Experimental Exposure to Air Pollutants and Sympathetic Nerve Activity in Human Subjects (Particles)

The primary hypothesis of the study is that in healthy elderly subjects experimental exposure to air pollutants increases sympathetic nervous system activity compared with sham (clean air) exposure. The secondary hypothesis of the study is that combined experimental exposure to air pollutants (particles + ozone) increases sympathetic nervous system activity to a greater extent than does the exposure to particles alone.

Study Overview

• Status: Unknown
• Conditions: Cardiovascular Morbidity
• Intervention / Treatment: Other: ultrafine particles; Other: ultrafine particles and ozone; Other: clean air

Detailed Description

In a randomized, double-blind, and cross-over fashion, the participants will be exposed to clean air, ultrafine particles, or ultrafine particles and ozone in an exposure chamber. The investigators will determine blood pressure, heart rate, respiration as well as cardiac output and directly record sympathetic vasomotor tone using the microneurography technique. To elucidate the underlying mechanisms through which particles and ozone affect the autonomic nervous system, the investigators will assess the local and systemic inflammatory response as well as the changes in neurotrophic factors in sputum and blood. In addition, the activation of inflammatory cells in sputum and blood will be analyzed at different points in time after exposures. Changes in sympathetic activity will be correlated with the degree of airway inflammation and oxidative stress assessed in induced sputum and blood. This study will provide important insight in the mechanisms through which air pollution, particularly ultrafine particle exposure, increases cardiovascular risk in human subjects and generate a human model for mechanistic and therapeutic studies.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Hannover, Germany, 30625
    • Recruiting
    • Hannover Medical School
    • Contact: Marcus May, MD; Phone Number: 2722 +49 511 532; Email: may.marcus@mh-hannover.de
    • Sub-Investigator: Marcus May, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Elderly man or postmenopausal woman older than 50 years of age.
• Signed written informed consent.

Exclusion Criteria:

• Smoker.
• Cardiovascular and/or pulmonary disease.
• Medication with relevant impact on autonomic system function, e. g. norepinephrine reuptake inhibitors. Stable medication with slight to moderate autonomic effects is tolerable.
• Subject is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol.
• Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study.
• Subject unlikely to comply with protocol, e. g. uncooperative attitude or unlikelihood of completing the study.
• Known hypersensitivity to ozone.
• History of drug or alcohol abuse. Particles Study - Protocol version: October 19, 2012 14
• Blood donation of more than 500 mL during the previous 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ultrafine particles; Subjects will be exposed to ultrafine particles for three hours in an exposure chamber. During that time participants will perform intermittent bicycle ergometer training. Training intensity is adjusted individually to increase ventilation to 20 l/min/m². During exposure, heart rate will be monitored continuously via ECG. Blood pressure will be measured every 15 minutes. Ultrafine elemental carbon black particles are generated using a commercially available electric spark generator. Particle number, mass, and size distribution will be monitored during exposure.	Other: ultrafine particles; exposure to ultrafine particles
Active Comparator: ultrafine particles and ozone; Subjects will be exposed to ultrafine particles for three hours in an exposure chamber. During that time participants will perform intermittent bicycle ergometer training. Training intensity is adjusted individually to increase ventilation to 20 l/min/m². During exposure, heart rate will be monitored continuously via ECG. Blood pressure will be measured every 15 minutes. Ultrafine elemental carbon black particles are generated using a commercially available electric spark generator. Particle number, mass, and size distribution will be monitored during exposure.Ozone is generated from medical oxygen in order to maintain a concentration of 250 ppb.	Other: ultrafine particles and ozone; exposure to ultrafine particles and ozone
Placebo Comparator: clean air; Subjects will be exposed to clean air for three hours in an exposure chamber controlled for temperature, humidity, and gas/particle composition. During that time they will perform intermittent bicycle ergometer training for 15 minutes alternating with 15 minutes rest. Training intensity is adjusted individually to increase ventilation to 20 l/min/m². During exposure, heart rate will be monitored continuously via ECG. The blood pressure will be measured in time intervals of 15 minutes.	Other: clean air; Exposure to clean air.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle sympathetic nerve activity (MSNA)	Change of sympathetic vasoconstrictor nerve activity directed to skeletal muscle expressed as sympathetic bursts per minute. The primary hypothesis of the study is that in healthy elderly subjects experimental exposure to air pollutants increases sympathetic nervous system activity compared with sham (clean air) exposure.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MSNA burst incidence	Change of MSNA expressed as bursts/100 heart beats.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
total MSNA	Change of MSNA expressed as burst area/min.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood pressure	Change of blood pressure in mmHg.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
Heart rate	Change of heart rate in beat per minute.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
Cardiac output	Change of cardiac output in l/min.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
Total peripheral resistance	Change in total peripheral resistance expressed as dyn*s/cm^5.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
Heart rate variability.	Change in heart rate variability parameters in the time and frequency domain.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
Plasma norepinephrine concentration	Change of plasma norepinephrine in ng/l.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
Plasma renin concentration	Change of plasma renin concentration in	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
Baroreflex sensitivity	Change in baroreflex sensitivity expressed as ms/mmHg.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
Inflammation parameters	Change of the percentage of neutrophils in induced sputum.	3.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
Oxidative stress parameters	Change of plasma malondialdehyde(MDA)concentration.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
Correlation between inflammation, oxidative stress and cardiovascular regulation	Correlation coefficients between changes in parameters for inflammation and oxidative stress with changes in cardiovascular parameters.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
Forced expiratory volume in one second (FEV1)	Change in FEV1 in l	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
Forced vital capacity (FVC)	Change in FVC in l.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone
Percentage of neutrophils in peripheral blood	Change of percentage of neutrophils in peripheral blood.	2.5 hours after exposure to clean air, to ultrafine particles, or to a combination of ultrafine particles and ozone

Collaborators and Investigators

• Sponsor: Hannover Medical School
• Collaborators: Fraunhofer-Institute of Toxicology and Experimental Medicine

Publications and helpful links

General Publications

• Tank J, Biller H, Heusser K, Holz O, Diedrich A, Framke T, Koch A, Grosshennig A, Koch W, Krug N, Jordan J, Hohlfeld JM. Effect of acute ozone induced airway inflammation on human sympathetic nerve traffic: a randomized, placebo controlled, crossover study. PLoS One. 2011 Apr 8;6(4):e18737. doi: 10.1371/journal.pone.0018737.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Anticipated): December 1, 2015
• Study Completion (Anticipated): December 1, 2015

Study Registration Dates

• First Submitted: July 30, 2013
• First Submitted That Met QC Criteria: July 31, 2013
• First Posted (Estimate): August 2, 2013

Study Record Updates

• Last Update Posted (Estimate): August 2, 2013
• Last Update Submitted That Met QC Criteria: July 31, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: autonomic nervous system; inflammation; oxidative stress; cytokine; heart rate variability; ozone; air pollution; chemokine; sympathetic nerve activity; fine particle; plasma catecholamine
• Other Study ID Numbers: MHH-Particles EK-6142