Brian B. Koo

Association of Incident Cardiovascular Disease With Periodic Limb Movements During Sleep in Older Men Outcomes of Sleep Disorders in Older Men (MrOS) Study

Background— Periodic limb movements during sleep (PLMS) cause repetitive sympathetic activation and may be associated with increased cardiovascular risk. We hypothesized that PLMS frequency (periodic limb movement index [PLMI]) and PLMS arousal frequency (periodic limb movement arousal index [PLMAI]) are predictive of incident cardiovascular disease, including coronary heart disease, peripheral arterial disease, and cerebrovascular disease, in an elderly male cohort. Methods and Results— A total of 2911 men in the observational Outcomes of Sleep Disorders in Older Men (MrOS) Sleep Study cohort underwent in-home polysomnography with PLMS measurement and were followed up for 4 years for the outcomes coronary heart disease, cerebrovascular disease, peripheral arterial disease, and all-cause cardiovascular disease, which included coronary heart disease, cerebrovascular disease, and peripheral arterial disease. Cox proportional hazards regression assessed the association between PLMI, PLMAI, and these outcomes. Models were minimally adjusted for age, clinic, and body mass index and then fully adjusted for conventional cardiovascular risk factors. During follow-up, 500 men experienced all-cause cardiovascular disease: 345 coronary heart disease, 117 cerebrovascular disease, and 98 peripheral arterial disease events. In fully adjusted models, men with PLMAI ≥5 compared with the referent PLMA <1 group had a 1.26-fold increased relative hazard for all-cause cardiovascular disease. Similar findings were observed for PLMI and all-cause cardiovascular disease. For peripheral arterial disease, men with PLMI ≥30 compared with the referent PLMI <5 group had a 2-fold increased relative hazard (95% confidence interval, 1.14 to 3.49; P=0.025). Compared with the referent group, men with PLMI ≥30 had an increased risk of coronary heart disease (relative hazard, 1.31; 95% confidence interval, 1.01 to 1.70; P=0.045) after minimal adjustment, but this association was attenuated after further adjustments. After stratification, risk of incident all-cause cardiovascular disease among high-PLMI and high-PLMAI groups was significantly elevated only for men without prevalent hypertension (P for interactions <0.10). Conclusion— These findings provide evidence that PLMS frequency is associated with incident cardiovascular disease in community-dwelling elderly men.

Association of Incident Cardiovascular Disease With Periodic Limb Movements During Sleep in Older Men

Background— Periodic limb movements during sleep (PLMS) cause repetitive sympathetic activation and may be associated with increased cardiovascular risk. We hypothesized that PLMS frequency (periodic limb movement index [PLMI]) and PLMS arousal frequency (periodic limb movement arousal index [PLMAI]) are predictive of incident cardiovascular disease, including coronary heart disease, peripheral arterial disease, and cerebrovascular disease, in an elderly male cohort. Methods and Results— A total of 2911 men in the observational Outcomes of Sleep Disorders in Older Men (MrOS) Sleep Study cohort underwent in-home polysomnography with PLMS measurement and were followed up for 4 years for the outcomes coronary heart disease, cerebrovascular disease, peripheral arterial disease, and all-cause cardiovascular disease, which included coronary heart disease, cerebrovascular disease, and peripheral arterial disease. Cox proportional hazards regression assessed the association between PLMI, PLMAI, and these outcomes. Models were minimally adjusted for age, clinic, and body mass index and then fully adjusted for conventional cardiovascular risk factors. During follow-up, 500 men experienced all-cause cardiovascular disease: 345 coronary heart disease, 117 cerebrovascular disease, and 98 peripheral arterial disease events. In fully adjusted models, men with PLMAI ≥5 compared with the referent PLMA <1 group had a 1.26-fold increased relative hazard for all-cause cardiovascular disease. Similar findings were observed for PLMI and all-cause cardiovascular disease. For peripheral arterial disease, men with PLMI ≥30 compared with the referent PLMI <5 group had a 2-fold increased relative hazard (95% confidence interval, 1.14 to 3.49; P=0.025). Compared with the referent group, men with PLMI ≥30 had an increased risk of coronary heart disease (relative hazard, 1.31; 95% confidence interval, 1.01 to 1.70; P=0.045) after minimal adjustment, but this association was attenuated after further adjustments. After stratification, risk of incident all-cause cardiovascular disease among high-PLMI and high-PLMAI groups was significantly elevated only for men without prevalent hypertension (P for interactions <0.10). Conclusion— These findings provide evidence that PLMS frequency is associated with incident cardiovascular disease in community-dwelling elderly men.

