Novel physiologic predictors of positive airway pressure effectiveness (NICEPAP) study: rationale, design and methods.

PURPOSE: Continuous positive airway pressure (CPAP) is the primary therapy for obstructive sleep apnea (OSA); however the effectiveness of CPAP remains suboptimal. We describe the Novel PhysIologiC prEdictors of Positive Airway Pressure Effectiveness (NICEPAP) study. Its purpose is to determine whether physiological traits of OSA contribute to CPAP effectiveness. METHODS: NICEPAP (NCT05067088) is a prospective, observational cohort study conducted at an academic sleep center. Adults newly diagnosed with OSA (n = 267) are assessed for OSA traits of loop gain, arousal threshold, pharyngeal collapsibility, and muscle compensation from baseline polysomnography. We perform a comprehensive assessment of covariates relevant to CPAP adherence, efficacy, and patient-centered outcomes. Participants are followed for 12 months. Primary outcomes include (1) CPAP adherence (hours/night), (2) CPAP efficacy (apneas-hypopneas/hour), and (3) quality of life at six months measured by objective CPAP data and Functional Outcomes of Sleep Questionnaire. Secondary outcomes include sleep quality, sleepiness, insomnia, and neurocognitive function. RESULTS: Data on covariates, including demographics, sleep symptoms, medical history, medications, sleep quality, OSA and treatment self-efficacy, decisional balance, and socio-economic and social and partner support, are collected using validated instruments. The analysis for primary outcomes includes a generalized linear mixed model for an outcome (e.g., CPAP adherence) with OSA traits as exposures followed by the addition of relevant covariates. CONCLUSION: The findings of the NICEPAP study will inform research aimed to enhance CPAP effectiveness. Understanding the role of physiological OSA traits in CPAP effectiveness is a crucial step toward a precision medicine approach to OSA.

Ertugliflozin and incident obstructive sleep apnea: an analysis from the VERTIS CV trial.

PURPOSE: The sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin may reduce the incidence of obstructive sleep apnea (OSA) in patients with type 2 diabetes (T2D) and cardiovascular (CV) disease. This analysis of VERTIS CV, the CV outcome trial for the SGLT2i ertugliflozin conducted in a similar group of patients, explored the effects of ertugliflozin on reported incident OSA. METHODS: In VERTIS CV, patients ≥ 40 years with T2D and atherosclerotic CV disease (ASCVD) were randomized to ertugliflozin 5 or 15 mg or placebo. The primary endpoint was the composite of major adverse CV events. This exploratory analysis evaluated the impact of ertugliflozin (5 and 15 mg pooled) on incident OSA. Patients with prevalent OSA were excluded. Incident OSA events were based on investigator-reported events using the MedDRA SMQ term "sleep apnea syndrome." A multivariable Cox proportional hazards regression model was constructed to assess the association between ertugliflozin and incident OSA. RESULTS: Of 8246 patients enrolled, 7697 (93.3%) were without baseline OSA (placebo, n = 2561; ertugliflozin, n = 5136; mean age 64.4 years; BMI 31.7 kg/m2; HbA1c, 8.2%; 69.2% male; 88.3% White). The OSA incidence rate was 1.44 per 1000 person-years versus 2.61 per 1000 person-years among patients treated with ertugliflozin versus placebo, respectively, corresponding to a 48% relative risk reduction (HR 0.52; 95% CI 0.28-0.96; P = 0.04). CONCLUSIONS: In VERTIS CV, ertugliflozin reduced by nearly half the incidence of OSA in patients with T2D and ASCVD. These data contribute to the literature that SGLT2is may have a significant beneficial impact on OSA. CLINICALTRIALS: gov identifier: NCT01986881.

Costs and Resource Utilization of People with Stable Heart Failure and Insomnia: Evidence from a Randomized Trial of Cognitive Behavioral Therapy for Insomnia.

