Preacinar Arterial Dilation Mediates Outcomes of Quantitative Interstitial Abnormalities in the COPDGene Study

Abstract

Rationale: Quantitative interstitial abnormalities (QIAs) are a computed tomography (CT) measure of early parenchymal lung disease associated with worse clinical outcomes, including exercise capacity and symptoms. The presence of pulmonary vasculopathy in QIAs and its role in the QIA-outcome relationship is unknown. Objectives: To quantify radiographic pulmonary vasculopathy in QIAs and determine whether this vasculopathy mediates the QIA-outcome relationship. Methods: Ever-smokers with QIAs, outcomes, and pulmonary vascular mediator data were identified from the Genetic Epidemiology of COPD (COPDGene) study cohort. CT-based vascular mediators were right ventricle-to-left ventricle ratio, pulmonary artery-to-aorta ratio, and preacinar intraparenchymal arterial dilation (pulmonary artery volume, 5-20 mm² in cross-sectional area, normalized to total arterial volume). Outcomes were 6-minute walk distance and a modified Medical Council Research Council Dyspnea Scale score of 2 or higher. Adjusted causal mediation analyses were used to determine whether the pulmonary vasculature mediated the QIA effect on outcomes. Associations of preacinar arterial dilation with select plasma biomarkers of pulmonary vascular dysfunction were examined. Measurements and Main Results: Among 8,200 participants, QIA burden correlated positively with vascular damage measures, including preacinar arterial dilation. Preacinar arterial dilation mediated 79.6% of the detrimental impact of QIA on 6-minute walk distance (56.2-100%; P < 0.001). Pulmonary artery-to-aorta ratio was a weak mediator, and right ventricle-to-left ventricle ratio was a suppressor. Similar results were observed in the relationship between QIA and modified Medical Council Research Council dyspnea score. Preacinar arterial dilation correlated with increased pulmonary vascular dysfunction biomarker levels, including angiopoietin-2 and N-terminal brain natriuretic peptide. Conclusions: Parenchymal QIAs deleteriously impact outcomes primarily through pulmonary vasculopathy. Preacinar arterial dilation may be a novel marker of pulmonary vasculopathy in QIAs.

Keywords: QIAs; clinical outcomes; interstitial lung disease; pulmonary hypertension; pulmonary vasculopathy.

Figure 1.

CONSORT flow diagram showing patient selection from the Genetic Epidemiology of COPD (COPDGene) study. 6MWD = 6-minute walk distance; mMRC = modified Medical Research Council Dyspnea Scale score; QIA = quantitative interstitial abnormality; TLC_CT = TLC on computed tomography (in liters).

Figure 2.

Example of computed tomography (CT) reconstructions of pulmonary vascular mediators. (A) An automated reconstruction of cardiac chambers used to compute volumes of right (purple) and left (pink) ventricles. Right (light blue) and left (orange) atria are also included. (B) Ratio of pulmonary artery (21.6 mm) to aorta (26.5 mm) (PA/Ao). (C) The reconstructed pulmonary arterial vasculature from the right lung of a nonsmoking COPDGene participant. The preacinar arteries are displayed in yellow in the lung core (inner 80% of lung volume), with the remaining pulmonary tree displayed in blue. The vast majority of the vessels in the peel (the outer 20% of the lung) have a vascular cross-sectional area of less than 5 mm². Asc. Ao = ascending aorta; Desc. Ao = descending aorta; LA = left atrium; LPA = left pulmonary artery; LV = left ventricle; MPA = main pulmonary artery; RA = right atrium; RPA = right pulmonary artery; RV = right ventricle.

Figure 3.

Direct acyclic graphs (DAGs) displaying the relationship between exposure, outcome, and mediator. Left: the proposed DAGs for the outcome of 6-minute walk distance (6MWD). Right: the actual relationships determined through causal mediation analysis. The PM shows the percentage of the total effect mediated through the indirect pathway. The weight of the arrow approximates the amount of the effect of QIA on 6MWD through the respective pathway. BV5-20/TBV = arterial volume of vessels 5–20 mm² in cross-sectional area normalized to total arterial blood volume; LV = left ventricle; PA/Ao ratio = pulmonary artery–to–aorta ratio; PM = percentage mediated; QIA = quantitative interstitial abnormality; RV = right ventricle.

Figure 4.

OR for the presence of preacinar dilation by pulmonary vascular biomarker level within the subgroup with high quantitative interstitial abnormality (QIA) percentage (defined as ⩾4.48%). Expressed per unit change of 1 in natural log-transformed relative fluorescence units. *Adjusted for continuous QIA percentage. CI = confidence interval; GDF-15 = growth differentiation factor-15; NT-proBNP = N-terminal brain natriuretic peptide; OR = odds ratios.