Incidence of restless legs syndrome and its correlates

BACKGROUND Restless legs syndrome (RLS) is a common sensorimotor disorder whose incidence is not known. The aim of the study was to determine the incidence and correlates of RLS in a population-based sample. METHODS We obtained data from the Tucson Cohort of the Sleep Heart Health Study, a prospective multicenter study. This cohort included 535 participants aged ≥ 40 years, who answered questions regarding RLS on the 2002 and 2006 sleep surveys. For this study, RLS was defined as the presence of all 4 International RLS Study Group criteria, with symptoms occurring ≥ 5 days/month and associated with at least moderate distress. RESULTS Mean age of the predominantly Caucasian (90.8%) participants on the 2002 survey was 59.8 ± 9.7 years; 52.2% were women. RLS prevalence was 4.1% in 2002 and 7.7% in 2006. The yearly incidence of RLS was 1.7% (6.6% over 4 years). Multivariate analyses demonstrated that estrogen use (OR = 2.5, 95% CI: 1.17-5.10) and self-reported obstructive lung disease (OR = 2.8, 95% CI: 1.37-5.83) were independent risk factors predicting incident RLS. Incident RLS was associated with higher prevalence of insomnia (26.5% vs. 7.6%, p = 0.001), increased sleepiness (38.2% vs. 22%, p = 0.036); and higher sleeping pill use in 2006 (23.5% vs. 9.7%, p = 0.019). CONCLUSION The incidence of RLS in this population sample was 1.7% per year. Use of estrogen and history of obstructive lung disease were associated with a significantly higher incidence of RLS. RLS, in turn, was associated with insomnia and increased sleepiness.

Rapid Eye Movement-Related Sleep-Disordered Breathing : Influence of Age and Gender

BACKGROUND Sleep-disordered breathing (SDB) occurring during rapid eye movement (REM) sleep occurs more frequently in women than men. We sought to characterize REM SDB prevalence by gender and age to identify factors that could account for this discrepancy. METHODS Subjects with REM SDB were identified among 2,486 patients referred to a university sleep laboratory with an apnea-hypopnea index (AHI) >or= 5 events per hour. REM SDB was defined as non-REM (NREM) AHI <or= 15/h and REM AHI/NREM AHI ratio >or= 2. Regression analyses were utilized to determine factors associated with REM SDB. RESULTS REM SDB prevalence was 40.8% in women and 21.0% in men. After adjusting for age and obesity, female sex remained a risk factor for REM SDB (odds ratio, 3.0; 95% confidence interval [CI], 1.8 to 4.2). REM SDB prevalence waned with increasing age in both sexes, such that the odds of having REM SDB fell by 26.7% (95% CI, 15.2 to 38.2%) per decade. REM AHI/NREM AHI decreased with age only in women, falling 10.9% (95% CI, 5.5 to 16.3%) per decade. NREM AHI in women increased the most with age (16.0%; 95% CI, 11.1 to 20.9%) per decade, and least with body mass index (BMI) [13.0%; 9.1 to 16.9%] for every 5-unit BMI increase when compared to REM AHI for women and either index for men. CONCLUSIONS REM SDB prevalence decreases with age in women as does REM AHI/NREM AHI, perhaps secondary to a disproportionate age-dependent rise in NREM vs REM AHI in women. Younger women may be protected from SDB during NREM sleep, even in the face of obesity. These patterns may reflect age-related decreases in female hormones.