OBJECTIVES: Nearly half of patients with chronic heart failure (HF) report insomnia symptoms. The purpose of this study was to examine the impact of CBT-I versus HF self-management on healthcare costs and resource utilization among patients with stable chronic HF who participated in a clinical trial of the effects of CBT-I compared to HF self-management education (attention control) over 1 year. METHODS: We measured resource utilization as self-reported (medical record review) physician office visits, emergency department visits, and inpatient admissions at 3-month intervals for 1 year after enrollment. Costs were estimated by applying price weights to visits and adding self-reported out-of-pocket and indirect costs. Univariate comparisons were made of resource utilization and costs between CBT-I and the HF self-management group. A generalized linear model (GLM) was used to model costs, controlling for covariates. RESULTS: The sample included 150 patients [79 CBT-I; 71 self-management (M age = 62 + 13 years)]. The CBT-I group had 4.2 inpatient hospitalizations vs 4.6 for the self-management group (p = .40). There were 13.1 outpatient visits, in the CBT-I compared with 15.4 outpatient visits (p-value range 0.39-0.81) for the self-management group. Total costs were not significantly different in univariate or ($7,813 CBT-I vs. $7,538 self-management), p = .96) or multivariable analyses. CONCLUSIONS: Among patients with both HF and insomnia, CBT-I and HF self-management were associated with similar resource utilization and total costs. Additional research is needed to estimate the value of CBT-I relative to usual care and other treatments for insomnia in patients with HF.

Symptom Cluster Profiles Among Adults with Insomnia and Heart Failure.

OBJECTIVE/BACKGROUND: Both heart failure (HF) and insomnia are associated with high symptom burden that may be manifested in clustered symptoms. To date, studies of insomnia have focused only on its association with single symptoms. The purposes of this study were to: (1) describe daytime symptom cluster profiles in adults with insomnia and chronic HF; and (2) determine the associations between demographic and clinical characteristics, insomnia and sleep characteristics and membership in symptom cluster profiles. PARTICIPANTS: One hundred and ninety-five participants [M age 63.0 (SD12.8); 84 (43.1%) male; 148 (75.9%) New York Heart Association Class I/II] from the HeartSleep study (NCT0266038), a randomized controlled trial of the sustained effects of cognitive behavioral therapy for insomnia (CBT-I). METHODS: We analyzed baseline data, including daytime symptoms (fatigue, pain, anxiety, depression, dyspnea, sleepiness) and insomnia (Insomnia Severity Index), and sleep characteristics (Pittsburgh Sleep Quality Index, wrist actigraphy). We conducted latent class analysis to identify symptom cluster profiles, bivariate associations, and multinomial regression. RESULTS: We identified three daytime symptom cluster profiles, physical (N = 73 participants; 37.4%), emotional (N = 12; 5.6%), and all-high symptoms (N = 111; 56.4%). Body mass index, beta blockers, and insomnia severity were independently associated with membership in the all-high symptom profile, compared with the other symptom profile groups. CONCLUSIONS: Higher symptom burden is associated with more severe insomnia in people with stable HF. There is a need to understand whether treatment of insomnia improves symptom burden as reflected in transition from symptom cluster profiles reflecting higher to lower symptom burden.

Obstructive Sleep Apnea as a Risk Factor for Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: To determine whether obstructive sleep apnea (OSA) is associated with intracerebral hemorrhage (ICH) risk, we assessed premorbid OSA exposure of patients with nontraumatic ICH and matched controls. METHODS: Ethnic/Racial Variations of Intracerebral Hemorrhage is a multicenter, case-control study evaluating risk factors for ICH that recruited 3000 cases with ICH and 3000 controls. OSA status was ascertained using the Berlin Questionnaire as a surrogate for premorbid OSA. We performed logistic regression analyses to evaluate the association between OSA and ICH. RESULTS: Two thousand and sixty-four (71%) cases and 1516 (52%) controls were classified as having OSA by the Berlin Questionnaire. Cases with OSA were significantly more likely to be male and have hypertension, heart disease, hyperlipidemia, and higher body mass index compared with those without OSA. OSA was more common among cases compared with controls (71% versus 52%, odds ratio, 2.28 [95% CI, 2.05-2.55]). In a multivariable logistic regression model, OSA was associated with increased risk for ICH (odds ratio, 1.47 [95% CI, 1.29-1.67]). CONCLUSIONS: OSA is a risk factor for ICH.

