Numerous epidemiological studies have established that there is a disproportionately high frequency of adverse cardiovascular events around 9 AM (e.g., sudden cardiac death, myocardial infarction). The mechanisms have been loosely attributed to behavioral stressors occurring at specific times of day (e.g., change in posture or activity). But, the independent role of the internal body clock (circadian pacemaker) in this day/night pattern has never been studied with appropriate techniques. Our preliminary data show a marked endogenous circadian rhythm in some markers of cardiovascular risk that may be implicated in the day/night pattern of adverse cardiovascular events. Thus, we have two Specific Aims: (1) Determine the effect upon cardiovascular risk markers of the circadian pacemaker (independent from behaviors); (2) Determine the interaction between circadian and behavioral influences upon cardiovascular risk markers (i.e., an interaction by which behavioral stressors have different effects at different circadian phases). To achieve these aims, we will utilize an intensive 12-day """"""""Forced Desynchrony"""""""" protocol, wherein subjects' standardized behaviors and sleep occur at all phases of the circadian cycle. As this will be the first formal study in this area, we will begin by studying healthy individuals to define the normal human physiological rhythms and responses that could be implicated in the day/night pattern of cardiovascular risk. During the protocol standardized behavioral stressors include changes in posture (tilt table), activity (bicycle exercise) and sleep/wake state. The measures that can be implicated in triggering adverse cardiovascular events in vulnerable individuals, will include (i) autonomic nervous system activity (catecholamines, sympatho-vagal balance); (ii) hemodynamic factors (heart rate, blood pressure); (iii) Hemostatic factors (platelet aggregability and count); and (iv) vascular endothelial function (flow mediated vasodilatation). Based on preliminary data, we anticipate that behavioral stressors will have different effects at specific phases of the circadian cycle revealing vulnerable times for certain behaviors (likely corresponding to the peak in cardiovascular vulnerability from epidemiological studies). This project may ultimately help us to rationalize chronobiological therapies for cardiovascular diseases in terms of modification of behavior and timed pharmacological intervention. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076409-02
Application #
6948604
Study Section
Special Emphasis Panel (ZRG1-CCVS (01))
Program Officer
Jobe, Jared B
Project Start
2004-09-15
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$503,109
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Scheer, Frank A J L; Shea, Steven A (2014) Human circadian system causes a morning peak in prothrombotic plasminogen activator inhibitor-1 (PAI-1) independent of the sleep/wake cycle. Blood 123:590-3
Scheer, Frank A J L; Morris, Christopher J; Shea, Steven A (2013) The internal circadian clock increases hunger and appetite in the evening independent of food intake and other behaviors. Obesity (Silver Spring) 21:421-3
Hu, Kun; Scheer, Frank A J L; Laker, Michael et al. (2011) Endogenous circadian rhythm in vasovagal response to head-up tilt. Circulation 123:961-70
Scheer, Frank A J L; Michelson, Alan D; Frelinger 3rd, Andrew L et al. (2011) The human endogenous circadian system causes greatest platelet activation during the biological morning independent of behaviors. PLoS One 6:e24549
Shea, Steven A; Hilton, Michael F; Hu, Kun et al. (2011) Existence of an endogenous circadian blood pressure rhythm in humans that peaks in the evening. Circ Res 108:980-4
Scheer, Frank A J L; Hu, Kun; Evoniuk, Heather et al. (2010) Impact of the human circadian system, exercise, and their interaction on cardiovascular function. Proc Natl Acad Sci U S A 107:20541-6
Hu, Kun; Van Someren, Eus J W; Shea, Steven A et al. (2009) Reduction of scale invariance of activity fluctuations with aging and Alzheimer's disease: Involvement of the circadian pacemaker. Proc Natl Acad Sci U S A 106:2490-4
Scheer, Frank A J L; Hilton, Michael F; Mantzoros, Christos S et al. (2009) Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A 106:4453-8
Hu, Kun; Scheer, Frank A J L; Buijs, Ruud M et al. (2008) The circadian pacemaker generates similar circadian rhythms in the fractal structure of heart rate in humans and rats. Cardiovasc Res 80:62-8
Hu, Kun; Scheer, Frank A J L; Buijs, Ruud M et al. (2008) The endogenous circadian pacemaker imparts a scale-invariant pattern of heart rate fluctuations across time scales spanning minutes to 24 hours. J Biol Rhythms 23:265-73

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