OBJECTIVE:To examine the acute cardiovascular responses to a single dose of Adderall (a combination of amphetamine-dextroamphetamine salts widely abused off-prescription for recreational use) in healthy Adderall-naïve individuals to better understand the mechanistic implications for acute cardiovascular events and increased emergency room visits associated with illicit Adderall use. PARTICIPANTS AND METHODS:We examined effects of Adderall vs identical placebo in 30 healthy volunteers who were free of attention-deficit/hyperactivity disorder and naïve to Adderall, using a randomized double-blind placebo-controlled crossover study conducted between June 15, 2018, and July 23, 2021. Each participant consumed a single 25-mg dose of oral generic Adderall or placebo. Adderall and placebo tablets were compounded and encapsulated in lactose powder by the Mayo Clinic Research Pharmacy. Resting blood pressure (BP), heart rate (HR), and plasma catecholamine levels were measured before and 3 hours after consuming Adderall or placebo. RESULTS:The study group consisted of 29 participants (16 females; mean ± SE age, 27±1 years) who completed both Adderall and placebo studies. Adderall increased systolic BP significantly from 116±2 mm Hg to 126±2 mm Hg, whereas no change in systolic BP was observed with placebo (group by time interaction, P<.001). Similarly, diastolic BP and mean BP increased by 6±1 mm Hg and 7±1 mm Hg, respectively, and HR increased by 10±2 beats/min after Adderall (all P<.01), with no changes after placebo. Plasma norepinephrine levels increased significantly after Adderall consumption from 215±15 pg/mL to 301±14 pg/mL but was unchanged after consumption of placebo (group by time interaction, P=.027). CONCLUSION:Healthy Adderall-naïve participants consuming a single dose of Adderall manifest striking increases in BP, HR, and sympathetic activation, even at rest. These findings may have important mechanistic implications for understanding acute cardiovascular events associated with illicit Adderall use. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT02979327.

Chronic short sleep duration is associated with cardiovascular disease (CVD) risk, especially in females. The impact of biological sex on hemodynamic reactivity to spontaneous nocturnal arousals following experimental sleep restriction remains largely unknown. We therefore investigated the effect of 9-day 4-h sleep restriction on heart rate (HR) and pulse transit time (PTT) changes following spontaneous arousals in healthy males and females. We hypothesized that HR and PTT reactivity would be augmented following sleep restriction, and these responses would be more robust in females. Nineteen participants (8 females; 23 ± 5 yr) were enrolled into this study, which included two 16-day in-patient studies comprised of sleep restriction (4-h sleep opportunity) and normal sleep (9-h sleep opportunity) study arms. Overnight polysomnography on days 2 (acclimation), 5 (early experimental), 11 (late experimental), and 14 (recovery) of each sleep intervention was used to analyze HR and PTT responses to spontaneous arousals. Sleep restriction did not alter HR or PTT reactivity in males or females during the early experimental phase (day 5; interaction: P > 0.05). The HR response to arousal was altered in a sex-dependent manner following sleep restriction during the late experimental phase (day 11, interaction: P = 0.013). Continued sleep loss resulted in greater PTT reduction following spontaneous arousals in females, but not in males (day 11, interaction: P = 0.007). Sustained sleep curtailment disrupts nocturnal vascular responsiveness to spontaneous arousals, more evident in females than in males. These findings provide mechanistic insight into the sex-specific relationship between shortened sleep duration and CVD risk in females. Clinical Trials Registration: Physiologic Effects of Sleep Restriction, https://clinicaltrials.gov/study/NCT01433315?term=NCT01433315&rank=1, NCT01433315.NEW & NOTEWORTHY Augmented cardiovascular responses to spontaneous nocturnal arousals were previously shown in chronic short-sleeping adults, without known sex differences. Sustained 4-h sleep restriction produced a sex-dependent alteration in heart rate responses to arousals and resulted in a prolonged reduction in postarousal pulse transit time in females only. These findings yield the first sex-specific characterization of nocturnal cardiovascular responses to spontaneous arousals following sleep restriction, and may place females at greater sleep truncation-related cardiovascular disease risk.

