Adverse cardiovascular events, including sudden cardiac death, myocardial infarction and ventricular arrhythmias all have their highest incidence around 9 AM. In healthy humans, we discovered that our internal body clock causes many cardiovascular (CV) disease risk markers to peak at this time. These include sympatho-vagal responses to stress, markers of thrombosis or clot formation (PAI-1 and platelet aggregation), and the stress hormone cortisol. It is precisely at this vulnerable body clock time that people encounter additional stresses elicited by behaviors: arousal from sleep, altered posture, and increased activity also induce numerous CV responses. Some, such as increased sympatho-vagal balance and blood coagulability, might be beneficial in healthy people but represent risk factors in populations vulnerable to CV disease, such as those with hypertension or obstructive sleep apnea (OSA). Subjects with OSA are of particular interest from both CV risk and circadian rhythms perspectives because OSA increases vulnerability to CV disease, is associated with greater incidence of a perilous nocturnal non-dipping blood pressure (BP), and leads to completely different day/night patterns in incidence of myocardial infarction and sudden cardiac death - with peaks during the night rather than the morning.
Our specific aims are to determine if endogenous circadian rhythms in CV function during rested wakefulness (Aim 1) and in the reactivity of CV function to standardized stressors (posture, exercise;
Aim 2) are disturbed in people with untreated OSA compared to people treated with continuous positive airway pressure (CPAP) and matched controls. Dependent CV risk markers will include measures of hemodynamics, hemostasis, autonomic nervous system activity, endothelial function, and oxidative stress. To document circadian rhythms, subjects will spend 5 days in a laboratory in a constant environment including dim light. To test CV function at all phases of the internal clock while controlling for behaviors that precede the tests, such as meals or the duration of time awake, subjects will live on recurring 5 hour 20 minute `days' during which behavior is tightly controlled. In protocols like this, we have measured BP continuously during sleep. This technique will allow us to determine the causes of OSA-associated non-dipping BP in terms of effects from the internal body clock, sleep itself, or the sleep disruptions caused by apneas. We hypothesize that people with OSA will have: (i) abnormally advanced circadian phase in BP and its regulators including catecholamines and cortisol, and (ii) deleterious circadian amplitudes in key CV risk markers. These two effects are hypothesized to explain the increased vulnerability and earlier timing of adverse CV events in OSA. This study will provide the first evidence of the relative role of internal circadian rhythms and specific behavioral stressors on CV function in OSA. By pointing to novel mechanisms by which OSA is linked to its comorbidities, this study may shed better light on nocturnal myocardial infarction and sudden cardiac death, help lead to treatment strategies based on time of day, and ultimately lead to a reduction in CV-related deaths.

Public Health Relevance

Adverse cardiovascular events, such as heart attacks and sudden cardiac death occur most commonly at ~9 AM in the general population, but most frequently ~3 AM in people with obstructive sleep apnea. We aim to determine if the internal body clock affects cardiovascular function differently in those with treated and untreated sleep apnea compared to healthy people, perhaps explaining the different timing of adverse events in this population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL125893-04
Application #
9462819
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Stoney, Catherine
Project Start
2015-07-15
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Neurosciences
Type
Overall Medical
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Thosar, Saurabh S; Wiggins, Chad C; Shea, Steven A et al. (2015) Brachial artery endothelial function is stable across the morning in young men. Cardiovasc Ultrasound 13:42