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Mircea Gabriel Stoleriu,1,2,&ast; Michael Pienn,3,4,&ast; Rudolf A Joerres,5 Peter Alter,6 Tamas Fero,7 Martin Urschler,8 Gabor Kovacs,3,9 Horst Olschewski,3,9 Hans-Ulrich Kauczor,7,10 Mark Wielpütz,7,10 Bertram Jobst,7,10 Tobias Welte,11 Jürgen Behr,2,12 Franziska C Trudzinski,10,13 Robert Bals,14,15 Henrik Watz,16 Claus F Vogelmeier,6 Jürgen Biederer,10,17,18,&ast; Kathrin Kahnert2,12,19,&ast; On behalf of the COSYCONET Study Group1Division for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich (LMU) and Asklepios Medical Center; Munich-Gauting, Gauting, 82131, Germany; 2Institute for Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive; Helmholtz Center Munich; Member of the German Lung Research Center (DZL), Munich, 81377, Germany; 3Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; 4Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 5Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Hospital of Ludwig-Maximilians-University Munich (LMU), Munich, 80336, Germany; 6Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, 35033, Germany; 7Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany; 8Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria; 9University Clinic for Internal Medicine, Medical University of Graz, Division of Pulmonology, Graz, Austria; 10Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research DZL, Heidelberg, Germany; 11Department of Respiratory Medicine and Infectious Disease, Member of the German Center of Lung Research, Hannover School of Medicine, Hannover, Germany; 12Department of Medicine V, LMU University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany; 13Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany; 14Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg, 66421, Germany; 15Helmholtz Institute for Pharmaceutical Research, Saarbrücken, 66123, Germany; 16Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Centre North, German Centre for Lung Research, Großhansdorf, Germany; 17Faculty of Medicine, Christian-Albrechts-Universität Zu Kiel, Kiel, Germany; 18University of Latvia, Faculty of Medicine, Riga, LV-1586, Latvia; 19MediCenterGermering, Germering, Germany&ast;These authors contributed equally to this workCorrespondence: Mircea Gabriel Stoleriu, Division of Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich (LMU) and Asklepios Lung Clinic Munich-Gauting, Marchioninistr. 15, 81377 Munich and Robert-Koch-Allee 2, Gauting, 82131, Germany, Tel +49 89 85791 4201, Email gabriel.stoleriu@helmholtz-munich.dePurpose: The aim of this study was to evaluate the association between computed tomography (CT) quantitative pulmonary vessel morphology and lung function, disease severity, and mortality risk in patients with chronic obstructive pulmonary disease (COPD).Patients and Methods: Participants of the prospective nationwide COSYCONET cohort study with paired inspiratory-expiratory CT were included. Fully automatic software, developed in-house, segmented arterial and venous pulmonary vessels and quantified volume and tortuosity on inspiratory and expiratory scans. The association between vessel volume normalised to lung volume and tortuosity versus lung function (forced expiratory volume in 1 sec [FEV1]), air trapping (residual volume to total lung capacity ratio [RV/TLC]), transfer factor for carbon monoxide (TLCO), disease severity in terms of Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D, and mortality were analysed by linear, logistic or Cox proportional hazard regression.Results: Complete data were available from 138 patients (39% female, mean age 65 years). FEV1, RV/TLC and TLCO, all as % predicted, were significantly (p < 0.05 each) associated with expiratory vessel characteristics, predominantly venous volume and arterial tortuosity. Associations with inspiratory vessel characteristics were absent or negligible. The patterns were similar for relationships between GOLD D and mortality with vessel characteristics. Expiratory venous volume was an independent predictor of mortality, in addition to FEV1.Conclusion: By using automated software in patients with COPD, clinically relevant information on pulmonary vasculature can be extracted from expiratory CT scans (although not inspiratory scans); in particular, expiratory pulmonary venous volume predicted mortality.Trial Registration: NCT01245933.Keywords: COPD, computed tomography, pulmonary vasculature, vessel volume, vessel tortuosity, lung function