Perceived Stress, Subjective, and Objective Symptoms of Disturbed Sleep in Men and Women with Stable Heart Failure.

Objective/Background: Sleep disturbance is prevalent among patients with heart failure (HF) and is associated with increased morbidity and mortality. Stress also affects health and quality of life among patients with cardiovascular disease and likely plays a prominent role in HF. However, little is known about the associations between stress and sleep among HF patients.Participants: One hundred fifty-three stable New York Heart Association (NYHA) Classification I-IV HF patients with at least low symptoms of insomnia (Mage:63.0 ± 12.8, 42% Women).Methods: We examined baseline stress, sleep disturbance, and sleep-related characteristics from a randomized controlled trial of cognitive behavioral therapy for insomnia, including the Perceived Stress Scale, Insomnia Severity Index, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Sleep Disturbance Questionnaire, Dysfunctional Beliefs about Sleep Scale, PROMIS Cognitive Ability, SF-36 Mental Health, and wrist actigraphy. We used Pearson correlations and general linear models to assess stress-sleep associations, including the potential moderating effects of sex and symptom severity (NYHA).Results: There were moderate-to-large correlations between stress and self-reported sleep disturbance, dysfunctional beliefs about sleep, cognitive ability, and mental health (p's < 0.01). High stress was associated with more objectively-measured (i.e., actigraph-assessed) awakenings and sleep fragmentation among women than men (ß = - 0.04, p < 0.01; ß = - 0.71, p = 0.04). Relationships between stress and objectively-measured sleep did not vary by symptom severity.Conclusions: Perceived stress is related to sleep disturbance among HF patients, and effects may be sex-dependent. Subsequent research should determine the temporal links between sleep and stress, and optimal opportunities for intervention among HF patients.

Day-to-day Relationships between Physical Activity and Sleep Characteristics among People with Heart Failure and Insomnia.

OBJECTIVE: Examine the bidirectional relationships between within-person day-to-day fluctuations in physical activity (PA) and sleep characteristics among people with heart failure (HF) and insomnia. PARTICIPANTS: Ninety-seven community-dwelling adults [median age 61.9 (interquartile range 55.3,70.9) years, female 41%] with stable HF and insomnia (insomnia severity index >7). METHODS: This sub-study longitudinally analyzed 15 consecutive days and nights of wrist actigraphy recordings, that were collected for baseline data prior to participation in a randomized controlled trial of cognitive behavioral therapy for insomnia. We used two-level mixed models of within- (daily) and between-participants variation to predict daytime PA counts/minutes from sleep variables (total sleep time, sleep efficiency) and predict sleep variables from PA. RESULTS: PA counts/minutes were low compared to prior cohorts that did not have HF (209 (166,259)) and negatively associated with NYHA class (standardized coefficient ßs = -0.14, p < .01), age (ßs = -0.13, p = .01), comorbidities (ßs = -0.19, p < .01), and body mass index (ßs = -0.12, p = .04). After adjustment for all significant covariates, the within-participant association of total sleep time with next-day PA was estimated to be positive among participants with NYHA class II-IV HF (ßs = 0.09, p = .01), while the within-participant association of PA with same-night total sleep time was estimated to be positive among participants aged ≥60 years (ßs = 0.10, p = .03). CONCLUSIONS: Depending upon age and HF class, daytime PA was associated with longer same-night sleep and/or longer sleep was associated with greater next-day PA. Among those with more advanced HF, realistic sleep improvements were associated with clinically meaningful PA gains the next day.

Mechanisms of reduced sleepiness symptoms in heart failure and obstructive sleep apnea.

Patients with both heart failure and obstructive sleep apnea often have poor, repeatedly disrupted sleep, and yet they frequently do not complain of excessive daytime sleepiness. Understanding this lack of perceived sleepiness is crucial for the case identification and treatment of obstructive sleep apnea in the heart failure population at high risk of this disease, especially given the association between untreated obstructive sleep apnea and mortality among patients with heart failure. In this review, we present epidemiologic evidence concerning the lack of sleepiness symptoms in heart failure and obstructive sleep apnea, explore possible mechanistic explanations for this relationship, assess the benefits of treatment in this population, discuss implications for clinical practice and explore directions for future research.