Objectives Obstructive sleep apnea (OSA) and cardiovascular disease (CVD) are common among former National Football League (NFL) athletes. The Living Heart Foundation Heart-Obesity-Prevention-Education Group aimed to provide an in-depth health assessment for CVD risk factors among former NFL players to examine the role of OSA on blood pressure (BP) and echocardiographic measurements. We hypothesized that OSA, maladaptive echocardiographic measurements, and elevated BP would be highly prevalent in former NFL athletes, and that OSA presence would detrimentally impact echocardiographic parameters. Methods One hundred fifty-three former NFL athletes were enrolled in the present study by the Living Heart Foundation. Participants (n = 86) completed a cardiovascular health assessment consisting of clinical BP readings and transthoracic echocardiography (TTE), which included measurements of ejection fraction, left atrial size, left ventricle diastolic diameter, intraventricular septal thickness, and ascending aortic diameter. Participants (n = 110) were offered an at-home overnight sleep test to estimate sleep apnea presence and severity. Results Eighty percent (n = 80) of our sample exhibited at least mild OSA. Further, 34% (n = 29) displayed elevated intraventricular septal thickness and subclinical aortic dilation was present in 47% (n = 40) of retired NFL athletes. In a subanalysis of former players with at-home sleep apnea testing results and TTE measures (n = 43), NFL retirees with OSA demonstrated greater ascending aortic diameter compared to former NFL athletes without OSA (p = .048). Conclusions There is a high prevalence of suspected OSA, in addition to maladaptive cardiac remodeling, among retired NFL athletes. Aortic abnormalities may be related to untreated OSA in this population.

INTRODUCTION:The relationship between sleep-disordered breathing (SDB), bone mineral density (BMD), and risk of osteoporosis is unclear. Obesity, a condition often comorbid with SDB, has been associated with high BMD, yet its impact on bone health remains controversial. The purpose of this study was to evaluate the implications of obesity in the relationship between SDB and BMD. METHODS:A total of 225 adults aged 20-65 years were enrolled in this study. Participants were nonsmokers, free of major cardiovascular diseases, and not receiving treatment for SDB. Participants completed overnight polysomnography and whole-body dual-energy X-ray absorptiometry (DEXA) scans. SDB was defined as apnea-hypopnea index of ≥5 events/hour. Total body BMD (g/cm2), T scores, and Z scores were obtained from DEXA scans. Height and weight measures were collected for computation of body mass index (BMI, kg/m2). Multivariable linear regression analysis was conducted to test the association between SDB and BMD metrics and the contribution of relevant covariates. RESULTS:Participants with SDB (n = 74, 32.9% of the sample) had higher total-body BMD (p = 0.003), T score (p = 0.017), and Z score (p = 0.011) compared to non-SDB controls. In multivariable models adjusted for demographic characteristics, SDB was not significantly associated with total-body bone measures. However, when including BMI, significant inverse relationships between SDB and total body BMD (p = 0.046), T score (p = 0.049), and Z score (p = 0.049) became apparent. Such associations persisted after controlling for lifestyle, clinical and sleep variables (fully adjusted models, total BMD, p = 0.036; T score, p = 0.037; Z score, p = 0.034). In sensitivity analysis, there were no associations between SDB and bone measures in models adjusted for body fat in lieu of BMI. CONCLUSION:An inverse, albeit modest, association between SDB and BMD exists, and this relationship emerges when considering BMI but not body fat. Hence, our data suggest that elevated body mass rather than adiposity may mask the negative association between SDB and bone health, thus possibly explaining prior conflicting evidence. Longitudinal investigations corroborating these findings and evaluating their implications for osteoporosis risk in patients with SDB are needed.

