© 2007 American Thoracic Society doi: 10.1164/rccm.200709-1428ED
Vascular Structure and Function in Chronic Obstructive Pulmonary DiseaseA Chicken and Egg Issue?
Cardiff University There is an inverse relationship between FEV1 and cardiovascular risk in the general population (1), which is reflected in the link between airway obstruction and cardiovascular events in chronic obstructive pulmonary disease (COPD) (2, 3). In such patients, cardiovascular mortality is increased two- to threefold (3–5), independent of smoking and other risk factors (5). Although the mechanisms underlying the relationship between COPD and cardiovascular disease are currently unknown, alterations in arterial stiffness and endothelial function are likely to be important, since they both predict cardiovascular risk in a number of diseases and healthy populations (6, 7). This is in keeping with the accepted view that COPD is a precursor of cardiovascular disease. However, there is growing evidence that microvascular changes in response to cigarette smoking are important in early alveolar injury and the development of emphysema. Thus, is there a shared pathophysiologic mechanism linking early pulmonary vascular changes and later cardiovascular disease? Two studies in this issue of the Journal (pp. 1200–1207 and pp. 1208–1214) provide further information on the relationship between COPD and cardiovascular disease. Barr and colleagues (8) report a relationship among FEV1, percentage of emphysema on computed tomography (CT), and endothelial function in an unselected sample of ex-smokers studied in the Emphysema and Cancer Action Project (EMCAP). Endothelial function was determined by flow-mediated dilatation (FMD) (7), a validated measure of endothelium-dependent nitric oxide vasodilatation. In fully adjusted regression models, a fall in FMD by 1 SD, indicating endothelial dysfunction, was associated with a 132-ml decrease in FEV1 and a 2.6% increase in CT percentage of emphysema (both P < 0.05). These associations were independent of age and other confounders of endothelial function, and were present across the spectrum of airway obstruction and in subjects with nonobstructive post-bronchodilator spirometry. The authors suggest that their findings could be explained in the context of reduced expression of vascular endothelin growth factor, and that endothelial dysfunction may be directly implicated in the pathogenesis of COPD. However, an equally likely explanation is that factors associated with COPD, such as tissue hypoxia, oxidative stress, and systemic inflammation, may lead to endothelial dysfunction. An important finding in this study is that the association between FEV1 and FMD was entirely attributable to CT percentage of emphysema, suggesting that anatomic emphysema, rather than airway obstruction, is responsible for impaired vascular function. The concept that anatomic emphysema leads to pulmonary vascular changes is not new. Alterations in vascular structure and vessel compression secondary to emphysema are believed to have a role in the pathogenesis of pulmonary hypertension in COPD (9). Furthermore, pulmonary vascular endothelial dysfunction has been demonstrated at both ends of the COPD spectrum and is also implicated in the pathogenesis of pulmonary hypertension (10, 11). However, this does not answer the question of how emphysematous changes in the lung are associated with later degenerative disease in the extrapulmonary vasculature? The study by McAllister and colleagues (12) in this issue of the Journal also explored the relationship between emphysema and systemic vascular function. This cross-sectional analysis demonstrated a relationship between emphysema severity by high-resolution CT scanning and brachial artery pulse-wave velocity, an indicator of arterial stiffness, independent of confounders such as age and smoking and even airway obstruction. The authors speculate that this relationship may be mediated by similar alterations in the content and architecture of elastin in the lung and the vasculature. Such alterations may be genetically predetermined or acquired as a result of increased activity of elastolytic enzymes. Although this study provides new insights into the relationship between emphysema and the systemic vasculature, its results must interpreted with caution. The brachial artery is predominantly a muscular artery and, as such, is affected by a range of factors influencing vascular smooth muscle tone. As the authors comment, carotid-femoral (aortic) pulse-wave velocity, a measure of large elastic artery stiffness, would have been the ideal choice when investigating the relationship between emphysema and systemic vascular function. Furthermore, aortic pulse-wave velocity is considered the gold-standard measure of arterial stiffness and, in contrast to brachial pulse-wave velocity, is a proven predictor of cardiovascular risk (6, 13). Taken together, these studies offer further insight into the effects of COPD, in particular the emphysematous form, on vasculature structure and function, and suggest that the lungs and vasculature are involved in similar or parallel pathologic processes. Although the two groups investigated different aspects of the vascular function, the results are complementary since it is widely accepted that endothelial function is an important factor influencing arterial stiffness (14). Moreover, both studies suggest that anatomic emphysema, rather than FEV1, is important when considering the effects of COPD on systemic vascular function. Such conclusions are supported by recent evidence of increased arterial stiffness and endothelial dysfunction in patients with COPD compared with matched control subjects (15). Furthermore, the association of arterial stiffness with osteoporosis could be interpreted as adding further to the concept of a wide-scale alteration in connective tissue physiology in COPD. Both studies raise a number of important questions. If the effects of emphysema on vascular structure and function occur independently of FEV1, does this mean that patients with COPD and chronic bronchitis are less susceptible to cardiovascular disease? At least one report would argue against this hypothesis (16). What is the role of systemic inflammation and oxidative stress in the relationship between emphysema and vascular structure and function? Perhaps the most important question is whether any interventions to improve arterial stiffness and endothelial function will be effective in reducing cardiovascular and overall mortality in patients with COPD. Further studies, in particular large-scale longitudinal studies, to describe the natural history of the association between COPD and cardiovascular disease are now needed to answer these important questions. FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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