Increased pulmonary serotonin transporter in patients with chronic obstructive pulmonary disease who developed pulmonary hypertension

Abstract

Purpose: Pulmonary hypertension (PH) is characterized by a progressive remodelling of the pulmonary vasculature resulting in right heart failure and eventually death. The serotonin transporter (SERT) may be involved in the pathogenesis of PH in patients with chronic-obstructive pulmonary disease (COPD). This study investigated for the first time the SERT in vivo availability in the lungs of patients with COPD and PH (COPD+PH).

Methods: SERT availability was assessed using SERT-selective [¹¹C]DASB and positron emission tomography/computed tomography (PET/CT) with dynamic acquisition over 30 min in 4 groups of 5 participants each: COPD, COPD+PH, pulmonary arterial hypertension, and a healthy control (HC). Time activity curves were generated based on a volume of interest within the middle lobe. Tissue-to-blood concentration ratios after 25 to 30 min (TTBR_25-30) served as receptor parameter for group comparison and were corrected for lung tissue attenuation. Participants underwent comprehensive pulmonary workup. Statistical analysis included group comparisons and correlation analysis.

Results: [¹¹C]DASB uptake peak values did not differ among the cohorts after adjusting for lung tissue attenuation, suggesting equal radiotracer delivery. Both the COPD and COPD+PH cohort showed significantly lower TTBR_25-30 values after correction for lung attenuation than HC. Attenuation corrected TTBR_25-30 values were significantly higher in the COPD+PH cohort than those in the COPD cohort and higher in non-smokers than in smokers. They positively correlated with invasively measured severity of PH and inversely with airflow limitation and emphysema. Considering all COPD patients ± PH, they positively correlated with right heart strain (NT-proBNP).

Conclusion: By applying [¹¹C]DASB and PET/CT, semiquantitative measures of SERT availability are demonstrated in the lung vasculature of patients with COPD and/or PH. COPD patients who developed PH show increased pulmonary [¹¹C]DASB uptake compared to COPD patients without PH indicating an implication of pulmonary SERT in the development of PH in COPD patients.

Keywords: Chronic obstructive pulmonary disease; Computed tomography; Positron emission tomography; Pulmonary hypertension; Serotonin transporter.

Fig. 1

Artwork showing study design and study procedures. (a) Description of cohort’s characteristics (± emphysema, ± vasculopathy). (b) Pathway of [¹¹C]DASB through the vascular system with binding to serotonin transporter (SERT) on the pulmonary artery smooth muscle cell (PASMC) surface. (c) Time points of PET acquisitions and blood sampling after [¹¹C]DASB administration (d) Representative coregistered transversal PET/CT image of a patient with COPD and PH showing a manually and click-wise selected volume of interest (VOI) in the middle lobe of the lung. On right side of the PET/CT image, a color scale shows the range of SUV values. 5-HT 5-hydroxtryptamine, A adventitia, Cl^- chloride ion, COPD chronic obstructive pulmonary disease, EC endothelial cell, HC healthy control, I intima, L lumen, n number of participants, Na⁺ sodium ion, M media, min minute, PAH pulmonary arterial hypertension, PASMC pulmonary arterial smooth muscle cells, PH pulmonary hypertension, SUV standardized uptake value, TPH1 tryptophan hydroxylase 1

Fig. 2

Time activity curves of pulmonary [¹¹C]DASB uptake measured within the middle lobe. The time course of [¹¹C]DASB uptake is made of the individual measuring points of each participant and is overlaid with mean values ± 95% confidence interval. The labelling of the axes applies to all panels within the figure, respectively. Each panel contains a representative transversal PET image including the middle lobe at 25- to 30-min post injection, and a black-white scale showing the range of SUV values. CI confidence interval, COPD chronic obstructive pulmonary disease, HC healthy control, PAH pulmonary arterial hypertension, PH pulmonary hypertension, SUV standardized uptake value, VOI volume of interest

Fig. 3

Group comparisons of lung tissue attenuation and pulmonary [¹¹C]DASB uptake between the cohorts. (a) Distribution of lung tissue attenuation values among the cohorts measured in HU derived from CT imaging. Overall differences were calculated by means of ANOVA. (b) Group comparison of maximum pulmonary [¹¹C]DASB uptake between the cohorts: After correction for blood activity (TTBR_max) and for attenuation values by means of ANCOVA, the maximum pulmonary [¹¹C]DASB uptake, i.e., pulmonary blood flow, did not differ between the cohorts. (c) Group comparisons of [¹¹C]DASB uptake between the cohorts included the correction for blood activity (TTBR_25–30) and for lung tissue attenuation by means of ANCOVA. (d) Group differences in TTBR_25–30 of [¹¹C]DASB in relation to smoking status. Statistical significance was accepted at a level of a two-sided P < 0.05. Statistically non-significant comparisons are not labelled, *P < 0.05, **P < 0.01. Group differences are shown by mean ± standard deviation. ANCOVA analysis of covariance, ANOVA analysis of variance, COPD chronic obstructive pulmonary disease, HC healthy control, n.s. not significant, PAH pulmonary arterial hypertension, PH pulmonary hypertension, SD standard deviation, TTBR tissue-to-blood concentration ratio

Fig. 4

Scatter plots of [¹¹C]DASB uptake and hemodynamic (a, b) and clinical parameters (c–h). Partial Spearman rank correlation analysis was performed to correct for lung tissue attenuation. Results are depicted as Spearman rank correlation coefficient rho (ρ). Statistical significance was accepted at a two-sided P < 0.05. The labelling of the abscissa applies to all panels. 6MWD 6-min walking distance, COPD chronic obstructive pulmonary disease, FEV₁ forced expiratory volume in 1 s, FVC forced vital capacity, HC healthy control, PaO₂/FiO₂ oxygenation ratio: arterial oxygen tension/inspiratory oxygen fraction, PAH pulmonary arterial hypertension, PAPm mean pulmonary arterial pressure, PaCO₂ arterial oxygen tension, PH pulmonary hypertension, PVR pulmonary vascular resistance, RV residual volume, TLC total lung capacity, TTBR_25-30 tissue-to-blood concentration ratio after 25 to 30 minutes of [¹¹C]DASB administration