BACKGROUND:Obstructive sleep apnea (OSA) is a risk factor for hypertension and some evidence suggests this risk may not be mitigated with positive airway pressure. Low-intensity statin therapy can modestly reduce blood pressure (BP). In this exploratory analysis, we examined if six months of high-intensity statin therapy could lower resting or ambulatory BP in patients with OSA. METHODS:39 patients with OSA (13F, age = 49 ± 9yrs, body mass index = 32.9 ± 4.2kg/m2, apnea-hypopnea index = 22.2 ± 12.4 events/hour) were randomized to high-intensity atorvastatin or placebo. BP was assessed using seated, "office" measurements and in 20-minute intervals over 24 consecutive hours at three timepoints (baseline, three- and six-months post-randomization). Participants maintained a diary denoting sleep and wake times for analysis. Changes (Δ) in BP from baseline were assessed and adjusted for adherence to participants' intervention (atorvastatin or placebo) as well as to their treatment for OSA (yes or no). RESULTS:There were no between-group differences in baseline BP variables (P = .09-.96). At three months, the changes in resting (P = .74-.87), 24 hour mean (P = .54-.96), daytime (P = .70-.96), nor nighttime (P = .74-.96) BP did not differ between groups. Similarly, the changes in resting (P = .23-.92), 24 hour mean (P = .51-.82), daytime (P = .17-.78), and nighttime (P = .51-1.00) BP did not differ between groups following six months of their respective intervention. CONCLUSIONS:Our data suggest that high-intensity atorvastatin does not lower resting or ambulatory BP in patients with OSA relative to a placebo. Thus, it does not appear that atorvastatin is a viable adjunct intervention for BP reduction in patients with OSA. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03308578.

Background: Although highly prevalent, obstructive sleep apnea (OSA) remains largely underdiagnosed, thus justifying the need for high-performing screening tools. Objectives: The authors sought to develop a machine learning–powered algorithm to identify OSA from the 12-lead electrocardiogram (ECG), a routine clinical test. Methods: A retrospective population of 11,299 patients who completed sleep evaluation and underwent 12-lead ECG at Mayo Clinic were included. OSA was defined as an apnea-hypopnea index ≥5. A deep convolutional neural network model was constructed to detect OSA from the ECG (artificial intelligence [AI]-ECG). Predictive performance of the algorithm in the total sample and separately in males and females was evaluated using the receiver-operating characteristic curve with area under the curve (AUC). Results: The population consisted of 7,170 patients with OSA and 4,129 controls (53.7% males, median [Q1-Q3] of age 58 [47-68] years). The AUC of the AI-ECG model for identification of OSA in the test sample was 0.80 (95% CI: 0.77-0.83), with accuracy, sensitivity, and specificity of 73.7%, 77.0%, and 68.6%, respectively. The model showed better discriminatory performance in females (AUC: 0.82; 95% CI: 0.79-0.86) than in males (AUC: 0.73; 95% CI: 0.68-0.78; P < 0.001). Sensitivity analyses showed that the predictive abilities of the model were robust across different time intervals and even when including ECG recordings manifesting cardiac abnormalities. Conclusions: Our AI-ECG model demonstrated good diagnostic performance as an ECG-based screening tool for OSA in a clinical population, particularly among females. Incorporating this algorithm in medical practice may enable widespread low-cost screening for OSA, optimizing early diagnosis and therapy.

Cardiovascular disease (CVD) remains the leading cause of death in the United States. We previously showed a high prevalence of obstructive sleep apnea (OSA) among former National Football League (NFL) players. Further, we hypothesized that post-career OSA impacts CVD risk among retired professional athletes, even though these former NFL players are often near peak physical fitness for a significant portion of their lifespan. The Living Heart Foundation Heart-Obesity-Prevention-Education Group aimed to provide an in-depth health assessment for CVD risk factors among former NFL players to examine the role of OSA on blood pressure (BP) and echocardiographic measurements. Forty-three former NFL players completed an at-home sleep study and outpatient health assessment to determine CVD risk including office BP and transthoracic echocardiogram (TTE) measurements. Seated BP readings were made in triplicate, TTE measurements, including ejection fraction, left atrial size, left ventricular size and thickness, and ascending aortic diameter, were obtained in 17 former NFL players without OSA (age: 46±10 years, BMI: 32±5 kg/m2, apnea-hypopnea index: 3±1 events/hour) and 26 with OSA (age: 51±9 years, BMI: 33±5 kg/m2, apnea-hypopnea index: 17±12 events/hour). Independent sample t-tests were utilized to determine differences in blood pressure and TTE measurements between OSA and non-OSA groups (α=0.05). Systolic BP was similar in non-OSA vs. OSA groups (131±12 vs. 135±16 mmHg, p=0.443), while diastolic BP was higher in former NFL players with OSA (78±8 vs. 86±9 mmHg, p=0.007). Ejection fraction, left atrial size, left ventricular size, and left ventricular thickness were similar between groups (p>0.05 for all). However, ascending aortic diameter was modestly larger in former NFL players with OSA (3.3±0.19 vs. 3.5±0.40 cm, p=0.048). These findings suggest OSA may be a primary driver of increased BP and increased aortic diameter in former NFL players, and impact cardiac structural health, suggesting augmented CVD risk in former NFL players. Future work is warranted to investigate impact of race and player position on OSA-mediated CVD risk in retired NFL players. NFL Players Association, NIH T32-DK007013, and the American Heart Association (24POST1241616)