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.

Using Sleep Interventions to Engage and Treat Heavy-Drinking College Students: A Randomized Pilot Study.

BACKGROUND: Continued high alcohol consumption levels by college students highlight the need for more effective alcohol interventions and novel treatment engagement strategies. The purpose of this study was to investigate a behavioral sleep intervention as a means to engage heavy-drinking college students in treatment and reduce alcohol use and alcohol-related consequences. METHODS: Heavy-drinking college students (N = 42) were assigned to 1 of 2 web-based interventions comprised of 4 modules delivered over 4 weeks. The experimental intervention focused primarily on sleep and included evidence-based sleep content (i.e., stimulus control instructions, sleep scheduling [consistent bed/rise times; ideal sleep duration for adolescents/young adults], sleep hygiene advice, relaxation training, cognitive strategies to target sleep-disruptive beliefs), and alcohol content (i.e., normative and blood alcohol level feedback, moderate drinking guidelines, controlled drinking strategies, effects of alcohol on sleep and the body, advice to moderate drinking for improved sleep) in young adults. The control condition Healthy Behaviors provided basic advice about nutrition, exercise, sleep (i.e., good sleep hygiene only), and drinking (i.e., effects of alcohol on the body, moderate drinking guidelines, advice to moderate drinking for sleep). Participants in both conditions monitored their sleep using daily web-based diaries and a wrist-worn sleep tracker. RESULTS: Recruitment ads targeting college students with sleep concerns effectively identified heavy-drinking students. The program generated a high number of inquiries and treatment completion rates were high. Both interventions significantly reduced typical week drinking and alcohol-related consequences and improved sleep quality and sleep-related impairment ratings. The control condition yielded greater reductions in total drinks in a heaviest drinking week. The effects on drinking were larger than those observed in typical brief alcohol intervention studies for college students. Greater sleep improvement tended to predict better subsequent drinking outcomes. CONCLUSIONS: The results suggest that sleep treatment may be a promising strategy for targeting and treating heavy-drinking college students.

Reducing cardiovascular risk through treatment of obstructive sleep apnea: 2 methodological approaches.

Obstructive sleep apnea (OSA) significantly impacts cardiovascular health, demonstrated by observational investigations showing an independently increased risk of ischemic heart disease, diabetes, hypertension, congestive heart failure, acute coronary syndrome, stroke, cardiovascular mortality, and all-cause mortality. Positive airway pressure (PAP), a medical therapy for sleep apnea, reverses airway obstruction and may help reduce cardiovascular risk. Prior to planning large phase III randomized controlled trials to test the impact of PAP on cardiovascular outcomes, several gaps in knowledge need to be addressed. This article describes 2 independent studies that worked collaboratively to fill these gaps. The populations, design features, and relative benefits/challenges of the 2 studies (SleepTight and BestAIR) are described. Both studies were encouraged to have multidisciplinary teams with expertise in behavioral interventions to improve PAP compliance. Both studies provide key information that will be useful to the research community in future large-scale, event-driven, randomized trials to evaluate the efficacy and/or effectiveness of strategies to identify and treat significant OSA for decreasing risk of major adverse cardiovascular events in high-risk patients.

Observational Study of Obstructive Sleep Apnea in Wake-Up Stroke: The SLEEP TIGHT Study.

