Michelle A. Miller

Sleep duration predicts cardiovascular outcomes: a systematic review and meta-analysis of prospective studies

Aims To assess the relationship between duration of sleep and morbidity and mortality from coronary heart disease (CHD), stroke, and total cardiovascular disease (CVD). Methods and results We performed a systematic search of publications using MEDLINE (1966-2009), EMBASE (from 1980), the Cochrane Library, and manual searches without language restrictions. Studies were included if they were prospective, follow-up >3 years, had duration of sleep at baseline, and incident cases of CHD, stroke, or CVD. Relative risks (RR) and 95% confidence interval (CI) were pooled using a random-effect model. Overall, 15 studies (24 cohort samples) included 474 684 male and female participants (follow-up 6.9-25 years), and 16 067 events (4169 for CHD, 3478 for stroke, and 8420 for total CVD). Sleep duration was assessed by questionnaire and incident cases through certification and event registers. Short duration of sleep was associated with a greater risk of developing or dying of CHD (RR 1.48, 95% CI 1.22-1.80, P < 0.0001), stroke (1.15, 1.00-1.31, P = 0.047), but not total CVD (1.03, 0.93-1.15, P = 0.52) with no evidence of publication bias (P = 0.95, P = 0.30, and P = 0.46, respectively). Long duration of sleep was also associated with a greater risk of CHD (1.38, 1.15-1.66, P = 0.0005), stroke (1.65, 1.45-1.87, P < 0.0001), and total CVD (1.41, 1.19-1.68, P < 0.0001) with no evidence of publication bias (P = 0.92, P = 0.96, and P = 0.79, respectively). Conclusion Both short and long duration of sleep are predictors, or markers, of cardiovascular outcomes.

Quantity and Quality of Sleep and Incidence of Type 2 Diabetes A systematic review and meta-analysis

OBJECTIVE To assess the relationship between habitual sleep disturbances and the incidence of type 2 diabetes and to obtain an estimate of the risk. RESEARCH DESIGN AND METHODS We conducted a systematic search of publications using MEDLINE (1955–April 2009), EMBASE, and the Cochrane Library and manual searches without language restrictions. We included studies if they were prospective with follow-up >3 years and had an assessment of sleep disturbances at baseline and incidence of type 2 diabetes. We recorded several characteristics for each study. We extracted quantity and quality of sleep, how they were assessed, and incident cases defined with different validated methods. We extracted relative risks (RRs) and 95% CI and pooled them using random-effects models. We performed sensitivity analysis and assessed heterogeneity and publication bias. RESULTS We included 10 studies (13 independent cohort samples; 107,756 male and female participants, follow-up range 4.2–32 years, and 3,586 incident cases of type 2 diabetes). In pooled analyses, quantity and quality of sleep predicted the risk of development of type 2 diabetes. For short duration of sleep (≤5–6 h/night), the RR was 1.28 (95% CI 1.03–1.60, P = 0.024, heterogeneity P = 0.015); for long duration of sleep (>8–9 h/night), the RR was 1.48 (1.13–1.96, P = 0.005); for difficulty in initiating sleep, the RR was 1.57 (1.25–1.97, P < 0.0001); and for difficulty in maintaining sleep, the RR was 1.84 (1.39–2.43, P < 0.0001). CONCLUSIONS Quantity and quality of sleep consistently and significantly predict the risk of the development of type 2 diabetes. The mechanisms underlying this relation may differ between short and long sleepers.

Gender-specific associations of short sleep duration with prevalent and incident hypertension: the Whitehall II Study.

