Impaired flow-mediated dilation is associated with low pulmonary function and emphysema in ex-smokers: the Emphysema and Cancer Action Project (EMCAP) Study

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 +/- 5 years, 46% were female, and pack-years averaged 48 +/- 26. Mean FMD was 3.8 +/- 3.1%; mean post-bronchodilator FEV(1), 2.3 +/- 0.8 L; and mean CT percentage of emphysema, 26 +/- 10%. A 1 SD decrease in FMD was associated with a 132-ml (95% confidence interval, 16-248 ml; P = 0.03) decrement in post-bronchodilator FEV(1) and a 2.6% (95% confidence interval, 0.5-4.7%; P = 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 = 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.

Figure 1.

Multivariate association of the post-bronchodilator FEV₁ and flow-mediated dilation (FMD) of the brachial artery in former smokers. Solid line = smoothed regression line adjusted for covariates listed in Table 3, model 3; dashed lines = 95% confidence intervals; vertical lines = rug plot of data points. The multivariate relationship between FEV₁ and FMD was statistically significant (P = 0.02). The smoothed curve did not differ significantly from a straight line (P = 0.30), suggesting a linear relationship between FEV₁ and FMD.

Figure 2.

Multivariate association of the computed tomography (CT) percentage of emphysema and flow-mediated dilation (FMD) of the brachial artery in former smokers. Solid line = smoothed regression line adjusted for covariates listed in Table 3, model 3; dashed lines = 95% confidence intervals; vertical lines = rug plot of data points. The multivariate relationship between CT percentage of emphysema and FMD was statistically significant (P = 0.005). The smoothed curve did not differ significantly from a straight line (P = 0.24), suggesting a linear relationship between CT percentage of emphysema and FMD.