Calvin, Andrew D.

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.

Introduction: Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke; however the causal mechanisms are unknown. Understanding etiology of stroke in OSA patients may: (1) aid in ascertaining how OSA exerts its influence in increasing stroke risk, and (2) facilitate tailoring recurrent stroke prevention management strategies in OSA patients. Our study compares stroke subtypes in OSA cases versus controls without significant sleep disordered breathing. Hypothesis: We hypothesized cardioembolic (CE) strokes would occur more frequently in OSA cases than in controls. Methods: Consecutive patients were identified who underwent polysomnography (PSG) at Mayo Clinic and suffered an ischemic stroke within one year after PSG. Patients with an apnea-hypopnea index (AHI) ≤ 10 were classified as controls; AHI > 10 classified as OSA cases. Mechanism of stroke was determined using (1) the Causative Classification System for Ischemic Stroke (CCS) and (2) the phenotype definitions used in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Information on cardiovascular risk factors, neuroimaging, and echocardiography data were collected on each patient. Results: In 53 total subjects, CE strokes were more common among OSA cases (72% vs 33%, p=0.01). Large artery atherosclerosis and small vessel occlusion strokes were more common in controls. Atrial fibrillation (AF) was more frequent in OSA patients (59% vs 24%, p=0.01). Frequency of CE stroke increased with OSA severity. The association between OSA and CE stroke remained significant after controlling for AF (p=0.03, OR 4.5). Echocardiogram data revealed CE stroke risk factors were more frequent in OSA cases (84% vs 52% p=0.02). There were no significant differences between groups for left ventricular ejection fraction, left atrial volume index, or right ventricular systolic pressure. Conclusions: The results demonstrate a strong association between OSA and CE stroke. In OSA patients presenting with cryptogenic stroke, high clinical suspicion for cardioembolism is warranted. This may lead to consideration of further studies (eg, transesophageal echocardiography, Holter monitoring, or extended cardiac monitoring) to identify cardioembolic risk factors such as paroxysmal AF.

Introduction: Identifying and mitigating factors that promote obesity will have a large public health impact. Sleep may be an important regulator of metabolism and energy expenditure. Voluntary sleep restriction is common, with 27% of US adults regularly getting ≤6 h of sleep per day. Epidemiologic evidence suggests a link between short sleep duration and obesity. Human experiments suggest that acute sleep deprivation reduces the anorexigenic hormone leptin, increases the orexigenic factor ghrelin, and promotes caloric intake. Meanwhile, increased energy expenditure during prolonged wakefulness may counterbalance any increased caloric intake associated with a lack of sleep. Hypothesis: We hypothesized that 8 days of modest sleep restriction would reduce leptin, increase ghrelin, promote caloric intake, and increase activity energy expenditure. Methods: We studied 17 healthy individuals age 18–40 y. Subjects completed a protocol consisting of one week of home actigraphy, a 3 night acclimation phase, followed by an 8 night experimental phase in which they were randomized to sleep ad lib or two-thirds of their normal sleep time. Blood was collected at the end of the two periods, food was freely available and caloric intake was calculated daily, and activity energy expenditure was assessed by a comprehensively validated system comprised of inclinometers and accelerometers. Sleep was confirmed using continuous electroencephalography. Mean change from the acclimation period ± standard deviation are presented, with statistical testing by two sample t tests on the changes between acclimation and experimental periods. Results: Subjects included 11 men and 6 women, of whom 8 were randomized to sleep deprivation and 9 served as controls. Sleep duration during the acclimation period averaged 6.5±0.9 h/day but fell to 5.2±0.1 h/d among those randomized to sleep deprivation. The sleep deprivation group consumed +549±583 kcal/d, whereas those randomized to ad lib sleep consumed −143±420 kcal/d (P<0.01). Activity energy expenditure by did not change in either group (+1.2±33.0% vs +8.4±34.0%, P=0.68). Sleep deprivation was associated with a trend towards increased leptin (+8.4±4.7% versus −9.8±13.5%, P=0.12) and decreased ghrelin (−4.9±5.3% vs +4.6±7.0%, P=0.38). Conclusions: Eight days of modest sleep restriction, similar to that encountered in everyday life, was associated with a striking increase in caloric intake with no change in activity energy expenditure. Contrary to expectations, we observed a trend towards increased circulating concentrations of leptin and reduced concentrations of ghrelin, more consistent with a consequence of a positive energy balance than a cause. Our data suggest that chronic sleep restriction may be an important and modifiable behavior promoting obesity.

