Quantitative Dual-Energy Computed Tomography Supports a Vascular Etiology of Smoking-induced Inflammatory Lung Disease

Abstract

Rationale: Endothelial dysfunction is of interest in relation to smoking-associated emphysema, a component of chronic obstructive pulmonary disease (COPD). We previously demonstrated that computed tomography (CT)-derived pulmonary blood flow (PBF) heterogeneity is greater in smokers with normal pulmonary function tests (PFTs) but who have visual evidence of centriacinar emphysema (CAE) on CT.

Objectives: We introduced dual-energy CT (DECT) perfused blood volume (PBV) as a PBF surrogate to evaluate whether the CAE-associated increased PBF heterogeneity is reversible with sildenafil.

Methods: Seventeen PFT-normal current smokers were divided into CAE-susceptible (SS; n = 10) and nonsusceptible (NS; n = 7) smokers, based on the presence or absence of CT-detected CAE. DECT-PBV images were acquired before and 1 hour after administration of 20 mg oral sildenafil. Regional PBV and PBV coefficients of variation (CV), a measure of spatial blood flow heterogeneity, were determined, followed by quantitative assessment of the central arterial tree.

Measurements and main results: After sildenafil administration, regional PBV-CV decreased in SS subjects but did not decrease in NS subjects (P < 0.05), after adjusting for age and pack-years. Quantitative evaluation of the central pulmonary arteries revealed higher arterial volume and greater cross-sectional area (CSA) in the lower lobes of SS smokers, which suggested arterial enlargement in response to increased peripheral resistance. After sildenafil, arterial CSA decreased in SS smokers but did not decrease in NS smokers (P < 0.01).

Conclusions: These results demonstrate that sildenafil restores peripheral perfusion and reduces central arterial enlargement in normal SS subjects with little effect in NS subjects, highlighting DECT-PBV as a biomarker of reversible endothelial dysfunction in smokers with CAE.

Keywords: COPD; emphysema; endothelial dysfunction; pulmonary blood flow; sildenafil.

Figures

Figure 1.

The process of pulmonary blood volume (PBV) imaging from acquisition, data collection, processing, and comparison of regional PBV measures. (A) Dual-energy computed tomography (DECT) PBV imaging is performed using 80-kVp and Sn140-kVp energies, detectors 95° apart, which acquires low- and high-energy contrast-enhanced CT images. (B) Axial CT images obtained after the test bolus injection were used to determine where to draw a region of interest in the left atrium to compute a time versus contrast density curve (red circle). This curve was used to establish the delay time in seconds necessary between the start of contrast injection and the start of the DECT acquisition. The delay time was determined by computing the interval in seconds between the start of contrast injection and the contrast density reaching 100 Hounsfield units (HU) in the left atrium (vertical line). (C) Images derived from 80-kVp and Sn140-kVp data used to calculate PBV maps. (D) Global and regional PBV analysis, showing lung mask outlining only the lung parenchyma. Large vessels and airways are excluded. (E) Image registration: images are warped from Sn140-kVp images (post is moving, pre is target). The displacement for this registration is used to warp the postsildenafil PBV image to the presildenafil PBV image. This is done to ensure accurate comparison of the coefficients of variation for the same regions before and after sildenafil. CV = coefficient of variation.

Figure 2.

Example of pulmonary blood volume–coefficient of variation (PBV-CV) measures derived from dual-energy computed tomography images for nonsusceptible smoker (NS) and susceptible smoker (SS) subjects. (A) The whole lung was divided into dependent, middle, and nondependent thirds by vertical height, and the PBV-CVs were calculated for each of these regions. (B and C) A representative SS and NS subject (SS-1 and NS-1) before and after sildenafil, using image matching. PBV images divided into 30 × 30 × 40 regions of interest were used to compute PBV-CV for each region. Midcoronal sections from subject SS-1 (top row) and NS-1 (bottom row) are depicted in B with presildenafil images on the left and postsildenafil images on the right. CVs for each region are scaled as per color bars shown in the middle of each image pair. (C) A representative CV histogram for SS-1/NS-1 subjects before and after sildenafil.

Figure 3.

Regional and whole-lung pulmonary blood volume–coefficient of variation (PBV-CV) changes before and after sildenafil. The PBV images for nonsusceptible smoker (NS) (white bars; ±SE) and susceptible smoker (SS) (gray bars; ±SE) subjects were divided by vertical height into the nondependent (ventral), middle, and dependent (dorsal) regions, depicted in the lower left sagittal PBV image. The relative percent change [i.e., (postsildenafil − presildenafil)/presildenafil] in CV in response to sildenafil for the SS subjects significantly decreased for each lung region, whereas there were no significant changes in CV in any of the lung regions for the NS subjects. *P < 0.01, within SS subjects (presildenafil vs. postsildenafil).

Figure 4.

Volumetric computed tomography evaluation of total pulmonary arterial volume before and after sildenafil. The normalized pulmonary arterial tree volume (TPAVnorm) of the right lower lobe (RLL) was identified as the largest in susceptible smoker (SS) subjects before sildenafil (upper left inset). The relative (Rel) change in TPAVnorm from before to after sildenafil was inversely correlated with the RLL–pulmonary blood volume (PBV) change in SS subjects (R2 = 0.62) but not in nonsusceptible smoker (NS) subjects (R2 = 0.13).

Figure 5.

Volumetric computed tomography evaluation of arterial cross-sectional area (CSA) before and after sildenafil. (A and B) Segmental branches of the arterial tree (associated with the RB10 and LB10 bronchial segments) were sampled in the right and left lower lobes. (A) RB10 (left side) and LB10 (right side) airway-associated arterial segments are in red. (B) RB10 CSA (green) and associated arterial segment (blue) are shown with their superposition in top left for a susceptible smoker (SS) subject and a nonsusceptible smoker (NS) subject. (C) Arterial CSA normalized to the airway CSA area (CSAnorm) was significantly larger in SS subjects before sildenafil, and this relationship was eliminated after sildenafil. (D) Pre- to postsildenafil change in CSAnorm in SS and NS subjects. Art. = arterial; Norm. = normalized; Rel = relative.