Obstructive sleep apnoea (OSA) is associated with an increased risk for cognitive impairment and dementia, which likely involves Alzheimer's disease pathology. Non-rapid eye movement slow-wave activity (SWA) has been implicated in amyloid clearance, but it has not been studied in the context of longitudinal amyloid accumulation in OSA. This longitudinal retrospective study aims to investigate the relationship between polysomnographic and electrophysiological SWA features and amyloid accumulation. From the Mayo Clinic Study of Aging cohort, we identified 71 participants ≥60 years old with OSA (mean baseline age = 72.9 ± 7.5 years, 60.6% male, 93% cognitively unimpaired) who had at least 2 consecutive Amyloid Pittsburgh Compound B (PiB)-PET scans and a polysomnographic study within 5 years of the baseline scan and before the second scan. Annualized PiB-PET accumulation [global ΔPiB(log)/year] was estimated by the difference between the second and first log-transformed global PiB-PET uptake estimations divided by the interval between scans (years). Sixty-four participants were included in SWA analysis. SWA was characterized by the mean relative spectral power density (%) in slow oscillation (SO: 0.5-0.9 Hz) and delta (1-3.9 Hz) frequency bands and by their downslopes (SO-slope and delta-slope, respectively) during the diagnostic portion of polysomnography. We fit linear regression models to test for associations among global ΔPiB(log)/year, SWA features (mean SO% and delta% or mean SO-slope and delta-slope), and OSA severity markers, after adjusting for age at baseline PiB-PET, APOE ɛ4 and baseline amyloid positivity. For 1 SD increase in SO% and SO-slope, global ΔPiB(log)/year increased by 0.0033 (95% CI: 0.0001; 0.0064, P = 0.042) and 0.0069 (95% CI: 0.0009; 0.0129, P = 0.026), which were comparable to 32% and 59% of the effect size associated with baseline amyloid positivity, respectively. Delta-slope was associated with a reduction in global ΔPiB(log)/year by -0.0082 (95% CI: -0.0143; -0.0021, P = 0.009). Sleep apnoea severity was not associated with amyloid accumulation. Regional associations were stronger in the pre-frontal region. Both slow-wave slopes had more significant and widespread regional associations. Annualized PiB-PET accumulation was positively associated with SO and SO-slope, which may reflect altered sleep homeostasis due to increased homeostatic pressure in the setting of unmet sleep needs, increased synaptic strength, and/or hyper-excitability in OSA. Delta-slope was inversely associated with PiB-PET accumulation, suggesting it may represent residual physiological activity. Further investigation of SWA dynamics in the presence of sleep disorders before and after treatment is necessary for understanding the relationship between amyloid accumulation and SWA physiology.

