Body Weight, Sleep, and Heart Health

Circadian Mechanisms of Cardiovascular Risk in Obesity

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.

Study Overview

• Status: Completed
• Conditions: Obesity; Cardiovascular Risk Factor; Circadian Dysregulation
• Intervention / Treatment: Radiation: PET Imaging; Behavioral: Circadian Study Protocol; Drug: 11C-Meta-Hydroxyephedrine (mHED); Drug: 11C-CGP12177; Drug: O15-water

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Andrew W McHill, PhD; Phone Number: 5033463808; Email: circadian@ohsu.edu
• Study Contact Backup: Name: Daniel Chess, BS/BA; Phone Number: 5854904146; Email: circadian@ohsu.edu

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Normal Weight; 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; Positron Emission Tomography (PET) imaging for research.; Behavioral: Circadian Study Protocol; 5-day circadian study schedule; Drug: 11C-Meta-Hydroxyephedrine (mHED); 11C-meta-hydroxyephedrine will be used during PET imaging to measure cardiac presynaptic norepinephrine transporter function.; Other Names: 11C-mHED; Drug: 11C-CGP12177; Cardiac beta adrenergic receptor density will be measured via PET imaging with infusion of 11C-CGP12177.; Drug: O15-water; Blood flow will be measured via PET imaging with infusion of O15-water.
Experimental: Overweight; 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; Positron Emission Tomography (PET) imaging for research.; Behavioral: Circadian Study Protocol; 5-day circadian study schedule; Drug: 11C-Meta-Hydroxyephedrine (mHED); 11C-meta-hydroxyephedrine will be used during PET imaging to measure cardiac presynaptic norepinephrine transporter function.; Other Names: 11C-mHED; Drug: 11C-CGP12177; Cardiac beta adrenergic receptor density will be measured via PET imaging with infusion of 11C-CGP12177.; Drug: O15-water; Blood flow will be measured via PET imaging with infusion of O15-water.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Oregon Health and Science University
• Investigators: Principal Investigator: Steven A Shea, PhD, Oregon Institute of Occupational Health Sciences; Principal Investigator: Jeanne M Link, PhD, OHSU Center for Radiochemistry Research

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2018
• Primary Completion (Actual): March 15, 2023
• Study Completion (Actual): March 15, 2023

Study Registration Dates

• First Submitted: December 20, 2017
• First Submitted That Met QC Criteria: December 29, 2017
• First Posted (Actual): January 3, 2018

Study Record Updates

• Last Update Posted (Actual): May 22, 2023
• Last Update Submitted That Met QC Criteria: May 18, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Chronobiology Disorders; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Adrenergic Agonists; Adrenergic beta-Agonists; CGP 12177
• Other Study ID Numbers: IRB00017489

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No