Circadian rhythms and cardiovascular risk

Research project

Description

? DESCRIPTION (provided by applicant): 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.
StatusActive
Effective start/end date7/15/153/31/19

Funding

  • National Institutes of Health: $502,996.00
  • National Institutes of Health: $682,927.00

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Obstructive Sleep Apnea
Circadian Rhythm
Sleep
Blood Pressure
Sudden Cardiac Death
Cardiovascular Diseases
Myocardial Infarction
Incidence
Posture
Hydrocortisone
Continuous Positive Airway Pressure
Wakefulness
Plasminogen Activator Inhibitor 1
Autonomic Nervous System
Vulnerable Populations
Apnea
Arousal
Hemostasis
Platelet Aggregation
Catecholamines

Keywords

  • Medicine(all)