Cardiovascular Effects of Exposure to Ozone (MOSES)

Multicenter Ozone Study in Elderly Subjects

The Multicenter Ozone Study in Elderly Subjects will investigate whether short-term exposure of elderly volunteers to ambient levels of ozone in a controlled exposure setting causes acute cardiovascular responses as assessed by changes in blood pressure, cardiac function, and systemic biomarkers of inflammation, endothelial dysfunction, and thrombosis.

Study Overview

• Status: Unknown
• Conditions: Cardiovascular Injury

Detailed Description

This multicenter study will investigate whether short-term exposure of elderly volunteers to ambient levels of O3 in a controlled exposure setting while intermittently exercising causes acute cardiovascular responses. The study is based on the suppositions that: 1) elderly people are a susceptible group for cardiovascular effects; and 2) effects are more likely with exercise.

The study will involve approximately 90 healthy volunteers aged ≥55 and ≤70 who meet strict criteria for inclusion. They will be exposed for 3 hours to clean air, 0.07 ppm O3 (near the current NAAQS), and 0.12 ppm O3 (a level measured in several locations in the US). A suite of cardiovascular and pulmonary endpoints will be measured on the day before the exposure and up to 22 hours after the exposures. The study is being conducted at three centers using a common protocol and common SOPs. Most the endpoints will be analyzed by core laboratories to reduce the variability in the results. A Data Coordination and Analysis Center will assemble all the data generated by the three centers and conduct the statistical analyses on the combined data sets.

The study has 3 main objectives:

1. To determine the relationship of altered autonomic balance (measured as changes in heart rate and heart rate variability (HRV)), cardiac arrhythmia, and repolarization and ozone exposure.
2. To identify instances of altered systemic vascular function [measured as brachial artery flow-mediated dilation (FMD)without and with nitroglycerin (NTG) when exposed to ozone.
3. To identify pro-thrombotic vascular state (measured as increase in von Willebrand factor antigen in blood - primary endpoints) when exposed to ozone.

Additional objectives include:

1. To identify any increase in micro particle-associated tissues factor (measured as number of particles and tissue factor activity) and platelet activation) in ozone exposure.
2. To identify if markers of systemic oxidative stress and inflammation and any correlation with the cardiovascular effects and degree of airway injury (measured as CC16) and airway inflammatory effects (neutrophils and cytokines in induced sputum) in ozone exposure.
3. To determine if cardiovascular effects in ozone exposure are correlated with airway inflammatory effects, but not lung function effects.

• Study Type: Observational
• Enrollment (Anticipated): 90

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California at San Francisco
      • Contact: Hofer Wong; Phone Number: 415-206-8951; Email: howong@sfghoem.ucsf.edu
      • Principal Investigator: John Balmes, MD
  • Massachusetts
    • Watertown, Massachusetts, United States, 02472
      • Active, not recruiting
      • New England Research Institutes, Inc.
  • New York
    • Rochester, New York, United States, 14642
      • Recruiting
      • University of Rochester
      • Contact: Erika Little; Phone Number: 585-275-4163; Email: erika_little@urmc.rochester.edu
      • Principal Investigator: Mark Frampton, MD
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Recruiting
      • University of North Carolina at Chapel Hill
      • Contact: Martha Almond; Phone Number: 919-966-0759; Email: martha_almond@med.unc.edu
      • Principal Investigator: Philip Bromberg, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Healthy elderly volunteers living in or around San Francisco, CA, Research Triangle Park, NC, and Rochester, NY

Description

Inclusion Criteria:

• males and females of all ethnic backgrounds.
• Normal spirometry (FEV1 and FVC >75% of predicted and FEV1/FVC >0.65).
• Ability to complete the exposure exercise regimen chosen to induce a ventilation rate of 15 to 17 L/min/m2 without exceeding 80% of predicted maximal heart rate.
• Normal baseline 12-lead resting ECG, and absence of significant ST depression while performing the 15-minute required level of exercise targeted for the exposure period.
• Subjects must be able to avoid certain medication supplements listed for 1 week before the exposure.