Periodic Limb Movements During Sleep and Prevalent Hypertension in the Multi-Ethnic Study of Atherosclerosis

Periodic limb movements during sleep (PLMS) are associated with immediate increases in blood pressure. Both PLMS and hypertension have different distributions across racial/ethnic groups. We sought to determine whether PLMS is associated with hypertension among various racial/ethnic groups. A total of 1740 men and women underwent measurement of blood pressure and polysomnography with quantification of PLMS. Hypertension was defined as systolic blood pressure (SBP) ≥140, diastolic BP ≥90, or taking antihypertensive medication. For those taking antihypertensives, an estimated pretreatment SBP value was derived based on observed SBP and medication type/dose. Measures of PLMS, PLMS index, and PLMS arousal index were the main explanatory variables. Hypertension and SBP were modeled with logistic and multivariable regression adjusted for age, sex, body mass index, cardiovascular risk factors, lifestyle/habitual factors, apnea-hypopnea index, and race/ethnicity. In the overall cohort, prevalent hypertension was modestly associated with PLMS index (10 U; odds ratio, 1.05; 95% confidence interval, 1.00–1.10) and PLMS arousal index (1 U; 1.05; 1.01–1.09) after adjusting for confounders. Association in the overall cohort was influenced by large effect sizes in blacks, in whom the odds of prevalent hypertension increased by 21% (1%–45%) for 10 U PLMS index increase and 20% (2%–42%) for 1-U PLMS arousal index increase. In blacks, every 1-U PLMS arousal index increase was associated with SBP 1.01 mm Hg higher (1.01; 0.04–1.98). Associations between PLMS and blood pressure outcomes were also suggested among Chinese-Americans but not in whites or Hispanics. In a multiethnic cohort of community-dwelling men and women, prevalent hypertension and SBP are associated with PLMS frequency in blacks.

Restless legs syndrome: relationship between prevalence and latitude.

PurposeRestless legs syndrome (RLS) has a broad worldwide prevalence between 0.01% and 18.3%. While differences in RLS definitions and data ascertainment methods account for some variability, other factors likely contribute. The circadian nature of RLS and the fact that RLS symptoms track with endogenous melatonin levels suggest that light or ultraviolet radiation (UVR) may be related to RLS expression. As the amount of UVR decreases with latitude, we considered the potential effect of geography on RLS prevalence with the thought being that RLS prevalence rises with increasing latitude.MethodsRLS epidemiologic studies were sought via Pubmed search in the period between January 1, 1992 and November 15, 2010. Prevalence was mapped for each country or specific region studied and examined by continent. Pearson’s correlational testing was carried out for RLS prevalence and latitude of the region studied.ResultsGlobal RLS prevalence ranges from 0.01% in Africa, 0.7% to 12.5% in Asia, 2.0% to 18.9% in the Americas, and 3.2% to 18.3% in Europe. Mapping RLS prevalence by country or region in both the Americas and in Europe suggests increasing RLS frequency with greater northern latitude. RLS prevalence is positively correlated with northern latitude in both North America and Europe with correlation coefficients of r = 0.77 (0.15, 0.96; p = 0.02) and r = 0.74 (0.44, 0.89; p = 0.0002), respectively. In Europe, lower latitudinal countries like Greece and Turkey had RLS prevalence (per 1,000 persons) of 38 and 34, respectively, middle latitudinal countries like France and England of 108 and 86, respectively, and high latitudinal countries like Norway and Iceland of 143 and 183, respectively.ConclusionsRLS epidemiology indicates an increase in RLS frequency in northern latitudinal countries as a function of distance from the equator, an effect most evident in Europe. This suggests that factors that track with latitude like UVR may be involved in the expression of RLS.

Iron, dopamine, genetics, and hormones in the pathophysiology of restless legs syndrome

Restless legs syndrome (RLS) is a common, chronic neurologic condition, which causes a persistent urge to move the legs in the evening that interferes with sleep. Human and animal studies have been used to study the pathophysiologic state of RLS and much has been learned about the iron and dopamine systems in relation to RLS. Human neuropathologic and imaging studies have consistently shown decreased iron in different brain regions including substantia nigra and thalamus. These same areas also demonstrate a state of relative dopamine excess. While it is not known how these changes in dopamine or iron produce the symptoms of RLS, genetic and hormone studies of RLS have identified other biologic systems or genes, such as the endogenous opioid and melanocortin systems and BTBD9 and MEIS1, that may explain some of the iron or dopamine changes in relation to RLS. This manuscript will review what is known about the pathophysiology of RLS, especially as it relates to changes in iron, dopamine, genetics, and hormonal systems.

