Combustion Derived Air Pollution and Vascular Function

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

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

Conditions
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Endothelial Dysfunction

Intervention / Treatment
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* Procedure: Forearm Vascular Study
* Procedure: Badimon Chamber


Participation Criteria
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Eligibility Criteria
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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
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: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Filtered Air Exposure<br>1 hour exposure to filtered air during intermittent exercise | Procedure: Forearm Vascular Study<br>* 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).<br>* Other names: ACh;Procedure: Badimon Chamber<br>* Ex-vivo assessment of thrombus formation using Badimon Chamber<br>|
| Experimental: Diesel Exhaust Exposure<br>1 hour exposure to dilute diesel exhaust at a concentration of 300 µg/m3 during intermittent exercise | Procedure: Forearm Vascular Study<br>* 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).<br>* Other names: ACh;Procedure: Badimon Chamber<br>* Ex-vivo assessment of thrombus formation using Badimon Chamber<br>|
| Experimental: Filtered Diesel Exposure<br>1 hour exposure to diesel exhaust with all particulates filtered out using teflon filter with intermittent exercise | Procedure: Forearm Vascular Study<br>* 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).<br>* Other names: ACh;Procedure: Badimon Chamber<br>* Ex-vivo assessment of thrombus formation using Badimon Chamber<br>|
| Experimental: PALAS Exposure<br>1 hour exposure to pure carbon particles produced by PALAS generator during intermittent exercise | Procedure: Forearm Vascular Study<br>* 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).<br>* Other names: ACh;Procedure: Badimon Chamber<br>* Ex-vivo assessment of thrombus formation using Badimon Chamber<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Air Pollution, Particles, Particulate Matter, Vascular function, Endothelial function, Thrombosis