Aim
Cardiac arrhythmias and sudden deaths have diurnal rhythms in humans. The underlying mechanisms are unknown. Mice with cardiomyocyte‐specific disruption of the molecular clock genes have lower heart rate than control. Because changes in the QT interval on the electrocardiogram is a clinically used marker of risk of arrhythmias, we sought to test if the biological rhythms of QT intervals are dependent on heart rate and if this dependency is changed when the molecular clock is disrupted.
Methods
We implanted radio transmitters in male mice with cardiomyocyte‐specific Bmal1 knockout (CBK) and in control mice and recorded 24‐h ECGs under diurnal and circadian conditions. We obtained left ventricular monophasic action potentials during pacing in hearts ex vivo.
Results
Both RR and QT intervals were longer in conscious CBK than control mice (RR: 117 ± 7 vs 110 ± 9 ms, P < .05; and QT: 53 ± 4 vs 48 ± 2 ms, P < .05). The prolonged QT interval was independent of the slow heart rate in CBK mice. The QT interval exhibited diurnal and circadian rhythms in both CBK and control mice. The action potential duration was longer in CBK than in control mice, indicating slower repolarization. Action potential alternans occurred at lower pacing rate in hearts from CBK than control mice (12 ± 3 vs 16 ± 2 Hz, respectively, P < .05).
Conclusion
The bradycardic CBK mice have prolonged ventricular repolarization independent of the heart rate. Diurnal and circadian rhythms in repolarization are preserved in CBK mice and are not a consequence of the 24‐h rhythm in heart rate. Arrhythmia vulnerability appears to be increased when the cardiac clock is disrupted.
BACKGROUND Torsades de pointes arrhythmia is a potentially lethal polymorphic ventricular tachyarrhythmia (pVT) in the setting of long QT syndrome. Arrhythmia susceptibility is influenced by risk factors modifying repolarization.OBJECTIVE The purpose of this article was to characterize repolarization duration and heterogeneity in relation to pVT inducibility and maintenance.METHODS Sotalol was infused regionally or globally in isolated Langendorff blood-perfused pig hearts (N 5 7) to create repolarization time (RT) heterogeneities. Programmed stimulation and epicardial activation and repolarization mapping were performed. The role of RT (heterogeneities) was studied in more detail using a computer model of the human heart.RESULTS pVTs (n 5 11) were inducible at a critical combination of RT and RT heterogeneities. The pVT cycle lengths were similar in the short and long RT regions. Short-lasting pVTs were maintained by focal activity while longer-lasting pVTs by reentry wandering along the interface between the 2 regions. Local restitution curves from the long and short RT regions crossed. This was associated with Twave inversion at coupling intervals at either side of the crossing point. These experimental observations were confirmed by the computer simulations.CONCLUSION pVTs are inducible within a critical range of RT and RT heterogeneities and are maintained by reentry wandering along the repolarization gradient. Double potentials localize at the core of the reentrant circuit and reflect phase singularities. RT gradient and T waves invert with short-coupled premature beats in the long RT region as a result of the crossing of the restitution curves allowing reentry initiation.
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