Sleep deprivation (≤5 hour per night) was associated with a higher risk of hypertension in middle-aged American adults but not among older individuals. However, the outcome was based on self-reported diagnosis of incident hypertension, and no gender-specific analyses were included. We examined cross-sectional and prospective associations of sleep duration with prevalent and incident hypertension in a cohort of 10 308 British civil servants aged 35 to 55 years at baseline (phase 1: 1985–1988). Data were gathered from phase 5 (1997–1999) and phase 7 (2003–2004). Sleep duration and other covariates were assessed at phase 5. At both examinations, hypertension was defined as blood pressure ≥140/90 mm Hg or regular use of antihypertensive medications. In cross-sectional analyses at phase 5 (n=5766), short duration of sleep (≤5 hour per night) was associated with higher risk of hypertension compared with the group sleeping 7 hours, among women (odds ratio: 2.01; 95% CI: 1.13 to 3.58), independent of confounders, with an inverse linear trend across decreasing hours of sleep (P=0.003). No association was detected in men. In prospective analyses (mean follow-up: 5 years), the cumulative incidence of hypertension was 20.0% (n=740) among 3691 normotensive individuals at phase 5. In women, short duration of sleep was associated with a higher risk of hypertension in a reduced model (age and employment) (6 hours per night: odds ratio: 1.56 [95% CI: 1.07 to 2.27]; ≤5 hour per night: odds ratio: 1.94 [95% CI: 1.08 to 3.50] versus 7 hours). The associations were attenuated after accounting for cardiovascular risk factors and psychiatric comorbidities (odds ratio: 1.42 [95% CI: 0.94 to 2.16]; odds ratio: 1.31 [95% CI: 0.65 to 2.63], respectively). Sleep deprivation may produce detrimental cardiovascular effects among women.

Correlates of short and long sleep duration: a cross-cultural comparison between the United Kingdom and the United States: the Whitehall II Study and the Western New York Health Study.

The authors examined sociodemographic, lifestyle, and comorbidity factors that could confound or mediate U-shaped associations between sleep duration and health in 6,472 United Kingdom adults from the Whitehall II Study (1997-1999) and 3,027 US adults from the Western New York Health Study (1996-2001). Cross-sectional associations between short (<6 hours) and long (>8 hours) durations of sleep across several correlates were calculated as multivariable odds ratios. For short sleep duration, there were significant, consistent associations in both samples for unmarried status (United Kingdom: adjusted odds ratio (AOR) = 1.49, 95% confidence interval (CI): 1.15, 1.94; United States: AOR = 1.49, 95% CI: 1.10, 2.02), body mass index (AORs were 1.04 (95% CI: 1.01, 1.07) and 1.02 (95% CI: 1.00, 1.05)), and Short Form-36 physical (AORs were 0.96 (95% CI: 0.95, 0.98) and 0.97 (95% CI: 0.96, 0.98)) and mental (AORs were 0.95 (95% CI: 0.94, 0.96) and 0.98 (95% CI: 0.96, 0.99)) scores. For long sleep duration, there were fewer significant associations: age among men (AORs were 1.08 (95% CI: 1.01, 1.14) and 1.05 (95% CI: 1.02, 1.08)), low physical activity (AORs were 1.75 (95% CI: 0.97, 3.14) and 1.60 (95% CI: 1.09, 2.34)), and Short Form-36 physical score (AORs were 0.96 (95% CI: 0.93, 0.99) and 0.97 (95% CI: 0.95, 0.99)). Being unmarried, being overweight, and having poor general health are associated with short sleep and may contribute to observed disease associations. Long sleep may represent an epiphenomenon of comorbidity.

Inflammation, Sleep, Obesity and Cardiovascular Disease

UNLABELLED Evidence is emerging that disturbances in sleep and sleep disorders play a role in the morbidity of chronic conditions. However, the relationship between sleep processes, disease development, disease progression and disease management is often unclear or understudied. Numerous common medical conditions can have an affect on sleep. For example, diabetes or inflammatory conditions such as arthritis can lead to poor sleep quality and induce symptoms of excessive daytime sleepiness and fatigue. It has also been suggested that poor sleep may lead to the development of cardiovascular disease for which an underlying inflammatory component has been proposed. It is therefore important that the development and progression of such disease states are studied to determine whether the sleep effect merely reflects disease progression or whether it may be in some way causally related. Sleep loss can also have consequences on safety related behaviours both for the individuals and for the society, for example the increased risk of accidents when driving while drowsy. Sleep is a complex phenotype and as such it is possible that there are numerous genes which may each have a number of effects that control an individuals sleep pattern. This review examines the interaction between sleep (both quantity and quality) and parameters of cardiovascular risk. We also explore the hypothesis that inflammation plays an essential role in cardiovascular disease and that a lack of sleep may play a key role in this inflammatory process. AIM To review current evidence regarding the endocrine, metabolic, cardiovascular and immune functions and their interactions with regard to sleep, given the current evidence that sleep disturbances may affect each of these areas.

A population-based study of reduced sleep duration and hypertension: the strongest association may be in premenopausal women.