BACKGROUND: Wake-up stroke (WUS) accounts for a quarter of all ischemic strokes. Its conspicuous occurrence during sleep suggests that WUS may be associated with obstructive sleep apnea (OSA). We investigated the potential association among WUS, OSA, and measures of sympathetic hyperactivity. METHODS: This is a cross-sectional analysis of data from the Sleep Apnea in Transient Ischemic Attack and Stroke (SLEEP TIGHT) study. Ischemic stroke patients were divided into WUS and non-WUS groups. Participants underwent polysomnography and ambulatory blood pressure monitoring. Collected data included demographic, medical, stroke characteristics (including severity by National Institutes of Health Stroke Scale), cholesterol, serum catecholamines, C-reactive protein, interleukin-6, B-type natriuretic peptide, blood pressure, and polysomnographic (apnea-hypopnea index (AHI); measures of hypoxia). Because both stroke and OSA affect men and women to varying degrees, the cohort was considered as a whole and by gender stratification. RESULTS: Among 164 participants, 30.3% had WUS. The mean age was 62.0 ± 11.3 and the mean body mass index was 30.2 ± 7.9 kg/m2. One-hundred-and-five participants (63.6%) were males and 92 participants (56.8%) were Caucasian. Neither AHI nor OSA (AHI ≥5) frequency differed between WUS and non-WUS groups. Men tended to be more likely than women to have WUS (74.0 vs. 59.6%; p = 0.08), but this was not statistically significant. In gender-stratified analyses, men with WUS compared to men with non-WUS had significantly higher rates of severe OSA (AHI >30: 45.0 vs. 17.6%; p = 0.03) and tended toward more 3% oxygen desaturation events (57.0 ± 63.9 vs. 31.8 ± 22.9; p = 0.06). These differences were not seen in women. WUS patients tended to be of the male gender (74.0 vs. 59.6%; p = 0.08). History of stroke, hypertension, diabetes, dyslipidemia, or atrial fibrillation, serum catecholamines, and inflammatory biomarkers was no different between the groups. Low-density lipoprotein (LDL) was significantly higher in WUS (114.5 ± 36.3 vs. 101.4 ± 37.6; p = 0.04). Baseline diastolic blood pressure (DBP) was significantly greater in the WUS group. There was no difference in systolic or ambulatory blood pressure (including nighttime blood pressure) between WUS and non-WUS groups. CONCLUSIONS: WUS may be associated with severe OSA with more oxygen desaturation in men but not in women. WUS may be associated with high DBP and increased LDL cholesterol.

Sleep apnea is independently associated with peripheral arterial disease in the Hispanic Community Health Study/Study of Latinos.

OBJECTIVE: Sleep apnea (SA) has been linked with various forms of cardiovascular disease, but little is known about its association with peripheral artery disease (PAD) measured using the ankle-brachial index. This relationship was evaluated in the Hispanic Community Health Study/Study of Latinos. APPROACH AND RESULTS: We studied 8367 Hispanic Community Health Study/Study of Latinos participants who were 45 to 74 years of age. Sleep symptoms were examined with the self-reported Sleep Health Questionnaire. SA was assessed using an in-home sleep study. Systolic blood pressure was measured in all extremities to compute the ankle-brachial index. PAD was defined as ankle-brachial index <0.90 in either leg. Multivariable logistic regression was used to investigate the association between moderate-to-severe SA, defined as apnea-hypopnea index ≥15, and the presence of PAD. Analyses were adjusted for covariates. The prevalence of PAD was 4.7% (n=390). The mean apnea-hypopnea index was significantly higher among adults with PAD compared with those without (11.1 versus 8.6 events/h; P=0.046). After adjusting for covariates, moderate-to-severe SA was associated with a 70% increase in the odds of PAD (odds ratio, 1.7; 95% confidence interval, 1.1-2.5; P=0.0152). This association was not modified by sex (P=0.8739). However, there was evidence that the association between moderate-to-severe SA and PAD varied by Hispanic/Latino background (P<0.01). Specifically, the odds were stronger in Mexican (adjusted odds ratio, 2.9; 95% confidence interval, 1.3-6.2) and in Puerto Rican Americans (adjusted odds ratio, 2.0; 95% confidence interval, 0.97-4.2) than in other backgrounds. CONCLUSIONS: Moderate-to-severe SA is associated with higher odds of PAD in Hispanic/Latino adults.

The Determining Risk of Vascular Events by Apnea Monitoring (DREAM) study: design, rationale, and methods.

