Kv Channel-Interacting Proteins - biosynthesis; Kv Channel-Interacting Proteins - genetics; letter; Male; Medical sciences; Mice; Mice, Inbred C57BL; multidisciplinary; Muscle Cells - cytology; Promoter Regions, Genetic - genetics; Rats; Rodents; Science; Science (multidisciplinary); Statistical methods; Studies; Telemetry; Time Factors; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10852

Circadian rhythmicity of cardiac ion-channel expression and of an index of myocardial repolarization is under the control of Klf15, a clock-dependent oscillator that is required for generating transient outward potassium current, and deficiencies or excesses of which cause loss of rhythmic variation in myocardial and abnormal repolarization, and an enhanced susceptibility to ventricular arrhythmias. How the biological clock influences the heart Several physiological parameters in the cardiovascular system show diurnal variation. Mukesh Jain and colleagues now provide a link between circadian rhythms and arrhythmogenesis in mice. They show that the transcription factor Klf15 is regulated by components of the circadian clock, and Klf15 in turn regulates expression of the ion channel KChIP2. In gain- and loss-of-function experiments, the authors show that Klf15 regulates temporal variation in cardiac repolarization and susceptibility to arrhythmias. The findings raise the possibility that circadian factors contribute to the diurnal variation seen in occurrence of sudden cardiac death. Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease 1 , 2 , 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) 3 , 4 , 5 or pattern (for example, Brugada’s syndrome) 6 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 7 . 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.