Central sleep apnea (CSA) with nocturnal hypoxia is frequent in heart failure (HF). Hypoxia causes increased circulating erythropoietin (EPO) in healthy normals. EPO promotes increased vasoconstriction and exogenous EPO administration is associated with adverse cardiovascular events. No prior studies have related EPO concentration to apnea or hypoxia due to CSA. EPO is elevated in HF patients with nocturnal hypoxia due to CSA. Ambulatory, non-anemic HF patients (n = 29) with LVEF < 45% and healthy controls (n = 18) underwent polysomnography (PSG). Subjects with obstructive sleep apnea (OSA) were excluded. CSA was defined as apnea-hypopnea index (AHI) ≥ 15. Hypoxia was quantified as the proportion of sleep with arterial oxygen saturation < 90% (T90%). Blood for EPO was drawn post-PSG. Other clinical characteristics were summarized from the medical record. HF subjects and controls were similar age (54 vs 60 y, p = 0.09). CSA was present in 14 HF subjects; 13 were men compared to 8 of 15 without CSA (p = 0.04). HF subjects had 42% higher mean EPO than controls (p < 0.01) despite similar hemoglobin (13.9 vs 14.0 g/dL, p = 0.8). NYHA class III–IV HF subjects had 42% higher mean EPO than class I–II HF subjects (p = 0.05, figure ). EPO concentration was correlated with severity of nocturnal hypoxia by simple linear regression (r = 0.4; p = 0.02). By multivariate analysis, elevated EPO was associated with NYHA class III–IV HF and elevated AHI (p = 0.01 and 0.03, respectively; r = 0.6) after adjusting for age, gender, LVEF, renal function and hemoglobin. Nocturnal hypoxia due to CSA promotes increased endogenous EPO concentration in HF patients.

Introduction: Stress echocardiography (SE) has an established role in the evaluation of symptomatic patients, but its utility in asymptomatic patients is unclear. Current guidelines discourage the use of SE in most asymptomatic patients, citing lack of data to support its use. We therefore sought to describe the yield of SE in a group of asymptomatic individuals according to risk profile. Hypothesis: We hypothesized that SE would rarely be abnormal in asymptomatic individuals. Methods: We conducted a retrospective cohort study of all asymptomatic individuals who underwent exercise or pharmacologic SE between 2003 and 2013. Reasons for SE included screening for CAD, preoperative evaluation, abnormal ECG, coronary calcification, and assessment of established CAD (defined as prior myocardial infarction or coronary revascularization). We grouped subjects using both the 10-year Framingham risk equation and ATP3-suggested categories of low-risk (<10%), intermediate-risk (10-20%), and high-risk (>20%) for non-diabetic subjects without known CAD and by ACC/AHA Pooled Cohort risk estimates for subjects with and without diabetes. Subjects with established CAD were considered separately. Abnormal echocardiograms were defined as having ischemic, fixed, or mixed defects. Results: The study population comprised 19,170 subjects; 63% men, mean±SD age was 64±13 years, and 52% underwent pharmacologic SE. The likelihood of abnormal SE results was proportional to risk, with the highest yield in those with established CAD (59%). Those with diabetes had a yield similar to those with a 10 year risk of 10-20% by both ATP3/FRS and ACC/AHA. Conclusions: SE abnormalities are commonly seen in asymptomatic individuals; the likelihood of abnormal SE results was proportional to patients’ estimated risk. The frequency of SE abnormalities in diabetic patients is similar to that of intermediate-risk, but not high-risk patients.