Objectives: To evaluate dual-layer dual-energy computed tomography (dlDECT)-derived pulmonary perfusion maps for differentiation between acute pulmonary embolism (PE) and chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: This retrospective study included 131 patients (57 patients with acute PE, 52 CTEPH, 22 controls), who underwent CT pulmonary angiography on a dlDECT. Normal and malperfused areas of lung parenchyma were semiautomatically contoured using iodine density overlay (IDO) maps. First-order histogram features of normal and malperfused lung tissue were extracted. Iodine density (ID) was normalized to the mean pulmonary artery (MPA) and the left atrium (LA). Furthermore, morphological imaging features for both acute and chronic PE, as well as the combination of histogram and morphological imaging features, were evaluated., Results: In acute PE, normal perfused lung areas showed a higher mean and peak iodine uptake normalized to the MPA than in CTEPH (both p < 0.001). After normalizing mean ID in perfusion defects to the LA, patients with acute PE had a reduced average perfusion (ID mean,LA ) compared to both CTEPH patients and controls (p < 0.001 for both). ID mean,LA allowed for a differentiation between acute PE and CTEPH with moderate accuracy (AUC: 0.72, sensitivity 74%, specificity 64%), resulting in a PPV and NPV for CTEPH of 64% and 70%. Combining ID mean,LA in the malperfused areas with the diameter of the MPA (MPA dia ) significantly increased its ability to differentiate between acute PE and CTEPH (sole MPA dia : AUC: 0.76, 95%-CI: 0.68-0.85 vs. MPA dia + 256.3 * ID mean,LA - 40.0: AUC: 0.82, 95%-CI: 0.74-0.90, p = 0.04)., Conclusion: dlDECT enables quantification and characterization of pulmonary perfusion patterns in acute PE and CTEPH. Although these lack precision when used as a standalone criterion, when combined with morphological CT parameters, they hold potential to enhance differentiation between the two diseases., Clinical Relevance Statement: Differentiating between acute PE and CTEPH based on morphological CT parameters is challenging, often leading to a delay in CTEPH diagnosis. By revealing distinct pulmonary perfusion patterns in both entities, dlDECT may facilitate timely diagnosis of CTEPH, ultimately improving clinical management., Key Points: • Morphological imaging parameters derived from CT pulmonary angiography to distinguish between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension lack diagnostic accuracy. • Dual-layer dual-energy CT reveals different pulmonary perfusion patterns between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension. • The identified parameters yield potential to enable more timely identification of patients with chronic thromboembolic pulmonary hypertension., (© 2023. The Author(s).)

Background: While computed tomography pulmonary angiography (CTPA) is an integral part of the work-up in patients with suspected pulmonary hypertension (PH), there is no established CTPA-derived prognostic marker. We aimed to assess whether quantitative readouts of lung vessel morphology correlate with established prognostic indicators in PH., Methods: We applied a fully-automatic in-house developed algorithm for segmentation of arteries and veins to determine lung vessel morphology in patients with precapillary PH who underwent right heart catheterization and CTPA between May 2016 and May 2019. Primary endpoint of this retrospective study was the calculation of receiver operating characteristics for identifying low and high mortality risk according to the 3-strata risk assessment model presented in the current guidelines., Results: We analyzed 73 patients, median age 65 years (interquartile range (IQR): 54-76), female/male ratio 35/38, median mean pulmonary arterial pressure 37 mm Hg (IQR: 30-46), and found significant correlations with important prognostic factors in pulmonary arterial hypertension. N-terminal pro-brain natriuretic peptide, cardiac index, mixed venous oxygen saturation, and 6-minute walking distance were correlated with the ratio of the number of arteries over veins with vessel diameters of 6-10 mm (Spearman correlation coefficients ρ = 0.64, p < 0.001; ρ = -0.60, p < 0.001; ρ = -0.47, p = 0.005; ρ = -0.45, p = 0.001, respectively). This ratio predicted a low- and high-risk score with an area under the curve of 0.73 (95% confidence interval (CI): 0.56-0.90) and 0.86 (95% CI: 0.74-0.97), respectively., Conclusions: The ratio of the number of arteries over veins with diameters between 6 and 10 mm is significantly correlated with prognostic markers in pulmonary hypertension and predicts low and high mortality risk., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objectives: It has recently become possible to assess lung vascular and parenchymal changes quantitatively in thoracic CT images using automated software tools. We investigated the vessel parameters of patients with SSc, quantified by CT imaging, and