Abstract 14050: The Cardiomyocyte Molecular Clock Augments K+ Channel Gene Expression to Safeguard Against a Large Circadian Oscillation in the QT Interval
Circadian rhythms are ~24-hour biological cycles that synchronize the timing of an organism’s physiology to daily changes. The mechanism that underlies circadian function is the molecular clock: a transcription-translation feedback loop comprised of the core clock genes Bmal1, Clock, Per1, Per2, Cry1 and Cry2. Studies with Bmal1-, Per2-, and Cry1-null mice suggest a link between the molecular clock, cardiac K+ channel expression, and ventricular repolarization. However, these studies do not distinguish between disruptions of the central clock in the brain vs. the molecular clock in the heart. We tested the role of the clock in the heart using a tamoxifen-induced cardiomyocyte-specific Bmal1 knockout mouse. We used real-time PCR to measure the expression of KCNA1, KCNA5, KCNB1, KCNQ1, KCNH2, and KCNJ2 in ventricular tissue isolated every 4 hours for 28 hours from vehicle-treated control (iCSBmal1+/+) or tamoxifen-treated (iCSBmal1-/-) mice. In iCSBmal1+/+ hearts, KCNH2 showed a circadian rhythm in mRNA expression that was lost in iCSBmal1-/- hearts. Although the expression of KCNA5, KCNB1, KCNQ1, and KCNJ2 was not circadian in iCSBmal1+/+ hearts, the expression levels were reduced by ~50% in iCSBmal1-/- hearts (p<0.05). Consistent with a reduction in K+ channel gene expression, ECG telemetry showed that the average heart rate corrected QT interval (QTc) was ~15% longer in the iCSBmal1-/- mice (p<0.05; n=5-6 animals each). iCSBmal1+/+ and iCSBmal1-/- mice both showed a robust circadian rhythm in their RR, PQ and QT intervals that peaked 2-3 hours into the light phase. Fitting the circadian rhythms with a sinusoidal model revealed no difference in the the circadian amplitudes for the RR or PQ intervals, but the circadian amplitude of the QT interval was ~85% larger in the iCSBmal1-/- mice (p<0.05). Linear regression analyses between the natural logarithms of the QT and RR intervals showed that the amplified circadian oscillation of the QT interval in the iCSBmal1-/- mice increased the slope of the QT-RR relation by >65% (p<0.05). These data provide a direct link between the cardiomyocyte clock and ventricular repolarization: the cardiomyocyte clock enhances K+ channel gene expression to protect against large circadian fluctuations in the QT interval.
- © 2013 by American Heart Association, Inc.