Background Increasing evidence suggests that insufficient sleep is associated with increased morbidity and mortality. Studies linking short sleep with metabolic derangements such as obesity, insulin resistance and dyslipidemia, are especially persuasive. Nevertheless, the vast majority of these data have been obtained from observational studies. We sought to evaluate the effects of 9 days of partial sleep deprivation compared to normal sleep on lipid profile in healthy subjects undergoing an in‐laboratory, experimental protocol. Methods Eight healthy, nonobese, normolipidemic subjects (4 males, age 25.4±6.8 years, body mass index 25.2±3.9 kg/m 2 ) completed a randomized, controlled, crossover, 16‐day in‐patient study. Each sequence consisted of a 4‐day acclimation period, followed by 9 days of experimental partial sleep deprivation (4 hours of sleep opportunity; 00:30 AM – 4:30 AM); or normal sleep (9 hours of sleep opportunity; 10:00 PM – 7:00 AM), and a subsequent 3‐day recovery segment. Subjects consumed a controlled, weight maintenance diet (15% protein, 55% carbohydrates, and 30% fat) during the study. Fasting blood samples for measures of total cholesterol, high‐density lipoprotein (HDL) cholesterol, low‐density lipoprotein (LDL) cholesterol, and triglycerides were obtained in both study sequences on Days 4, 7, 10, 13, and 16. Results Compared to normal sleep, experimental partial sleep deprivation did not cause significant changes in total cholesterol (partial sleep deprivation vs normal sleep: 160.1±21.8 mg/dL vs 164.9±23.7 mg/dL, P=0.724), HDL cholesterol (54.1±14.7 mg/dL vs 52±12.8 mg/dL, P=0.75), LDL cholesterol (86.5±18.9 mg/dL vs 89.5±19.7 mg/dL, P=0.329), or triglycerides (97.7±26.6 mg/dL vs 96.6±38.3 mg/dL, P=0.633). Analysis of time course of lipid values across study days did not reveal appreciable patterns (all P>0.295). Likewise, body weight was similar during both study sequences (partial sleep deprivation vs normal sleep: 69.6±14.2 kg vs 69.2±13.5 kg, P=0.459). Conclusions Experimental sleep restriction does not alter circulating lipids or weight in healthy subjects. Aberrant metabolic effects of insufficient sleep may be mediated by dietary intake and occur when access to food is unrestricted, or may emerge only after longer exposure to sleep curtailment. Support or Funding Information American Heart Association grant 16SDG27250156; National Institutes of Health R01 grants HL114676 and HL114024; European Union project FNUSA‐ICRC no. CZ.1.05/1.1.00/02.0123. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Background Epidemiologic evidence suggests a link between short sleep duration and cardiovascular risk, although the nature of any relationship and mechanisms remain unclear. Short sleep duration has also been linked to an increase in cardiovascular events. Endothelial dysfunction has itself been implicated as a mediator of heightened cardiovascular risk. We sought to determine the effect of 8 days/8 nights of partial sleep restriction on endothelial function in healthy humans. Methods and Results Sixteen healthy volunteers underwent a randomized study of usual sleep versus sleep restriction of two‐thirds normal sleep time for 8 days/8 nights in a hospital‐based clinical research unit. The main outcome was endothelial function measured by flow‐mediated brachial artery vasodilatation ( FMD ). Those randomized to sleep restriction slept 5.1 hours/night during the experimental period compared with 6.9 hours/night in the control group. Sleep restriction was associated with significant impairment in FMD (8.6±4.6% during the initial pre‐randomization acclimation phase versus 5.2±3.4% during the randomized experimental phase, P =0.01) whereas no change was seen in the control group (5.0±3.0 during the acclimation phase versus 6.73±2.9% during the experimental phase, P =0.10) for a between‐groups difference of −4.40% (95% CI −7.00 to −1.81%, P =0.003). No change was seen in non‐flow mediated vasodilatation ( NFMD ) in either group. Conclusion In healthy individuals, moderate sleep restriction causes endothelial dysfunction. Clinical Trial Registration URL : ClinicalTrials.gov. Unique identifier: NCT 01334788.