Light phase-restricted feeding slows basal heart rate to exaggerate the type-3 long QT syndrome phenotype in mice

Abstract

Light phaserestricted feeding slows basal heart rate to exaggerate the type 3 long QT syndrome phenotype in mice. Am J Physiol Heart Circ Physiol 307: H1777-H1785, 2014. First published October 24, 2014 doi:10.1152/ajpheart.00341.2014.-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 ϩ/⌬KPQ ). 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 ϩ/ ⌬KPQ 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 ϩ/⌬KPQ mice, light phase-restricted feeding shifted the RR and QT rhythms ϳ12 h, increased their amplitudes greater than twofold, and raised the 24-h midline mean by ϳ10%. In contrast to WT mice, the QTc interval in Scn5a ϩ/⌬KPQ mice exhibited time-ofday prolongation that was flipped after light phase-restricted feeding. The time-of-day changes in the QTc intervals of Scn5a ϩ/⌬KPQ 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 genotypespecific differences in the QT intervals and aggravate the LQT3-related phenotype.long QT syndrome; heart rate; feeding; circadian rhythms; SCN5A CONGENITAL LONG QT SYNDROME (LQTS) is primarily an autosomal-dominant disease that delays ventricular repolarization and increases the risk for polymorphic ventricular tachycardia, which can cause syncope, seizures, and sudden cardiac arrest (26). The majority of LQTS cases are linked to mutations in three different cardiac ion channel genes: KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3) (27). These three major types of LQTS show differences in disease penetrance, electrocardiographic characteristics, symptomatic risk, triggers for events, and responsiveness to treatment (23,29). In particular, LQT3 is more lethal than LQT1 or LQT2, and LQT3 patients typically exhibit an abnormal increase in their heart ratecorrected QT (QTc) intervals and risk for life-threatening episodes at night (28,30, 33).Despite this strong time-of-day association between lifethreatening events in the LQT3 phenotype, the role that manipulating circadian rhythms has on the expressivity of the LQT3 phenotype has not yet been investigated. Circadian rhythms are Ϸ24-h rhythms that are regulated at the cellular level by a transcription-translation feedback loop referred to as the molecular clock. The mol...

The cardiomyocyte molecular clock regulates the circadian expression of Kcnh2 and contributes to ventricular repolarization

“…We and several other studies have not been able to resolve a circadian rhythm in the QTc interval in WT or control mice. 18, 19 More importantly, our work suggests that disruption of the cardiomyocyte molecular clock likely downregulates the expression for a number of different K + genes. A loss in overall K + channel expression would be expected to prolong the QT interval.…”

“…These findings are analogous to reports investigating the circadian relation between the RR interval and QT interval in a transgenic mouse model of long QT syndrome (LQTS), as well as clinical data investigating the relation between the RR and QT intervals in long QT syndrome patients. 18, 25 …”

“…8, 18 Briefly, mice were anesthetized with isoflurane and telemetry transmitter units (PhysioTel ETA-F10; Data Sciences International) were implanted in the peritoneal cavity. Two ECG leads were secured near the apex of the heart and the right acromion.…”

“…We used two complementary methods to quantify the QT interval. 18 The first method was to manually measure and calculate the QTc interval using a modified version of the Bazett’s formula adjusted for mice and described in detail by Mitchell and colleagues (1998). 19 For the second approach, we used an automated program written in Matlab (Mathworks) to compute hourly uncorrected QT intervals similar as described previously.…”

“…19 For the second approach, we used an automated program written in Matlab (Mathworks) to compute hourly uncorrected QT intervals similar as described previously. 18 Briefly, ECG traces recorded for each hour were aligned to the peak of the R wave to generate an hourly averaged trace and the QT calculation was done using the threshold method. The Q was defined as the base of the QRS complex (where the slope of the profile changed from negative or isoelectric to positive) and the T was defined as the point where the ECG returned 95% of the way from the T-wave minima to the isoelectric level.…”