Objectives Recent evidence indicates that reduced sleep duration may be associated with an increased risk of hypertension with possibly stronger effects among women than men. We therefore examined cross-sectional sex-specific associations of sleep duration with hypertension in a large population-based sample from the Western New York Health Study (1996<2001). Methods Participants were 3027 white men (43.5%) and women (56.5%) without prevalent cardiovascular disease (median age 56 years). Hypertension was defined as blood pressure at least 140 or at least 90&mmHg or regular use of antihypertensive medication. Multivariate logistic regression analyses were performed to estimate odds ratios (ORs) of hypertension comparing less than 6&h of sleep per night versus the reference category (&6&h) while accounting for a number of potential confounders. Results In multivariate analyses, less than 6&h of sleep was associated with a significant increased risk of hypertension compared to sleeping at least 6&h per night, only among women [OR&=&1.66 (1.09 to 2.53)]. No significant association was found among men [OR&=&0.93 (0.62 to 1.41)]. In subgroup analyses by menopausal status, the effect was stronger among premenopausal women [OR&=&3.25 (1.37 to 7.76)] than among postmenopausal women [OR&=&1.49 (0.92 to 2.41)]. Conclusion Reduced sleep duration, by increasing the risk of hypertension, may produce detrimental cardiovascular effects among women. The association is independent of socioeconomic status, traditional cardiovascular risk factors, and psychiatric comorbidities, and is stronger among premenopausal women. Prospective and mechanistic evidence is necessary to support causality.

Aldosterone synthase gene (CYP11B2) C-344T polymorphism, plasma aldosterone, renin activity and blood pressure in a multi-ethnic population

Background The aldosterone synthase gene (CYP1B2) locus is a candidate region involved in the development of hypertension. Objective To study the relationship between the C-344T CYP1B2 polymorphism, plasma aldosterone, renin activity and blood pressure in a multi-ethnic population. Design Population-based, cross-sectional study of 1313 middle-aged men and women (456 white, 441 of African origin and 416 South Asian). Anthropometry, blood pressure, biochemistry, questionnaire data and timed urine collections were taken with standardized techniques. All were genotyped for the C-344T CYP11B2 polymorphism. Results The frequency of the C allele was significantly lower in people of African origin (0.21) than in white (0.46) and South Asian (0.43) (P < 0.001). After adjustment for age, sex and ethnicity the TT genotype was associated with 14% higher plasma aldosterone levels, 3.7 mmHg higher systolic and 2.1 mmHg higher diastolic blood pressure than CC (P for linear trend < 0.05). No significant interactions with age, sex, ethnicity, body mass index (BMI) and fractional excretion of sodium were found in the associations between genotype and both blood pressure and aldosterone levels. In a sub-sample of participants in which plasma renin activity was measured (n = 457), a significant excess of T alleles was found in those with a raised (⩾ 750) aldosterone-to-renin ratio (ARR). Conclusion In this multi-ethnic population, the C-344T CYP1B2 polymorphism is associated with blood pressure, plasma aldosterone levels and ARR. Although significant differences in allele frequencies were found between groups, ethnicity does not explain the results.

Contrasting associations between aldosterone synthase gene polymorphisms and essential hypertension in blacks and in whites.

Background Genetic variability in the gene for aldosterone synthase – a key enzyme in the production of aldosterone – can affect sodium homeostasis and thereby blood pressure. The possibility of impaired aldosterone production for the development of hypertension is of particular relevance in black Afro-Caribbeans exposed to a high dietary sodium intake. Objectives To compare the frequency of three variants (−344C/T, intron 2 conversion, and the K173R polymorphism) of the aldosterone synthase gene in blacks and whites, and to determine any association of the variants with hypertension. Design and methods We made case–control comparisons of the three gene variants in relation to ethnic background and to essential hypertension in 193 white (51% hypertensive) and 245 black individuals (59% hypertensive) living in south London. Results The frequency of each of the variants was significantly different between the two ethnic groups. The T and the K alleles were more frequent in the black participants (79 compared with 50% for the −344T allele and 81 compared with 50% for K173 allele), whereas the frequency of the intron 2 conversion allele was much lower in that group (8 compared with 38%). None of these variants was associated with essential hypertension in the black participants. In contrast, in the white participants there was a significant and graded association between the intron 2 conversion allele and essential hypertension (odds ratio 1.86, 95% confidence interval 1.16 to 2.98; P = 0.01). Moreover, among the white population, the presence of homozygosity both of the T allele and of the intron 2 conversion alleles was associated with a much greater frequency of hypertension (71 compared with 43%; χ2 P = 0.03). Conclusions The contrasting associations between these variants and essential hypertension do not necessarily exclude the possibility that other, as yet undefined, variants of the aldosterone synthase gene could be linked with hypertension in black people. Nonetheless, the strong association between the intron 2 conversion allele and essential hypertension in the white population reinforces the view that the increased blood pressure may be due, at least in part, to abnormal expression of enzymes involved in the metabolism of adrenal mineralocorticoids.

