Andrew J. Lucking

Background: Traffic emissions including diesel engine exhaust are associated with increased respiratory and cardiovascular morbidity and mortality. Controlled human exposure studies have demonstrated impaired vascular function after inhalation of exhaust generated by a diesel engine under idling conditions. Objectives: To assess the vascular and fibrinolytic effects of exposure to diesel exhaust generated during urban-cycle running conditions that mimic ambient 'real-world' exposures. Methods: In a randomised double-blind crossover study, eighteen healthy male volunteers were exposed to diesel exhaust (approximately 250 μg/m³) or filtered air for one hour during intermittent exercise. Diesel exhaust was generated during the urban part of the standardized European Transient Cycle. Six hours post-exposure, vascular vasomotor and fibrinolytic function was assessed during venous occlusion plethysmography with intra-arterial agonist infusions. Measurements and Main Results: Forearm blood flow increased in a dose-dependent manner with both endothelial-dependent (acetylcholine and bradykinin) and endothelial-independent (sodium nitroprusside and verapamil) vasodilators. Diesel exhaust exposure attenuated the vasodilatation to acetylcholine (P < 0.001), bradykinin (P < 0.05), sodium nitroprusside (P < 0.05) and verapamil (P < 0.001). In addition, the net release of tissue plasminogen activator during bradykinin infusion was impaired following diesel exhaust exposure (P < 0.05). Conclusion: Exposure to diesel exhaust generated under transient running conditions, as a relevant model of urban air pollution, impairs vasomotor function and endogenous fibrinolysis in a similar way as exposure to diesel exhaust generated at idling. This indicates that adverse vascular effects of diesel exhaust inhalation occur over different running conditions with varying exhaust composition and concentrations as well as physicochemical particle properties. Importantly, exposure to diesel exhaust under ETC conditions was also associated with a novel finding of impaired of calcium channel-dependent vasomotor function. This implies that certain cardiovascular endpoints seem to be related to general diesel exhaust properties, whereas the novel calcium flux-related effect may be associated with exhaust properties more specific for the ETC condition, for example a higher content of diesel soot particles along with their adsorbed organic compounds.

Exposure to urban particulate matter has been associated with an increased risk of cardiovascular disease and thrombosis. We studied the effects of transient exposure to diesel particles on fibrin clot structure of 16 healthy individuals (age 21- 44). The subjects were randomly exposed to diesel exhaust and filtered air on two separate occasions. Blood samples were collected before exposure, and 2 and 6 hours after exposure. There were no significant changes on clot permeability, maximum turbidity, lag time, fibre diameter, fibre density and fibrinogen level between samples taken after diesel exhaust exposure and samples taken after filtered air exposure. These data show that there are no prothrombotic changes in fibrin clot structure in young, healthy individuals exposed to diesel exhaust.

Exposure to air pollution is associated with increased cardiovascular morbidity, although the underlying mechanisms are unclear. Vascular dysfunction reduces arterial compliance and increases central arterial pressure and left ventricular after-load. We determined the effect of diesel exhaust exposure on arterial compliance using a validated non-invasive measure of arterial stiffness.

Although the mechanism is unclear, exposure to traffic-derived air pollution is a trigger for acute myocardial infarction (MI). The aim of this study is to investigate the effect of diesel exhaust inhalation on platelet activation and thrombus formation in men. In a double-blind randomized crossover study, 20 healthy volunteers were exposed to dilute diesel exhaust (350 µg/m³) and filtered air. Thrombus formation, coagulation, platelet activation, and inflammatory markers were measured at 2 and 6 h following exposure. Thrombus formation was measured using the Badimon ex vivo perfusion chamber. Platelet activation was assessed by flow cytometry. Compared with filtered air, diesel exhaust inhalation increased thrombus formation under low- and high-shear conditions by 24% [change in thrombus area 2229 µm², 95% confidence interval (CI) 1143–3315 µm², P = 0.0002] and 19% (change in thrombus area 2451 µm², 95% CI 1190–3712 µm², P = 0.0005), respectively. This increased thrombogenicity was seen at 2 and 6 h, using two different diesel engines and fuels. Diesel exhaust also increased platelet–neutrophil and platelet–monocyte aggregates by 52% (absolute change 6%, 95% CI 2–10%, P = 0.01) and 30% (absolute change 3%, 95% CI 0.2–7%, P = 0.03), respectively, at 2 h following exposure compared with filtered air. Inhalation of diesel exhaust increases ex vivo thrombus formation and causes in vivo platelet activation in man. These findings provide a potential mechanism linking exposure to combustion-derived air pollution with the triggering of acute MI.

Acute Coronary Syndromes account for 15% of deaths in the UK, and patients remain at significant risk of re-admission for future complications and death. Pathologically the underlying process of atherosclerosis is driven by inflammatory mechanisms, which are activated in ACS patients. Previous studies have investigated the role of inflammatory markers in this process, including interleukin 1 (IL-1) and C Reactive Protein (CRP). Pre-clinical studies indicate that IL-1 may be a primary driver of ACS and that the naturally occurring interleukin-1 receptor antagonist (IL-1ra) may inhibit the atherosclerotic process. This study will investigate the effects of IL-1ra on inflammatory markers in man. Three centres in the UK are planning to recruit 186 Non-ST elevation myocardial infarction patients to receive either interleukin-1 receptor antagonist (Anakinra) or matching placebo. Patients will receive a daily subcutaneous injection of either study drug or placebo over a 14 day period. The primary outcome is area under the curve of high sensitivity C-Reactive Protein (CRP) over the first 7 days. The MRC-ILA-HEART Study is a proof of concept clinical trial investigating the effects of IL-1ra upon markers of inflammation in patients with Non-ST elevation myocardial infarction. It is hoped this will provide new and exciting information in relation to an "anti-inflammatory" strategy for patients with acute coronary syndrome. ISRCTN89369318

Stent thrombosis is the major cause of early adverse events during percutaneous coronary intervention. Its incidence has fallen considerably in recent years, principally due to the introduction of effective antithrombotic therapies. The selection of an appropriate antithrombotic regimen is critical in achieving a balance between reducing ischaemic events and minimising bleeding complications in patients undergoing percutaneous coronary intervention. In this article, evidence for the role of antiplatelet and anticoagulant therapies is discussed, including the thienopyridines, glycoprotein IIb/IIIa receptor antagonists, direct thrombin inhibitors and pentasaccharides.