In the current study, we examined sleep-related changes in RR and QT intervals in subjects with LQT1 and LQT2 and healthy controls. We found that the modulations of RR and QT intervals during sleep are altered in women with LQT2 but are preserved in men with either LQT1 or LQT2 and in women with LQT1. More specifically, (1) LQT2 women did not show the expected increase in RR during non-REM sleep; (2) LQT2 women, but not LQT1 women (), had striking increases in heart rates during REM, which appear to be an exaggeration of a pattern previously observed in their healthy counterparts19
such that heart rates during REM were faster even than during wakefulness; and (3) RR shortening during REM in LQT2 women was associated with a marked increase in rate-corrected QTc, using either the Bazett or Fridericia formula for heart rate correction. Such RR and QT changes during REM observed in LQT2 women appear to be sex specific as they were not observed in LQT2 men ().
About one third of major cardiac events in LQT2 patients occur during sleep or at rest, in the absence of any known arousal.11
The underlying mechanisms are not known. Women with LQT2 have been reported to have a worse prognosis than LQT2 men.13
An association between sex and the type of trigger of events (e.g., sleep or arousal) has not yet been reported. What is known is that female gender and QTc ≥500 ms are associated with increased risk of life-threatening cardiac events.4
In our study, QTc in REM in women with LQT2 increased to 532 ± 23 ms compared to only 481 ± 18 ms in women with LQT1.
This is the first study evaluating sleep stage–specific changes in QT and RR modulation in patients with congenital LQTS. A previous study using 24-hour Holter monitoring did not find any significant change in QTc during the nighttime compared to the daytime in subjects with LQT2.24
However, actual sleep, sleep stages, breathing changes, and any effects of sex on RR intervals and the QT/RR relationship were not taken into consideration.
In the present study using complete overnight polysomnography, we showed that REM sleep has distinct effects on modulation of the RR and the QT/RR relationship in women with LQT2 compared to women with LQT1 and in men with either LQT1 or LQT2. Importantly, such effects were mitigated when considering LQTS groups without distinguishing by sex (). Thus, our results suggest that REM sleep may induce significant cardiac activation and affect ventricular repolarization only in women but not men with the LQT2 genotype, suggesting a potential mechanism for generation of sleep-related life-threatening arrhythmias in these subjects.
As mentioned, the LQT2 women in our study showed an exaggeration of the physiologic response to REM sleep previously observed in normal women.19,25
Normal women, regardless of their age and hormonal status, have a more marked cardiorespiratory activation in response to REM sleep compared to their male counterparts.19,26
These gender differences also appear to be associated with significant prolongation of QT and QTc interval during REM in women19
that persists after menopause.26
Whether male hormonal mechanisms or nonhormonal gender-related central mechanisms are implicated in this difference requires further investigation.
One third of our LQTS patients were receiving beta-blocker therapy (atenolol, nadolol, or propranolol), which could not be discontinued for ethical reasons. In LQT2 women, significant QT prolongation during REM was evident whether or not subjects were taking beta-blockers. Nevertheless, beta-blocker use could have affected the ECG responses through sleep in LQTS women. Indeed, LQT1 women showed a blunted heart rate increase in response to REM compared to controls, conceivably an effect of beta-blocker treatment. LQT2 women, despite beta-blocker therapy and slower heart rate during presleep wakefulness, manifested a significant heart rate increase
in REM (faster even than wakefulness; ) and greater than the REM-related heart rate increase in controls () and in LQT2 men (), indicating the magnitude of REM-related cardiac activation among the LQT2 women. Therefore, in patients with LQT2 the neurophysiologic events occurring during REM and the associated surges in sympathetic activity27,28
appear to overcome the cardiac slowing action of beta-blockers.
Our findings suggest an explanation that can reconcile the apparent discrepancy between the variety of triggers for events in LQT2 patients, which include sleep and acoustic arousal. A proposed mechanism underlying the occurrence of arrhythmias during sudden intense arousal is abrupt neurally mediated release of catecholamines occurring while the heart rate is relatively slow and “without allowance of time for QT adaptation to faster heart rates.”11
During exercise in LQT2 patients, QT adequately shortens with progressive increase of heart rate.29
In contrast, a bolus injection of epinephrine induces a transient marked prolongation of QTc that is followed by “normalization” to baseline values during steady infusion.30,31
Experimental in vitro
cellular models mimicking the genetic defect of LQT2 describe prolongation of action potential duration and development of early afterdepolarization during early phases of isoproterenol infusion that normalized at steady state.32
Another experimental setting using wedge canine preparations of LQT2 reported that isoproterenol transiently increases transmembrane action potentials and induces torsades de pointes in association with transmural dispersion of repolarization.33
These data support the potential for sudden increases of sympathetic tone to induce transitory abnormal repolarization and ventricular arrhythmias in LQT2 patients. During REM sleep, phasic events such as bursts of rapid eye movements are accompanied by abrupt changes in autonomic tone with sudden increases in cardiac and peripheral sympathetic drive.16
These could reproduce the neurohumoral pattern evoked by an intense arousal, with an abrupt increase of heart rate and transient electrophysiologic changes translating into prolongation of QTc and increased arrhythmic vulnerability.
Precedence exists for supposing that the response to REM sleep has features in common with the responses to acoustic stimuli. Typical neurophysiologic features of REM sleep occurring with periods of phasically enhanced excitability and rapid eye movements (ponto-geniculo-occipital spikes)34
have been shown in animals to be elicited during wakefulness by intense auditory stimuli that evoke the startle and orienting response.35
Therefore, REM sleep and acoustic stimuli seem to activate common central pathways, which conceivably may be implicated in the genesis of arrhythmias in patients with LQT2, particularly women.
REM is the stage during which the most vivid and emotionally intense dreams occur.36
Fear and anger are common emotions during dreaming.37
Verrier et al38
related emotional stress such as anger to the occurrence of delayed myocardial ischemia and proposed that a strong emotional content of dreams may be able to precipitate life-threatening arrhythmias,14
possibly by acting through distinct pathways within the central nervous system and involving the sympathetic nervous system.39
Therefore, intense emotional states achieved during dreams could be implicated in the genesis of cardiac events during REM in some patients with LQT2, especially women.
Limitations of the study include the potentially confounding presence of beta-blocker therapy, which could not be discontinued, in one third of our LQTS subjects. Nevertheless, we were able to make some potentially important observations. The ineffectiveness of beta-blockers in moderating the sinus node response and ventricular repolarization during REM was a specific feature of LQT2 women, providing possible insight into the relatively lower efficacy of beta-blockers in preventing events in patients with LQT2.40
Second, because of the very low prevalence of patients with LQT3, LQT4, LQT5, LQT6, and other LQT genotypes, these patients were not included in this study. Thus, the study observations are limited to the two most common LQTS genotypes.
Modulation of RR and QT intervals during REM sleep is strikingly different in women with LQT2 than in men with either LQT1 or LQT2 and in women with LQT1. Women with LQT2 experience a significant increase in heart rate (RR shortening) during REM, despite therapy with beta-blockers. This cardiac chronotropic activation in LQT2 women is associated with an abnormal prolongation of QTc suggesting that REM-related changes in cardiac rate and ventricular repolarization may provide the substrate for sleep-related malignant arrhythmias in women with LQT2.