Comparisons of spot vs 24-h urine samples for estimating population salt intake: Validation study in two independent samples of adults in Britain and Italy

OBJECTIVES To assess the reliability and reproducibility of estimations of group mean 24-h urinary sodium (Na) excretion through timed spot urines compared to 24 h urinary Na output in two independent cross-sectional population samples including men and women and different ethnic groups. METHODS AND RESULTS Study 1 was carried out in Britain and included 915 untreated 40-59 yrs male and female participants (297 white, 326 of black African origin and 292 South Asian). Study 2 was carried out in Italy and included 148 white men (mean age 58.3 yrs). All participants provided both a 24-h urine collection and a timed urine sample as part of population surveys. Na, creatinine (Cr) and volume (V) were measured in all samples. Age, body mass index (BMI) and blood pressure (BP) were also measured. We compared the daily Na excretion through 24-h urine (gold standard) with its estimate from timed urine samples with two methods: Tanakas predictions and Arithmetic extrapolations, and assessed them with correlation coefficients, Bland-Altman plot, prediction of quintile position and Receiver Operating Characteristic (ROC) Areas Under the Curve (AUC) for a cut-off of <100 mmol of Na/day. In Study 1 (discovery study) with the Tanaka method there were poor correlations between predicted and measured 24-h Na excretions in different ethnic groups and genders (r Spearman from 0.055 [R(2) = 0.003] in black women to 0.330 [R(2) = 0.11] in white women). The Bland-Altman plots indicated consistent bias with overestimate for low and underestimate for high intakes. ROC AUCs varied from 0.521 to 0.652 with good sensitivity (95-100%) but very poor specificity (0-9%). With the Arithmetic extrapolations correlations varied from 0.116 [R(2) = 0.01] to 0.367 [R(2) = 0.13]. Bias was detected with both Bland-Altman plots and through quintile analyses (underestimate at low levels and overestimate at high levels). Finally, ROC AUCs varied from 0.514 to 0.640 with moderate sensitivity (64-70%) but low specificity (20-53%). In Study 2 (validation study) results were consistent with the discovery phase in white men. CONCLUSION Based on these results, 24-h urinary collection for the measurement of Na excretion remains the preferred tool for assessing salt intake when compared with reported methods based on timed spot urine samples.

Ethnic differences in circulating soluble adhesion molecules: the Wandsworth Heart and Stroke Study

The aim of this study was to investigate whether soluble adhesion molecule levels differ by ethnic group. Soluble plasma adhesion molecules [soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1)] were measured in 261 white (120 females), 188 African origin (99 females) and 215 South Asian (99 females) individuals living in England. All were free from coronary heart disease, stroke and other cardiovascular disease, diabetes, drug therapy for hypertension or high lipids, hormone-replacement therapy or oral contraceptive pill. The results of the study indicated that there were important differences in the levels of adhesion molecules by sex and smoking. However, when adjusting for these and other potential confounders, there were no differences in levels between white subjects and individuals of South Asian origin. In contrast, people of African origin had significantly lower levels of sICAM-1 [Caribbean -30% (-36 to -23%); West African -22% (-29 to -15%), values are means (95% confidence intervals)], sVCAM-1 [Caribbean -14% (-19 to -8%); West African -10% (-17 to -3%)] and sP-selectin [Caribbean -10% (-17 to -2%); West African -24% (-31 to -16%)] than white individuals. In conclusion, circulating levels of some soluble adhesion molecules are lower in individuals of Caribbean or West African origin compared with white or South Asian individuals. These relationships may contribute to the low risk of coronary heart disease seen in people of African origin living in England.