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Overview

Sleep, Physical Inactivity, Circadian Rhythms and Cardiovascular Vulnerability (First Award Fellowship)

Principal Investigator:
Saurabh Thosar, Ph.D.

Organization:
Oregon Health & Science University

Shift work is a risk factor for cardiovascular (CV) and metabolic diseases and an innate occupational health hazard in astronauts. The burden of CV risk further increases in this population due to exposure to additional stressors including but not limited to microgravity and sleep loss. CV diseases are leading causes of death and disability in the United States and it is highly likely that astronauts and other shift workers at NASA, and elsewhere are at an increased risk for CV diseases. In the general population adverse CV events such as sudden cardiac death, myocardial infarction, stroke and ventricular arrhythmia have the greatest incidence around 9 AM. Vascular endothelial function is becoming recognized as a better predictor of CV risk than traditional CV risk factors. Moreover, endothelial function is impaired during the vulnerable morning hours. We are trying to study the effects of the endogenous clock on endothelial function. Further, this project seeks to determine if a standardized working day impairs vascular function when undertaken during the biological night as compared to the biological day.

NASA Taskbook Entry


Technical Summary

Main Aim: To determine if an endogenous circadian rhythm exists in baseline endothelial function, with worst function at the circadian phase that corresponds to the peak in vulnerability to serious adverse cardiovascular events.

Exploratory Aim: To determine if the effects of standardized activities on endothelial function when performed when misaligned (akin to night shift work) result in worse endothelial function compared to when these identical activities are performed across a normally aligned day.

These aims will be achieved by studying human participants in a 5 day in-laboratory forced desynchrony protocol where all behaviors are held constant in dim light.

Participants: We will test 12 ostensibly healthy normal weight and overweight, but not obese (18.5<BMI<30 kg/m2) adults between ages 18-55 years. Participants will be free of any acute or chronic disease and will be free from any prescription medications, tobacco, alcohol and drug use. They will have no history of shift work for 12 months, and travel >3 time zones for at least 3 months.

Dependent variables

1) Endothelial function (flow mediated dilation)

2) Mechanistic variables

a) Sympathetic activity (cortisol, epinephrine, norepinephrine)

b) Oxidative stress

c) TNF-α

Independent variables

1) Circadian phase (from salivary melatonin)

2) Vigilance state (relaxed wakefulness vs. sleep stages)

 

At home phase: Before participating in the laboratory protocol, all participants maintain a stable 8 hour/night sleep schedule at least a week and will refrain from intake of alcohol, caffeine, nicotine and all over the counter supplements.

“Forced Desynchrony” protocol: All participants will undergo a 5 day forced desynchrony protocol in dim light where all activities (sleep times and wake behaviors) are scheduled such that the effects of the behaviors and the endogenous circadian system can be separated. Melatonin will be used to determine the circadian period and dim light melatonin onset will be used to establish circadian phase.

Upon arrival, participants will be instrumented with a full polysomnography, Holter monitor, electrocardiogram and an IV line such that blood sampling can take place from an adjacent room while asleep without disturbing the participants. Blood sampling will be carried out approximately every two hours and processed for subsequent hormonal assays.  

Sleep episodes: Sleep episodes will be polysomnographically recorded and include electrocardiogram (ECG), electroencephalogram (EEG), electro-oculogram (EOG), submental electromyogram (EMG) and arterial oxygen saturation (via pulse oximetry measured on the non-dominant index finger). Sleep stages, arousals, and any periodic limb movements or respiratory events will be scored in 30-second epochs according to scoring criteria of the American Academy of Sleep Medicine.  

Wake episodes: The schedule and testing procedures are identical during each wake episode. Participants are aroused from sleep using a standard auditory tone to minimize different arousal stimuli influences. Participants remain in bed in the supine posture while baseline measurements including endothelial function (flow mediated dilation; FMD) are made. Participants will eat one isocaloric meal during each wake period and will be asked to finish each meal in order to maintain metabolic homeostasis. There will be a battery of tests which constitute a standardized work day (including low intensity exercise, postural challenge, cognitive challenges and questionnaires) after which FMD is measured immediately before sleep. All these behaviors will be standardized across the entire protocol. During scheduled ‘free-time’, participants will be able to move about the suite as desired, except that they will not be permitted to lie down nap, or exercise. Each participant’s activity will be monitored for compliance by closed circuit TV and recorded by actigraphy.  

Cosinor analysis will be performed to determine if a circadian rhythm exists in vascular endothelial function. Similarly, blood biomarkers will be analyzed to establish mechanisms that may influence endothelial function at different times of the day and night.


Earth Applications

Although few studies have measured vascular endothelial function across the day and night, studies with sporadic measurements in the evening, morning and during the day have revealed a marked diurnal rhythm with the lowest function in the morning soon after waking: potentially due to the effects of (1) prior sleep; (2) prior supine posture and inactivity; and/or (3) an endogenous circadian effect. Our study will determine if this low function is at least in part due to the endogenous circadian system. If the endogenous circadian system is not responsible for this trough in function, behaviors such as inactivity and sleep can be investigated in future studies. Further, this study will set the stage to investigate vascular function in individuals with increased CV risk such as those with hypertension, diabetes, etc., and eventually allowing study of countermeasures against morning increase in adverse CV events.