Ventilatory patterning in a mouse model of stroke.

Cheyne-Stokes respiration (CSR) is a breathing pattern characterized by waxing and waning of breath volume and frequency, and is often recognized following stroke, when causal pathways are often obscure. We used an animal model to address the hypothesis that cerebral infarction is a mechanism for producing breathing instability. Fourteen male A/J mice underwent either stroke (n=7) or sham (n=7) procedure. Ventilation was measured using whole body plethysmography. Respiratory rate (RR), tidal volume (V(T)) and minute ventilation (V(e)) mean values and coefficient of variation were computed for ventilation and oscillatory behaviors. In addition, the ventilatory data were computationally fit to models to quantify autocorrelation, mutual information, sample entropy and a nonlinear complexity index. At the same time post-procedure, stroke when compared to sham animal breathing consisted of a lower RR and autocorrelation, higher coefficient of variation for V(T) and higher coefficient of variation for V(e). Mutual information and the nonlinear complexity index were higher in breathing following stroke which also demonstrated a waxing/waning pattern. The absence of stroke in the sham animals was verified anatomically. We conclude that ventilatory pattern following cerebral infarction demonstrated increased variability with increased nonlinear patterning and a waxing/waning pattern, consistent with CSR.

Polysomnographic phenotypes and their cardiovascular implications in obstructive sleep apnoea

Background Obstructive sleep apnoea (OSA) is a heterogeneous disorder, and improved understanding of physiologic phenotypes and their clinical implications is needed. We aimed to determine whether routine polysomnographic data can be used to identify OSA phenotypes (clusters) and to assess the associations between the phenotypes and cardiovascular outcomes. Methods Cross-sectional and longitudinal analyses of a multisite, observational US Veteran (n=1247) cohort were performed. Principal components-based clustering was used to identify polysomnographic features in OSA’s four pathophysiological domains (sleep architecture disturbance, autonomic dysregulation, breathing disturbance and hypoxia). Using these features, OSA phenotypes were identified by cluster analysis (K-means). Cox survival analysis was used to evaluate longitudinal relationships between clusters and the combined outcome of incident transient ischaemic attack, stroke, acute coronary syndrome or death. Results Seven patient clusters were identified based on distinguishing polysomnographic features: ‘mild’, ‘periodic limb movements of sleep (PLMS)’, ‘NREM and arousal’, ‘REM and hypoxia’, ‘hypopnoea and hypoxia’, ‘arousal and poor sleep’ and ‘combined severe’. In adjusted analyses, the risk (compared with ‘mild’) of the combined outcome (HR (95% CI)) was significantly increased for ‘PLMS’, (2.02 (1.32 to 3.08)), ‘hypopnoea and hypoxia’ (1.74 (1.02 to 2.99)) and ‘combined severe’ (1.69 (1.09 to 2.62)). Conventional apnoea–hypopnoea index (AHI) severity categories of moderate (15≤AHI<30) and severe (AHI ≥30), compared with mild/none category (AHI <15), were not associated with increased risk. Conclusions Among patients referred for OSA evaluation, routine polysomnographic data can identify physiological phenotypes that capture risk of adverse cardiovascular outcomes otherwise missed by conventional OSA severity classification.

Restless Leg Syndrome Across the Globe: Epidemiology of the Restless Legs Syndrome/Willis-Ekbom Disease.

There are more than 50 epidemiologic studies measuring the prevalence of restless legs syndrome/Willis-Ekbom disease (RLS/WED) across 5 of the 6 inhabited continents (not Australia), most conducted in North America and Europe. Sufficient studies have been conducted in Asia, North America, and Europe to make inferences on RLS/WED prevalence by region. RLS/WED prevalence is thought to be highest in North America and Europe and lower in Asia. These differences across regions may be explained by cultural, environmental, and genetic factors. Future investigation is needed to determine to what extent these factors affect expression of RLS/WED according to world region.