Abstract Obstructive sleep apnea (OSA) is associated with an increased risk for cognitive impairment and dementia, which likely involves Alzheimer’s disease (AD) pathology. Non-rapid eye movement (NREM) slow wave activity (SWA) has been implicated in amyloid clearance, but it has not been studied in the context of longitudinal amyloid accumulation in OSA. This longitudinal retrospective study aims to investigate the relationship between polysomnographic (PSG) and electrophysiological SWA features and amyloid accumulation. From the Mayo Clinic Study of Aging cohort, we identified 71 participants >=60 years old with OSA (mean baseline age=72.9 ± 7.5 years, 60.6% male, 93% cognitively unimpaired) who had at least two consecutive Amyloid Pittsburgh compound B (PiB)-PET scans and a PSG study within 5 years of the baseline scan and before the second scan. Annualized PiB-PET accumulation (global ΔPiB[log]/year) was estimated by the difference between the second and first log-transformed global PiB-PET uptake estimations divided by the interval between scans (years). Sixty-four participants were included for SWA analysis. SWA was characterized by the mean relative spectral power density (%) in slow oscillation (SO) (0.5-0.9 Hz) and delta (1-3.9 Hz) frequency bands, and by their downslopes (SO-slopes and delta-slope, respectively) during the diagnostic portion of PSG. We fit linear regression models to test for associations between global ΔPiB(log)/year, SWA features (mean SO% and delta% or mean SO-slope and delta-slope), and OSA severity markers, after adjusting for age at baseline PiB-PET, APOE ε4, and baseline amyloid positivity. For 1 s.d. increase in SO% and SO-slope, global ΔPiB(log)/year increased by 0.0033 (95% CI 0.0001; 0.0064, p=0.042) and 0.0069 (95% CI: 0.0009; 0.0129, P=0.026), which were comparable to 32% and 59% of the effect size associated with baseline amyloid positivity, respectively. Delta-slope was associated with a reduction in global ΔPiB(log)/year by -0.0082 (95% CI: -0.0143; -0.0021, P=0.009). Sleep apnea severity was not associated with amyloid accumulation. Regional associations were stronger in the prefrontal region. Both slow wave slopes had more significant and widespread regional associations. Annualized PiB-PET accumulation was positively associated with SO and SO-slopes, which may reflect altered sleep homeostasis due to increased homeostatic pressure in the setting of unmet sleep needs, increased synaptic strength and/or hyperexcitability in OSA. Delta-slope was inversely associated with PiB-PET accumulation, suggesting it may represent residual physiological activity. Further investigation of SWA dynamics in the presence of sleep disorders before and after treatment is necessary for understanding the relationship between amyloid accumulation and SWA physiology.

To assess whether polysomnographic (PSG) sleep features are associated with Amyloid-PET accumulation in patients with obstructive sleep apnea (OSA).

Introduction: Adderall, the brand name for a combination of dextroamphetamine and amphetamine salts, is used to treat attention deficit disorder and narcolepsy, but is widely abused for improving cognitive function and alertness in absence of a medical indication. While little is known of its acute cardiovascular (CV) physiologic effects, Adderall has been linked to acute CV events (myocardial infarction, tachyarrhythmias, heart failure, Takotsubo cardiomyopathy and sudden death) and to long term CV consequences including hypertension and arterial disease. Aim: To examine the acute CV responses to Adderall in healthy subjects not on stimulant therapy in a randomized double-blind placebo-controlled crossover study. (CT.gov NCT02979327) Methods: Thirty subjects were randomized to 25 mg Adderall versus placebo. We measured supine resting blood pressure (BP), heart rate (HR), and plasma catecholamines, before and 3 hours after consuming Adderall or placebo. Results: Twenty-nine subjects (16 females; aged 25±5 yrs) completed both Adderall and placebo conditions, with a median of 10 days between visits. Systolic BP (SBP) increased from 112±10 mmHg to 127±11 mmHg after use of Adderall but was unchanged before vs after placebo drug intake (112±8 mmHg and 112±9 mmHg respectively; group by time interaction p<0.01). Diastolic BP and mean BP increased by 6.8 mmHg and 8.5 mmHg respectively and HR increased by 7.3 beats/min with Adderall, but they did not change with placebo (p<0.01). Plasma norepinephrine increased from 217±79 pg/ml before to 323±105 pg/ml after Adderall but was unchanged after placebo (p<0.05) (Figure 1). Conclusions: Healthy subjects consuming a modest dose of Adderall manifest striking increases in BP, HR and sympathetic activation, even during supine rest. These findings may have important mechanistic implications for understanding acute CV events and long-term risk of CV disease associated with stimulant medications.