PURPOSE: The goal of the Determining Risk of Vascular Events by Apnea Monitoring (DREAM) study is to develop a prognostic model for cardiovascular outcomes, based on physiologic variables-related to breathing, sleep architecture, and oxygenation-measured during polysomnography in US veterans. METHODS: The DREAM study is a multi-site, retrospective observational cohort study conducted at three Veterans Affairs (VA) centers (West Haven, CT; Indianapolis, IN; Cleveland, OH). Veterans undergoing polysomnography between January 1, 2000 and December 31, 2004 were included based on referral for evaluation of sleep-disordered breathing, documented history and physical prior to sleep testing, and ≥2-h sleep monitoring. Demographic, anthropomorphic, medical, medication, and social history factors were recorded. Measures to determine sleep apnea, sleep architecture, and oxygenation were recorded from polysomnography. VA Patient Treatment File, VA-Medicare Data, Vista Computerized Patient Record System, and VA Vital Status File were reviewed on dates subsequent to polysomnography, ranging from 0.06 to 8.8 years (5.5 ± 1.3 years; mean ± SD). RESULTS: The study population includes 1840 predominantly male, middle-aged veterans. As designed, the main primary outcome is the composite endpoint of acute coronary syndrome, stroke, transient ischemic attack, or death. Secondary outcomes include incidents of neoplasm, congestive heart failure, cardiac arrhythmia, diabetes, depression, and post-traumatic stress disorder. Laboratory outcomes include measures of glycemic control, cholesterol, and kidney function. (Actual results are pending.) CONCLUSIONS: This manuscript provides the rationale for the inclusion of veterans in a study to determine the association between physiologic sleep measures and cardiovascular outcomes and specifically the development of a corresponding outcome-based prognostic model.

"What if that's your last sleep?" A qualitative exploration of the trauma of incarceration and sleep.

Study Background/Objectives: Sleep is an underexplored factor in the health of people involved in the criminal legal system. This study addresses the paucity of research on how individual, social, and physical environmental factors impact sleep health during and after incarceration by highlighting the voices of people involved in the criminal legal system through a community-engaged qualitative research approach. Methods: We conducted 20 semi-structured interviews with men recently released from prison for a study on trauma and healthcare during incarceration and after release. Interviews were coded and analyzed using reflexive thematic analysis and a critical realist framework. Our research team included people with a history of incarceration who performed central roles in the research process. Results: Three themes emerged from participants' descriptions of sleep during and after incarceration: (1) concerns about health contributing to sleep problems, (2) lack of access to treatment for sleep disorders leading to ongoing sleep problems, and (3) issues of safety contributing to sleep problems during incarceration and after release. Conclusions: This study identifies factors and domains influencing sleep during and after incarceration. By identifying which interpersonal, environmental, and structural factors impact sleep quality, medical and carceral staff are better equipped to ameliorate sleep health disparities within populations with a history of incarceration and those actively bound by the criminal legal system. Future research should examine other factors impacting sleep in incarcerated and recently released populations and develop multi-level interventions to improve sleep health. This paper is part of the Sleep and Circadian Health in the Justice System Collection.

Association of Periodic Limb Movements and Obstructive Sleep Apnea With Risk of Cardiovascular Disease and Mortality.

BACKGROUND: Obstructive sleep apnea is a well-established risk factor for cardiovascular disease (CVD). Recent studies have also linked periodic limb movements during sleep to CVD. We aimed to determine whether periodic limb movements during sleep and obstructive sleep apnea are independent or synergistic factors for CVD events or death. METHODS AND RESULTS: We examined data from 1049 US veterans with an apnea-hypopnea index (AHI) <30 events/hour. The primary outcome was incident CVD or death. Cox proportional hazards regression assessed the relationships between the AHI, periodic limb movement index (PLMI), and the AHI×PLMI interaction with the primary outcome. We then examined whether AHI and PLMI were associated with primary outcome after adjustment for age, sex, race and ethnicity, obesity, baseline risk of mortality, and Charlson Comorbidity Index. During a median follow-up of 5.1 years, 237 of 1049 participants developed incident CVD or died. Unadjusted analyses showed an increased risk of the primary outcome with every 10-event/hour increase in PLMI (hazard ratio [HR], 1.08 [95% CI, 1.05-1.13]) and AHI (HR, 1.17 [95% CI, 1.01- 1.37]). Assessment associations of AHI and PLMI and their interaction with the primary outcome revealed no significant interaction between PLMI and AHI. In fully adjusted analyses, PLMI, but not AHI, was associated with an increased risk of primary outcome: HR of 1.05 (95% CI, 1.00-1.09) per every 10 events/hour. Results were similar after adjusting with Framingham risk score. CONCLUSIONS: Our study revealed periodic limb movements during sleep as a risk factor for incident CVD or death among those who had AHI <30 events/hour, without synergistic association between periodic limb movements during sleep and obstructive sleep apnea.