Exclusion Criteria:

• Non-English speaking.
• Including, but not limited to as ascertained by the physicians: Subjects with chronic cardiovascular (such as ischemic heart disease) or respiratory (such as asthma or COPD) disease; diabetes, or other organ or system dysfunction; cerebrovascular disease; active psychiatric disorders that would interfere with the subject's ability to understand and participate in the study. Subjects who have tested positive for a disease that affects the immune system (such as HIV, lymphoma, leukemia) or current drug or alcohol abuse (defined as having more than 3 drinks per day or being unable to abstain from alcohol for 3 days).
• Subjects with atopy or allergic rhinitis will not be excluded as long as they do not require regular treatment with antihistamines or systemic steroids.
• Ever-smokers (smoked tobacco or marijuana during the last five years, or with history of >10 pack year for tobacco or > 1 joint year for marijuana, or living with a smoker who smokes inside the house).
• Subject having plasma cotinine level > 3ng/mL.
• BMI >35 or <18 (35 is the official cut off for class 1 obesity).
• Hypertension (defined as blood pressure >140 systolic or >90diastolic) or on anti-hypertension medications other than diuretics.
• Pregnancy or nursing (breastfeeding).
• On the following medications: prednisone, statins, beta-blockers, anticoagulants, current hormonal therapy, tamoxifen. Subjects will not be asked to discontinue needed prescription medications for the purpose of this study. If any of these medications becomes necessary during the course of the study, the subjects will be excluded. Use of other medications will be considered on an individual basis.
• Subjects taking aspirin or PDE5 inhibitors must be willing to abstain from these medications during the week preceding each exposure.
• Occupational exposures (exposed to high levels of vapors, dust, gases, or fumes on an on-going basis)

Study Plan

How is the study designed?

Design Details

• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
elderly subjects; Healthy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in endothelial function	Brachail artey flow-mediated dilation and nitroglycerin-mediated dilation	Baseline (16 hours before exposure) and 4 hours after exposure
Change in heart rate variability	measured with Holter monitor	Baseline (0.5 hours before exposure) and 0.2, 2, and 21.5 after exposure
Change in prothrombotic vascular state	Peripheral blood samples will be taken and stored as plasma for measurement of von Willenbrand Factor antigen	Baseline (17 hour before exposure) and 3.5 and 22 hours after exposure
Change in cardiac repolarization	from Holter monitor	Baseline (0.5 hours before exposure) and 0.2, 2, and 21.5 after exposure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in markers of systemic inflammation	Peripheral blood samples will be taken and stored as plasma for measurements of inflammatory markers	Baseline (17 hour before exposure) and 3.5 and 22 hours after exposure
Change in lung function	Spirometry	Baseline (0.2 hours before exposure) and 0.5, 3, and 22.5 hours after exposure
Lung inflammation	A sputum sample will be obtained and stored for measurement of inflammatory mediators	22 hours after exposure

Collaborators and Investigators

• Sponsor: Health Effects Institute
• Collaborators: University of California, San Francisco; University of North Carolina, Chapel Hill; HealthCore-NERI; University of Rochester
• Investigators: Principal Investigator: Anne Stoddard, PhD, HealthCore-NERI

Publications and helpful links

General Publications

• Rich DQ, Thurston SW, Balmes JR, Bromberg PA, Arjomandi M, Hazucha MJ, Alexis NE, Ganz P, Zareba W, Thevenet-Morrison K, Koutrakis P, Frampton MW. Do Ambient Ozone or Other Pollutants Modify Effects of Controlled Ozone Exposure on Pulmonary Function? Ann Am Thorac Soc. 2020 May;17(5):563-572. doi: 10.1513/AnnalsATS.201908-597OC.
• Arjomandi M, Balmes JR, Frampton MW, Bromberg P, Rich DQ, Stark P, Alexis NE, Costantini M, Hollenbeck-Pringle D, Dagincourt N, Hazucha MJ. Respiratory Responses to Ozone Exposure. MOSES (The Multicenter Ozone Study in Older Subjects). Am J Respir Crit Care Med. 2018 May 15;197(10):1319-1327. doi: 10.1164/rccm.201708-1613OC.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Anticipated): December 1, 2014
• Study Completion (Anticipated): December 1, 2014

Study Registration Dates

• First Submitted: December 1, 2011
• First Submitted That Met QC Criteria: December 5, 2011
• First Posted (Estimate): December 7, 2011

Study Record Updates

• Last Update Posted (Estimate): June 11, 2012
• Last Update Submitted That Met QC Criteria: June 8, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: inflammation; vascular function; ozone; air pollution; cardiac function
• Other Study ID Numbers: 10-01-4