Let her sleep...but how much

AN INCREASING NUMBER OF STUDIES ARE FINDING THAT SHORT SLEEP DURATION HAS A MORE PROFOUND IMPACT ON WOMEN'S CARDIOVASCULAR health than on men's. Data presented in the report by Miller and colleagues1 in this issue of SLEEP, “Gender differences in the cross-sectional relationships between sleep duration and markers of Inflammation: Whitehall II study,” point to inflammatory changes as a possible link between short sleep duration and cardiovascular disease in women. This study represents an important contribution on sex differences in the relationship of risk factors to sleep duration. Moreover, it is the first large-scale cohort study to describe the associations between sleep duration and inflammation, and it represents one more study in the growing list that shows nonlinear associations between sleep duration and cardiovascular risk factors. The investigators found a sex by sleep duration interaction for both inflammatory mediators under investigation (high sensitivity CRP (hsCRP) and interleukin-6 (IL-6), and therefore they stratified their sample and analyzed men and women separately. They found that men and women both had poorer health if they were obtaining, by self-report, less than 5 or more than 9, hours of sleep per night. At 5 or fewer hours of sleep per night, men had higher diastolic blood pressure and women higher systolic blood pressure than their cohorts with sleep durations in the 6-8 hour per night range. The relationship between small basal increases in levels of inflammatory mediators (particularly IL-6 and high sensitivity CRP), and the risk for developing cardiovascular disease has been established in the cardiovascular field for men and women.2,3 Combining this with the knowledge that experimental sleep deprivation leads to increased levels of inflammatory mediators,4,5 the prediction follows that inflammatory processes might underlie the relationship between short sleep duration and elevated cardiovascular risk. An earlier test of this prediction in a smaller sample of subjects not stratified by sex, failed to find an association,6 but in this issue of the journal, Miller and colleagues report a U-shaped relationship between sleep duration and hsCRP in women but not men. The work of Miller and colleagues, comes from the Whitehall II Study, of London civil servants aged 35-55. This group of investigators has also recently published data from this cohort, showing that among normotensive participants (2686 men and 1005 women), women with short sleep duration were at increased risk of developing hypertension even when data were corrected for cardiovascular risk factors and psychiatric comorbidities.14 In the current study, these investigators analyzed data from over 4,600 participants for whom they had self-reported data on average sleep time, and they examined relationships between sleep duration and IL-6 and hsCRP. The study represents a white, middle-aged sample of state employees. Fasting blood samples were taken within an approximately 7-hour window of time. IL-6 and hsCRP in peripheral circulation are not independent. While not the only mediator, IL-6 is one of the most potent stimulators of hepatic production of CRP. IL-6 has a shorter half-life and is therefore more likely to be influenced by transient factors and to show a diurnal rhythm than hsCRP, which has a half-life >15 hours,8 lacks a diurnal rhythm,9 and is known to be quite reliable when retested weeks and months later.10 For these reasons it is a more stable index of inflammatory status, and Miller et al., have demonstrated this stability in their sample by showing significant test-retest (approximately one-month interval) interclass correlations (r = 0.83) for hsCRP, and an expected reasonably less robust correlation for IL-6 (r = 0.62). When Miller and colleagues examined the Whitehall II data without removing variance attributable to known covariates, men showed a relationship between average sleep duration and IL-6 (but not hsCRP), with lowest values at 7 hours of sleep/night, and women showed a relationship between average sleep duration and hsCRP (but not IL-6) again with lowest levels seen at 7 h/night. The picture becomes more complicated when considering the fully corrected models, which include adjustments for age, marital status, body mass index, smoking, systolic blood pressure, and triglycerides. Here Miller et al fail to find a curvilinear relationship for IL-6 or hsCRP in men. They do however, find a significant curvilinear relationship for hsCRP and sleep duration in women. While the pattern for hsCRP are clear in women, IL-6 shows only a trend towards a curvilinear relationship in the fully corrected model. However, there is a dissociation of IL-6 and hsCRP in the pattern of their relationship with sleep duration. In women, the lowest levels of hsCRP are around 6 hours/night in the fully corrected model, and there is not much difference between 6-8 hours of sleep per night. Nine or more, and 5 or less hours of sleep per night are associated with abrupt increases in hsCRP levels. IL-6, on the other hand, is quite low from the shortest duration of sleep to 8 hours per night where it shows its nadir, and then increases at 9 or more hours of sleep per night. The dissociation is most puzzling in the short (≤ 5h) sleeping women who have relatively high hsCRP and low IL-6. What this dissociation is caused by is an open question for further investigation, but the mechanisms of CRP stimulation/production appear to be influenced by both sleep duration and sex. The study by Miller and colleagues points to several deficiencies in our knowledge and highlights a discrepancy between the results of population based and short term studies of short sleep or sleep deprivation. Sleep deprivation studies have most commonly been conducted with young healthy men as participants, yet several studies have shown increased markers of inflammation under normal ambulatory and light level conditions. Do the metabolic changes associated with insufficient sleep more quickly move men into an adjustment category? Are the inflammatory increases seen in experimental sleep deprivation only short-term reflections of the battle against sleepiness, carried out by highly motivated, super-healthy volunteers rallying to please their experimenters? Unfortunately we know very little about the effects of general health status, age and sex in the biological response to sleep loss. Furthermore, we know almost nothing of the biological effects of sleep extension in healthy normal sleepers. Clearly, a better understanding of the individual differences in biological effects of sleep curtailment would be useful in interpreting these data. Research is needed on individual differences in vulnerability to sleep loss or sleep extension, and sex, age, and race/ethnicity head the list. Gaining knowledge about individual differences in sleep need is a particularly important step in our quest for understanding vulnerability to disease and improving health maintenance. Individualized preventative medicine will challenge the sleep field to develop a better understanding of biological consequences of altering sleep duration. The study of Miller and colleagues raise many questions but at the same time bring us a step closer to understanding individual differences in sleep duration and health outcomes.