Combustion Derived Air Pollution and Vascular Function

The Effects of Combustion-Derived Air Pollution on Vascular Vasomotor and Fibrinolytic Function in Healthy Volunteers (Diesel Exposure)

Air pollution is a major cause of cardiovascular morbidity and mortality. The components of air pollution responsible and the mechanisms through which they might mediate these harmful effects remain only partially understood. The link between cardiovascular disease and air pollution is strongest for fine particulate matter. Fine particulate matter (PM) is produced from the combustion of fossil fuels with the most significant threat thought to be posed by small particles less than 10µm (PM 10) which can be inhaled into the lungs. We propose to identify the precise component of diesel exhaust that mediates the adverse cardiovascular effects using a carbon particle generator, and a particle concentrator. The aim of this study proposal is to assess the vascular effects of different types and components of air pollution in healthy subjects. We intend to test the hypotheses that:

1. Combustion derived nanoparticulate causes an acute impairment of endothelial vasomotor and fibrinolytic function in healthy volunteers.
2. Exposure to combustion derived air pollution is associated with increased thrombus formation.

Study Overview

• Status: Completed
• Conditions: Endothelial Dysfunction
• Intervention / Treatment: Procedure: Forearm Vascular Study; Procedure: Badimon Chamber

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EH16 4SB
    • University of Edinburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy volunteers

Exclusion Criteria:

• Current smokers
• Significant occupational exposure to air pollution
• History of lung disease
• Women of child-bearing potential
• Malignant arrhythmias
• Renal or hepatic failure
• Significant co-morbidity
• Systolic blood pressure >190 or <100 mmHg
• Previous history of blood dyscrasia
• Unable to tolerate the supine position
• Lack of informed consent
• Blood donation within last 3 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Filtered Air Exposure; 1 hour exposure to filtered air during intermittent exercise	Procedure: Forearm Vascular Study; Forearm venous occlusion plethysmography to measure forearm blood flow during intra-arterial infusion of the vasodilators Verapamil (10-100 µg/min), bradykinin (100-1000 pmol/min), sodium nitroprusside (2-8 µg/min) and Acetylcholine (5-20 mg/min).; Other Names: BK; SNP; ACh; Procedure: Badimon Chamber; Ex-vivo assessment of thrombus formation using Badimon Chamber
Experimental: Diesel Exhaust Exposure; 1 hour exposure to dilute diesel exhaust at a concentration of 300 µg/m3 during intermittent exercise	Procedure: Forearm Vascular Study; Forearm venous occlusion plethysmography to measure forearm blood flow during intra-arterial infusion of the vasodilators Verapamil (10-100 µg/min), bradykinin (100-1000 pmol/min), sodium nitroprusside (2-8 µg/min) and Acetylcholine (5-20 mg/min).; Other Names: BK; SNP; ACh; Procedure: Badimon Chamber; Ex-vivo assessment of thrombus formation using Badimon Chamber
Experimental: Filtered Diesel Exposure; 1 hour exposure to diesel exhaust with all particulates filtered out using teflon filter with intermittent exercise	Procedure: Forearm Vascular Study; Forearm venous occlusion plethysmography to measure forearm blood flow during intra-arterial infusion of the vasodilators Verapamil (10-100 µg/min), bradykinin (100-1000 pmol/min), sodium nitroprusside (2-8 µg/min) and Acetylcholine (5-20 mg/min).; Other Names: BK; SNP; ACh; Procedure: Badimon Chamber; Ex-vivo assessment of thrombus formation using Badimon Chamber
Experimental: PALAS Exposure; 1 hour exposure to pure carbon particles produced by PALAS generator during intermittent exercise	Procedure: Forearm Vascular Study; Forearm venous occlusion plethysmography to measure forearm blood flow during intra-arterial infusion of the vasodilators Verapamil (10-100 µg/min), bradykinin (100-1000 pmol/min), sodium nitroprusside (2-8 µg/min) and Acetylcholine (5-20 mg/min).; Other Names: BK; SNP; ACh; Procedure: Badimon Chamber; Ex-vivo assessment of thrombus formation using Badimon Chamber

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Forearm blood flow measured by forearm venous occlusion plethysmography in response to infused vasodilators	6-8 hours after exposure

Secondary Outcome Measures

Outcome Measure	Time Frame
Ex-vivo thrombus formation assessed using the Badimon chamber	6 hours after exposure
Arterial stiffness measured by radial artery tonometry	Before and after exposure
Heart rate and heart rate variability measured with 3 lead Holter electrographic monitors	During and for 24 hours after exposure
Blood pressure	During and after exposure and during forearm study
Plasma t-PA and PAI concentrations following infusion of bradykinin	During forearm study
Plasma inflammatory markers IL-6, TNF-alpha, IL-1 and hsCRP	Before and after exposure
Platelet monocyte binding as measured by flow cytometry	After the exposure

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: National Institute for Public Health and the Environment (RIVM)
• Investigators: Principal Investigator: Nicholas L Mills, MB BCh MRCP, University of Edinburgh

Publications and helpful links

General Publications

• Mills NL, Tornqvist H, Robinson SD, Gonzalez M, Darnley K, MacNee W, Boon NA, Donaldson K, Blomberg A, Sandstrom T, Newby DE. Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis. Circulation. 2005 Dec 20;112(25):3930-6. doi: 10.1161/CIRCULATIONAHA.105.588962.
• Langrish JP, Watts SJ, Hunter AJ, Shah AS, Bosson JA, Unosson J, Barath S, Lundback M, Cassee FR, Donaldson K, Sandstrom T, Blomberg A, Newby DE, Mills NL. Controlled exposures to air pollutants and risk of cardiac arrhythmia. Environ Health Perspect. 2014 Jul;122(7):747-53. doi: 10.1289/ehp.1307337. Epub 2014 Mar 25.

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): March 1, 2006
• Study Completion (Actual): March 1, 2006

Study Registration Dates

• First Submitted: October 16, 2008
• First Submitted That Met QC Criteria: October 16, 2008
• First Posted (Estimate): October 17, 2008

Study Record Updates

• Last Update Posted (Estimate): October 17, 2008
• Last Update Submitted That Met QC Criteria: October 16, 2008
• Last Verified: October 1, 2008

More Information

Terms related to this study

• Keywords: Air Pollution; Endothelial function; Thrombosis; Vascular function; Particulate Matter; Particles
• Other Study ID Numbers: 05/S1103/46