Short sleep duration is associated with future cardiovascular disease including hypertension, especially in females, but mechanistic evidence is largely lacking. Experimental sleep restriction has been shown to cause short sleep-mediated tachycardia and reduced heart rate variability, indicative of autonomic cardiac instability, in some but not all studies. Heart rate (HR) response to spontaneous cortical arousals can be regarded as an index of autonomic cardiac control given its characteristic temporal pattern. Whether the HR response to cortical arousals is altered during experimental sleep restriction remains unknown. We hypothesized that sleep restriction would result in augmented HR reactivity to spontaneous arousals, and that this response would be more marked in females. We studied 19 young, healthy subjects (eight females, age: 23.5 ± 5 years, body mass index [BMI]: 24.5 ± 3.6 kg/m2). In a randomized, crossover design, participants were tested during a normal sleep (NS, 9 hr sleep opportunity) or sleep restriction (SR, 4 hr sleep opportunity) study arm. Each 16-day study visit consisted of a 4-day study acclimation phase, 9-day experimental sleep perturbation segment, followed by a 3-day recovery period. An overnight polysomnography (PSG) study was conducted on study days 2, 5 and 11 (at baseline and after 1 and 7 days of restricted versus control sleep). A registered PSG technician provided sleep staging and spontaneous arousal scoring, which was confirmed by an investigator with sleep expertise (IMG). For each identified spontaneous arousal, the HR change was quantified for 30 cardiac cycles post-arousal onset and compared to a pre-arousal baseline (average HR 5 – 10 cardiac cycles prior to arousal). An arousal was considered valid for analysis if at least one minute of stage N2 or rapid eye movement (REM) sleep occurred following sleep stage transition and was at least 30 seconds apart from other sleep disturbance-related events (e.g., limb movement, apneic event, etc.). Given low prevalence of slow wave sleep (SWS) arousals, arousals occurring in that sleep stage were excluded from present analysis. Statistical analysis, including repeated measures ANOVA (RMANOVA, p < 0.05) with condition and time (cardiac cycles) as within-subjects factors and sex as the between-subjects factor, was conducted to compare the beat-to-beat HR response to arousal between study conditions. Additionally, average and peak HR responses to spontaneous arousals were compared via RMANOVA with condition and time (study days) as within-subjects and sex as between-subjects factors. HR response to spontaneous arousal in stage two and REM sleep was similar between NS and SR on study day 5 or day 11 (condition × time: p = 0.943, 0.865). Secondary analysis of average and peak HR responsiveness to spontaneous arousals in stage two and REM sleep between conditions and study days was also not statistically different (condition × time: p = 0.193, 0.185). Last, no significant sex differences were detected across comparisons (condition × time × sex: p > 0.05 for all). These findings suggest that a 9-day sleep restriction paradigm may not alter cardiac autonomic function in otherwise healthy adults. Future work is warranted to determine whether these results extend to individuals with established cardiovascular risk factors or cardiovascular disease. Support: NIH T32-DK007013, R01-114676, and CTSA grant UL1-TR002377. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

There are currently no effective biomarkers for diagnosing Parkinson’s disease (PD) or tracking its progression. Here, we developed an artificial intelligence (AI) model to detect PD and track its progression from nocturnal breathing signals. The model was evaluated on a large dataset comprising 7,671 individuals, using data from several hospitals in the United States, as well as multiple public datasets. The AI model can detect PD with an area-under-the-curve of 0.90 and 0.85 on held-out and external test sets, respectively. The AI model can also estimate PD severity and progression in accordance with the Movement Disorder Society Unified Parkinson’s Disease Rating Scale ( R = 0.94, P = 3.6 × 10 –25 ). The AI model uses an attention layer that allows for interpreting its predictions with respect to sleep and electroencephalogram. Moreover, the model can assess PD in the home setting in a touchless manner, by extracting breathing from radio waves that bounce off a person’s body during sleep. Our study demonstrates the feasibility of objective, noninvasive, at-home assessment of PD, and also provides initial evidence that this AI model may be useful for risk assessment before clinical diagnosis.

Sleep-disordered breathing (SDB) may be a treatable risk factor in patients with hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy. Evidence suggests a high prevalence of SDB in HCM. We summarize the pathophysiology of SDB as it relates to hypertension, coronary artery disease, atrial fibrillation, and sudden cardiac death in patients with HCM. The implications regarding the care of patients with HCM and SDB are discussed as well as the knowledge deficits needing further exploration.

