Body Weight, Sleep, and Heart Health

Study Overview
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Brief Summary
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A multidisciplinary investigation examining the circadian mechanisms regulating cardiovascular (CV) risk in obesity. Specifically, in a valid circadian protocol, the investigators aim to study resting cardiovascular risk markers and the reactivity of circadian rhythms in these risk markers to standardized stressors in obesity. Furthermore, using an ingenious approach, the investigators propose to explore impairment in pre/post synaptic function in the cardiac left ventricle.

Detailed Description
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Overall, these studies will help us answer whether CV rhythms predispose obese individuals to increased CV disease risk - particularly around the vulnerable morning period. The results will serve as a foundation for clinical trials of appropriately timed dosing of medications targeting aspects of the CV system in obesity that increase effectiveness while decreasing side-effects.

Official Title
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Circadian Mechanisms of Cardiovascular Risk in Obesity

Conditions
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Cardiovascular Risk Factor, Circadian Dysregulation, Obesity

Intervention / Treatment
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* Radiation: PET Imaging
* Behavioral: Circadian Study Protocol
* Drug: 11C-Meta-Hydroxyephedrine (mHED)
* Drug: 11C-CGP12177
* Drug: O15-water


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 25-65 Lean and overweight (BMI 18.5-40kg/m2) Habitually sedentary Exclusion Criteria: History of smoking/tobacco use Insomnia Moderate to severe obstructive sleep apnea. Prior shift work within 6 months prior to the study. Prescription medications Drugs of abuse Acute, chronic, or debilitating medical condition (including diabetes, hypertension, and metabolic syndrome)

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Normal Weight<br>Healthy lean controls [18.5<BMI<25 kg/m2 and WC <94/80 (men and women respectively)] will participate in a 5-day circadian study protocol with PET imaging using radiopharmaceuticals (11C-meta-hydroxyephedrine, 11C-CGP12177, and O15-water). | Radiation: PET Imaging<br>* Positron Emission Tomography (PET) imaging for research.<br>Behavioral: Circadian Study Protocol<br>* 5-day circadian study schedule<br>Drug: 11C-Meta-Hydroxyephedrine (mHED)<br>* 11C-meta-hydroxyephedrine will be used during PET imaging to measure cardiac presynaptic norepinephrine transporter function.<br>* Other names: 11C-mHED;Drug: 11C-CGP12177<br>* Cardiac beta adrenergic receptor density will be measured via PET imaging with infusion of 11C-CGP12177.<br>Drug: O15-water<br>* Blood flow will be measured via PET imaging with infusion of O15-water.<br>|
| Experimental: Overweight<br>Healthy obese [30≤BMI<40 and waist circumference (WC) ≥94/80 (men and women respectively)] will participate in a 5-day circadian study protocol with PET imaging using radiopharmaceuticals (11C-meta-hydroxyephedrine, 11C-CGP12177, and O15-water). | Radiation: PET Imaging<br>* Positron Emission Tomography (PET) imaging for research.<br>Behavioral: Circadian Study Protocol<br>* 5-day circadian study schedule<br>Drug: 11C-Meta-Hydroxyephedrine (mHED)<br>* 11C-meta-hydroxyephedrine will be used during PET imaging to measure cardiac presynaptic norepinephrine transporter function.<br>* Other names: 11C-mHED;Drug: 11C-CGP12177<br>* Cardiac beta adrenergic receptor density will be measured via PET imaging with infusion of 11C-CGP12177.<br>Drug: O15-water<br>* Blood flow will be measured via PET imaging with infusion of O15-water.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Pressure | Beat-by-beat and ambulatory blood pressure measurements. | 5 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart Rate | Heart rate via 2-channel echocardiogram (ECG) | 5 Days | 
| Epinephrine | Venous Epinephrine to estimate sympathetic output | 5 days | 
| Norepinephrine | Venous Norepinephrine to estimate sympathetic output | 5 days | 
| Cortisol | Saliva cortisol to estimate sympathetic output | 5 days | 
| Aldosterone | Venous Aldosterone to estimate sympathetic output | 5 days | 
| Endocannabinoid | Plasma endocannabinoid to estimate sympathetic regulation | 5 days | 
| Heart Rate Variability (HRV) | Analysis of HRV from 12-lead ECG to assess parasympathetic activity | 5 days | 
| malondialdehyde (MDA) adducts | Plasma MDA to measure oxidative stress and inflammation. | 5 days | 
| Flow Mediated Dilation (FMD) | FMD to measure endothelial function. | 5 days | 
| Tumor Necrosis Factor alpha (TNF-alpha) | TNF-alpha to assess inflammation. | 5 days | 
| Coronary blood flow | Radiolabeled water (O15-water) to measure coronary blood flow during PET Imaging. | 5 days. | 
| Norepinephrine reuptake transport | Radiolabeled meta-hydroxyephedrine (11C-mHED) to measure norepinephrine reuptake during PET Imaging. | 5 days. | 
| Beta-adrenergic receptor density | Radiolabeled agonist (11C-CGP12177) to measure beta-adrenergic receptors during PET Imaging. | 5 days. | 
| Dual Emission X-ray Absorbance (DEXA) Body composition | DEXA imaging to assess body composition. | 1 day | 
| Coronary Artery Calcium Score | Coronary Calcium Computed Tomography (CT) Scan | 1 scan. | 
| Coronary Microvascular Blood Flux | 1. Determine in lean healthy humans if coronary microvascular function, measured as coronary microvascular blood flux, has an endogenous circadian rhythm with lowest function in the morning. 2. Test the hypothesis that people with obesity have impaired coronary microvascular blood flux compared to lean individuals, with the exaggerated impairment during the morning. Measured using myocardial contrast echocardiography. | 3 days |