title: Light phase-restricted feeding slows basal heart rate to exaggerate the type-3 long QT syndrome phenotype in mice.
abstract: Long QT syndrome type 3 (LQT3) is caused by mutations in the SCN5A-encoded Nav1.5 channel. LQT3 patients exhibit time of day-associated abnormal increases in their heart rate-corrected QT (QTc) intervals and risk for life-threatening episodes. This study determines the effects of uncoupling environmental time cues that entrain circadian rhythms (time of light and time of feeding) on heart rate and ventricular repolarization in wild-type (WT) or transgenic LQT3 mice (Scn5a(+/ΔKPQ)). We used an established light phase-restricted feeding paradigm that disrupts the alignment among the circadian rhythms in the central pacemaker of the suprachiasmatic nucleus and peripheral tissues including heart. Circadian analysis of the RR and QT intervals showed the Scn5a(+/ΔKPQ) mice had QT rhythms with larger amplitudes and 24-h midline means and a more pronounced slowing of the heart rate. For both WT and Scn5a(+/ΔKPQ) mice, light phase-restricted feeding shifted the RR and QT rhythms ~12 h, increased their amplitudes greater than twofold, and raised the 24-h midline mean by ~10%. In contrast to WT mice, the QTc interval in Scn5a(+/ΔKPQ) mice exhibited time-of-day prolongation that was flipped after light phase-restricted feeding. The time-of-day changes in the QTc intervals of Scn5a(+/ΔKPQ) mice were secondary to a steeper power relation between their QT and RR intervals. We conclude that uncoupling time of feeding from normal light cues can dramatically slow heart rate to unmask genotype-specific differences in the QT intervals and aggravate the LQT3-related phenotype.
authors.affiliation: Department of Physiology, Center for Muscle Biology, University of Kentucky, Lexington, Kentucky;
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Schroder
authors.affiliation: Department of Physiology, Center for Muscle Biology, University of Kentucky, Lexington, Kentucky;
authors.forename: Don E
authors.initials: DE
authors.lastname: Burgess
authors.affiliation: Department of Physiology, Center for Muscle Biology, University of Kentucky, Lexington, Kentucky;
authors.forename: Cody L
authors.initials: CL
authors.lastname: Manning
authors.affiliation: Center for Biomedical Engineering, University of Kentucky, Lexington, Kentucky;
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, New York; and.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Moss
authors.affiliation: Center for Biomedical Engineering, University of Kentucky, Lexington, Kentucky;
authors.forename: Abhijit
authors.initials: A
authors.lastname: Patwardhan
authors.affiliation: Department of Cardiology, University of Kentucky, Lexington, Kentucky.
authors.forename: Claude S
authors.initials: CS
authors.lastname: Elayi
authors.affiliation: Department of Physiology, Center for Muscle Biology, University of Kentucky, Lexington, Kentucky;
authors.forename: Karyn A
authors.initials: KA
authors.lastname: Esser
authors.affiliation: Department of Physiology, Center for Muscle Biology, University of Kentucky, Lexington, Kentucky; brian.delisle@uky.edu.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Delisle
mesh_terms: D000818:Animals; D002940:Circadian Rhythm; D004435:Eating; D006339:Heart Rate; D008133:Long QT Syndrome / Q000503:physiopathology*; D051379:Mice; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype; D017440:Photoperiod; D013493:Suprachiasmatic Nucleus / Q000502:physiology
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse
keywords: SCN5A; circadian rhythms; feeding; heart rate; long QT syndrome