Although insufficient sleep is associated with increased cardiovascular risk, evidence of a causal relationship is lacking. We investigated the effects of prolonged sleep restriction on 24-hour ambulatory blood pressure (BP) and other cardiovascular measures in 20 healthy young participants (aged 23.4±4.8 years, 9 females), who underwent a randomized, controlled, crossover, 16-day inpatient study consisting of 4 days of acclimation, 9 days of sleep restriction (4 hours of sleep/night) or control sleep (9 hours), and 3 days of recovery. Subjects consumed a weight maintenance diet with controlled nutrient composition throughout. A 24-hour BP (primary outcome) and cardiovascular biomarkers were measured repeatedly. Polysomnographic monitoring was continuous. Comparing sleep restriction versus control sleep, 24-hour mean BP was higher (adjusted mean difference, day 12: 2.1 mm Hg [95% CI, 0.6–3.6], corrected P =0.016), endothelial function was attenuated ( P <0.001), and plasma norepinephrine increased ( P =0.011). Despite increased deep sleep, BP was elevated while asleep during sleep restriction and recovery. Post hoc analysis revealed that 24-hour BP, wakefulness, and sleep BP increased during experimental and recovery phases of sleep restriction only in women, in whom 24-hour and sleep systolic BP increased by 8.0 (5.1–10.8) and 11.3 (5.9–16.7) mm Hg, respectively (both P <0.001). Shortened sleep causes persistent elevation in 24-hour and sleep-time BP. Pressor effects are evident despite closely controlled food intake and weight, suggesting that they are primarily driven by the shortened sleep duration. BP increases are especially striking and sustained in women, possibly suggesting lack of adaptation to sleep loss and thus greater vulnerability to its adverse cardiovascular effects.

Abstract Introduction Voluntary sleep curtailment decreases insulin sensitivity. However, molecular mechanisms underlying impaired insulin signaling are not completely understood. To gain molecular insights, we examined the transcription of known cellular insulin-signaling regulators in adipose tissue obtained from subjects undergoing experimental sleep restriction. Methods Nineteen healthy subjects (males: 11; age: 19 - 36 years; BMI: 24.5 ± 3.6 kg/m2) underwent a normal (9 hours/night) and a restricted sleep (4 hours/night) sequence in a random order. Each inpatient stay included a screen visit followed by 4 days of acclimation and 9 days of experimental phase consisting of a controlled sleep opportunity. Eucaloric diet was provided to ensure weight maintenance. Abdominal fat sample was obtained at the screen and end of the experimental phase. mRNA was quantified by RT-PCR. Fasting morning blood draws were obtained at the end of acclimation and experimental phases. Mixed models were used for analysis. Results mRNA expression did not differ in normal and restricted sleep condition for SOCS3 [changes in normal Vs. restricted sleep, 0.02 (0.11, -0.01) Vs. 0.01 (0.12, -0.07), p=0.33], PTEN [-0.22 (0.18, -0.39) Vs. -0.10 (0.21, -0.20), p=0.22], PTB1B [-0.003 (0.04, -0.07) Vs. -0.01 (0.06, -0.06), p=0.74] and Cav-1 [-2.45 (0.78, -8.39) Vs. -6.31 (1.68, -8.29), p=0.34]. Further, transcription of insulin-receptor also did not change [0.01 (0.07, -0.06) Vs. -0.03 (0.09, -0.07), p=0.92]. However, within group analysis show significant decreases in Cav-1 mRNA only during sleep restriction (normal: p=0.09; restricted: p=0.003). Importantly, restricting sleep duration was associated with lowering of insulin (0.6 ± 1.9 Vs. -1.6 ± 1.7 uIU/ml; p=0.003), no change in glucose (-1.5 ± 3.8 Vs. -3.7 ± 4.12 mg/dl, p=0.06) and improvement in HOMA-IR index (0.12 ± 0.44 Vs -0.42 ± 0.43, p=0.002). Conclusion Chronic sleep restriction does not alter the transcription of cell-signaling regulators in abdominal adipose tissue. Moreover, restricting sleep duration without increasing calorie intake did not seem to decrease insulin sensitivity as determined by HOMA-IR. Support NIH grants HL114676, Mayo Clinic CCaTS UL1 TR002377; AHA grant 13POST16420009 to NC