Impaired Flow-mediated Dilation Is Associated with Low Pulmonary Function and Emphysema in Ex-smokers

Abstract

Rationale: Basic science research suggests a causal role for endothelial dysfunction in chronic obstructive pulmonary disease (COPD). Clinical studies examining endothelial function are lacking, particularly early in the disease. Flow-mediated dilation (FMD) is a physiologic measure of endothelial reactivity to endogenous nitric oxide. Objectives: We hypothesized that lower FMD among former smokers would be associated with lower post-bronchodilator FEV 1 , higher percentage of emphysema using computed tomography (CT) and lower diffusing capacity. Methods: We measured FMD, pulmonary function, and CT percentage of emphysema in a random sample of 107 cotinine-confirmed former smokers in the ongoing EMCAP study. FMD was defined as percentage change in the brachial artery diameter with reactive hyperemia. Generalized additive models were used to adjust for potential confounders and assess linearity. Measurements and Main Results: Mean age of participants was 71 6 5 years, 46% were female, and pack-years averaged 48 6 26. Mean FMD was 3.8 6 3.1%; mean post-bronchodilator FEV 1 , 2.3 6 0.8 L; and mean CT percentage of emphysema, 26 6 10%. A 1 SD decrease in FMD was associated with a 132-ml (95% confidence interval, 16-248 ml; P 5 0.03) decrement in post-bronchodilator FEV 1 and a 2.6% (95% confidence interval, 0.5-4.7%; P 5 0.02) increase in CT percentage of emphysema in fully adjusted models. These associations were linear across the spectrum from normality to disease, independent of smoking history, and also significant among participants without COPD. Associations with diffusing capacity were consistent but nonsignificant (P 5 0.09). The FMD-FEV 1 association was entirely attributable to percentage of emphysema. Conclusions: Impaired endothelial function, as measured by FMD, was associated with lower FEV 1 and higher CT percentage of emphysema in former smokers early in COPD.Keywords: pulmonary disease, chronic obstructive; bronchitis, chronic; pulmonary emphysema; endothelial dysfunction Recent research on the pathogenesis of chronic obstructive pulmonary disease (COPD) suggests that perturbations in the vasculature and, specifically, endothelial health may occur early in COPD (1). Decreased expression of vascular endothelial growth factor (VEGF) causes endothelial apoptosis, epithelial apoptosis, and emphysema (2-4). The second messenger lipid ceramide mediates VEGF blockade-induced apoptosis in COPD and ceramide instillation acutely triggers apoptosis in pulmonary endothelial cells, causing emphysema in mice (5).Apoptotic endothelial cells are present in the lungs of smokers with COPD (6, 7), and there are significant morphologic differences in the endothelium of smokers with mild, moderate, and severe COPD compared with smokers without COPD (8). Furthermore, nitric oxide (NO)-mediated, endotheliumdependent relaxation provoked by adenosine diphosphate and acetylcholine is attenuated in the excised pulmonary arteries of patients with COPD compared with those of smoking and nonsmoking control subjects (9, 10). Publ...

Association of ex vivo vascular and bronchial dysfunctions in smokers

“…It has been shown that an impairment of flow-mediated dilation in systemic circulation occurs early in COPD, and is associated with airflow limitation, independently of smoking history, further suggesting a link between vascular and bronchial functions [1]. We suggest that in former smokers, endothelial dysfunction of pulmonary arteries is associated with impairment of both spontaneous resting tone and cGMP-mediated dilation of airways, establishing a biological link between pulmonary arterial and bronchial functions.…”

“…Recent researches on the pathogenesis of chronic obstructive pulmonary disease (COPD) suggest that perturbations in the vasculature may occur early in COPD [1][2][3]. Nitric oxide (NO)-mediated, endothelium-dependent relaxation provoked by adenosine diphosphate and acetylcholine is attenuated in the excised pulmonary arteries of patients with COPD compared with those of smoking and non-smoking control subjects [4].…”

“…Nitric oxide (NO)-mediated, endothelium-dependent relaxation provoked by adenosine diphosphate and acetylcholine is attenuated in the excised pulmonary arteries of patients with COPD compared with those of smoking and non-smoking control subjects [4]. Barr and colleagues demonstrated that impaired flow-mediated dilation, assessed by brachial artery flow-mediated dilation, is associated with low pulmonary function and emphysema in ex-smokers [1]. In this latter study, a linear relationship was demonstrated between flow-mediated dilation and postbronchodilator FEV 1 , and the magnitude of this association was the same in former smokers who had not developed COPD (FEV 1 /FVC ≥ 70%) as in the overall sample (mild to severe COPD).…”

“…Barr and colleagues demonstrated that impaired flow-mediated dilation, assessed by brachial artery flow-mediated dilation, is associated with low pulmonary function and emphysema in ex-smokers [1]. In this latter study, a linear relationship was demonstrated between flow-mediated dilation and postbronchodilator FEV 1 , and the magnitude of this association was the same in former smokers who had not developed COPD (FEV 1 /FVC ≥ 70%) as in the overall sample (mild to severe COPD). The authors postulated that the systemic nature of endothelial function made likely the alteration of endothelial reactivity in the pulmonary circulation.…”

Heart–Lung Interaction via Infection

“…The coexistence of COPD and CVD is acknowledged as an important clinical syndrome that is likely stimulated by common inflammatory pathways and is associated with poor outcomes, including increased use of health resources and mortality (1)(2)(3)(4)(5). COPD is associated with adverse cardiovascular effects, including increases in endothelial dysfunction, arterial stiffness, and atherogenesis, which are independent of the effects of cigarette smoking (1,(6)(7)(8). FEV 1 is an important independent predictor of CVD even in nonsmokers, and smokers with COPD are more likely to have CVD than smokers without COPD (9).…”