Chronic obstructive pulmonary disease (COPD) is a significant burden on individuals
with the disease and on healthcare resources. By 2020 it is projected to be the third
leading cause of death worldwide. COPD is a condition that is characterised by
chronic lung inflammation and damage. However, it is now known that COPD not
only affects the lungs, but also has systemic associations, effects and consequences.
These include osteoporosis, skeletal muscle wasting and dysfunction, depression,
anaemia, systemic inflammation and cardiovascular disease. Population based studies
have identified that COPD is a risk factor for cardiovascular morbidity and mortality,
independent of traditional risk factors including cigarette smoking. The mechanisms
responsible for this association have yet to be established.In the studies in this thesis, I investigated a number of novel mechanisms that may
contribute to the increased cardiovascular risk in COPD. It is thought that the lowgrade systemic inflammation associated with COPD may have a role to play. In
addition, the enhanced systemic inflammatory response in exacerbations of COPD
may predispose these individuals to cardiovascular events. Activation of platelets and
interaction between platelets and monocytes are early processes in the pathogenesis of
atherothrombosis. I therefore measured markers of platelet activation in patients with
COPD and healthy controls. In a second study, platelet activation was measured in
patients admitted to hospital with an exacerbation of COPD and in convalescence.
Patients with COPD had higher platelet-monocyte aggregation in comparison to
controls matched for age and cigarette smoke exposure. This was further increased
during exacerbations.In addition to platelet activation, vascular dysfunction predisposes to cardiovascular
morbidity and mortality. I undertook comprehensive assessments of vascular function
(arterial stiffness, endothelial vasomotor function and endogenous fibrinolysis) in
patients with COPD and healthy ex-smoking controls. I confirmed that patients with
COPD have increased arterial stiffness independent of cigarette smoking. However,
contrary to prior popular assumption, endothelial vasomotor and fibrinolytic function
were not impaired in comparison to healthy controls matched for smoking history.We had previously reported an association between emphysema severity and arterial
stiffness. I hypothesised that the mechanism for this association in COPD patients
may be increased elastin degradation, not only in the lungs, but also in the large
arteries. To test the hypothesis that COPD is a condition with systemic elastin
degradation, I measured elastin degradation in skin biopsies from patients with COPD
and healthy controls. There was increased cutaneous elastin degradation in COPD
patients. In addition, there was increased expression of matrix metalloproteinases in
COPD skin biopsies, which may be a mechanism for this observation. Furthermore,
emphysema severity and arterial stiffness were associated with cutaneous elastin
degradation.These studies have identified platelet activation and arterial stiffness as novel
mechanisms for the development of cardiovascular disease in COPD. Platelet
inhibition and improvement of vascular function represent plausible targets for the
prevention of cardiovascular events in this population. In addition, I have provided
evidence for elastin degradation as a systemic effect of COPD and that systemic
upregulation of matrix metalloproteinases may be the unifying mechanism for this.
Focus on inflammatory pathways that result in this will provide more insight into the
pathogenesis of COPD and help direct future therapies