Suboptimal Sleep Duration Is Associated With Poorer Neuroimaging Brain Health Profiles in Middle-Aged Individuals Without Stroke or Dementia.

BACKGROUND: The American Heart Association's Life's Simple 7, a public health construct capturing key determinants of cardiovascular health, became the Life's Essential 8 after the addition of sleep duration. The authors tested the hypothesis that suboptimal sleep duration is associated with poorer neuroimaging brain health profiles in asymptomatic middle-aged adults. METHODS AND RESULTS: The authors conducted a prospective magnetic resonance neuroimaging study in middle-aged individuals without stroke or dementia enrolled in the UK Biobank. Self-reported sleep duration was categorized as short (<7 hours), optimal (7-<9 hours), or long (≥9 hours). Evaluated neuroimaging markers included the presence of white matter hyperintensities (WMHs), volume of WMH, and fractional anisotropy, with the latter evaluated as the average of 48 white matter tracts. Multivariable logistic and linear regression models were used to test for an association between sleep duration and these neuroimaging markers. The authors evaluated 39 771 middle-aged individuals. Of these, 28 912 (72.7%) had optimal, 8468 (21.3%) had short, and 2391 (6%) had long sleep duration. Compared with optimal sleep, short sleep was associated with higher risk of WMH presence (odds ratio, 1.11 [95% CI, 1.05-1.18]; P<0.001), larger WMH volume (beta=0.06 [95% CI, 0.04-0.08]; P<0.001), and worse fractional anisotropy profiles (beta=-0.04 [95% CI, -0.06 to -0.02]; P=0.001). Compared with optimal sleep, long sleep duration was associated with larger WMH volume (beta=0.04 [95% CI, 0.01-0.08]; P=0.02) and worse fractional anisotropy profiles (beta=-0.06 [95% CI, -0.1 to -0.02]; P=0.002), but not with WMH presence (P=0.6). CONCLUSIONS: Among middle-aged adults without stroke or dementia, suboptimal sleep duration is associated with poorer neuroimaging brain health profiles. Because these neuroimaging markers precede stroke and dementia by several years, these findings are consistent with other findings evaluating early interventions to improve this modifiable risk factor.

Investigating brain dynamics and their association with cognitive control in opioid use disorder using naturalistic and drug cue paradigms.

Objectives: Opioid use disorder (OUD) impacts millions of people worldwide. The prevalence and debilitating effects of OUD present a pressing need to understand its neural mechanisms to provide more targeted interventions. Prior studies have linked altered functioning in large-scale brain networks with clinical symptoms and outcomes in OUD. However, these investigations often do not consider how brain responses change over time. Time-varying brain network engagement can convey clinically relevant information not captured by static brain measures. Methods: We investigated brain dynamic alterations in individuals with OUD by applying a new multivariate computational framework to movie-watching (i.e., naturalistic; N=76) and task-based (N=70) fMRI. We further probed the associations between cognitive control and brain dynamics during a separate drug cue paradigm in individuals with OUD. Results: Compared to healthy controls (N=97), individuals with OUD showed decreased variability in the engagement of recurring brain states during movie-watching. We also found that worse cognitive control was linked to decreased variability during the rest period when no opioid-related stimuli were present. Conclusions: These findings suggest that individuals with OUD may experience greater difficulty in effectively engaging brain networks in response to evolving internal or external demands. Such inflexibility may contribute to aberrant response inhibition and biased attention toward opioid-related stimuli, two hallmark characteristics of OUD. By incorporating temporal information, the current study introduces novel information about how brain dynamics are altered in individuals with OUD and their behavioral implications.