correlated them with interstitial lung disease (ILD) features., Methods: SSc patients undergoing standard of care pulmonary function testing and CT evaluation were retrospectively evaluated. CT images were analysed for ILD patterns and total pulmonary vascular volume (PVV) extents with Imbio lung texture analysis. Vascular analysis (volumes, numbers and densities of vessels, separating arteries and veins) was performed with an in-house developed software. A threshold of 5% ILD extent was chosen to define the presence of ILD, and commonly used cut-offs of lung function were adopted., Results: A total of 79 patients [52 women, 40 ILD, mean age 56.2 (s.d. 14.2) years, total ILD extent 9.5 (10.7)%, PVV/lung volume % 2.8%] were enrolled. Vascular parameters for total and separated PVV significantly correlated with functional parameters and ILD pattern extents. SSc-associated ILD (SSc-ILD) patients presented with an increased number and volume of arterial vessels, in particular those between 2 and 4 mm of diameter, and with a higher density of arteries and veins of <6 mm in diameter. Considering radiological and functional criteria concomitantly, as well as the descriptive trends from the longitudinal evaluations, the normalized PVVs, vessel numbers and densities increased progressively with the increase/worsening of ILD extent and functional impairment., Conclusion: In SSc patients CT vessel parameters increase in parallel with ILD extent and functional impairment, and may represent a biomarker of SSc-ILD severity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Objective: This study aimed to investigate whether quantitative lung vessel morphology determined by a new fully automated algorithm is associated with functional indices in idiopathic pulmonary fibrosis (IPF)., Methods: A total of 152 IPF patients had vessel volume, density, tortuosity and heterogeneity quantified from computed tomography (CT) images by a fully automated algorithm. Separate quantitation of vessel metrics in pulmonary arteries and veins was performed in 106 patients. Results were evaluated against readouts from lung function tests., Results: Normalized vessel volume expressed as a percentage of total lung volume was moderately correlated with functional indices on univariable linear regression analysis: forced vital capacity (R 2 = 0.27, P < 1 × 10 -6 ), diffusion capacity for carbon monoxide (DL CO ; R 2 = 0.12, P = 3 × 10 -5 ), total lung capacity (TLC; R 2 = 0.45, P < 1 × 10 -6 ) and composite physiologic index (CPI; R 2 = 0.28, P < 1 × 10 -6 ). Normalized vessel volume was correlated with vessel density but not with vessel heterogeneity. Quantitatively derived vessel metrics (and artery and vein subdivision scores) were not significantly linked with the transfer factor for carbon monoxide (K CO ), and only weakly with DL CO . On multivariable linear regression analysis, normalized vessel volume and vessel heterogeneity were independently linked with DL CO , TLC and CPI indicating that they capture different aspects of lung damage. Artery-vein separation provided no additional information beyond that captured in the whole vasculature., Conclusion: Our study confirms previous observations of links between vessel volume and functional measures of disease severity in IPF using a new vessel quantitation tool. Additionally, the new tool shows independent linkages of normalized vessel volume and vessel heterogeneity with functional indices. Quantitative vessel metrics do not appear to reflect vasculopathic damage in IPF., (© 2019 The Authors Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Knowledge of the lung vessel morphology in healthy subjects is necessary to improve our understanding about the functional network of the lung and to recognize pathologic deviations beyond the normal inter-subject variation. Established values of normal lung morphology have been derived from necropsy material of only very few subjects. In order to determine morphologic readouts from a large number of healthy subjects, computed tomography pulmonary angiography (CTPA) datasets, negative for pulmonary embolism, and other thoracic pathologies, were analyzed using a fully-automatic, in-house developed artery/vein separation algorithm. The number, volume, and tortuosity of the vessels in a diameter range between 2 and 10 mm were determined. Visual inspection of all datasets was used to exclude subjects with poor image quality or inadequate artery/vein separation from the analysis. Validation of the algorithm was performed manually by a radiologist on randomly selected subjects. In 123 subjects (men/women: 55/68), aged 59 ± 17 years, the median overlap between visual inspection and fully-automatic segmentation was 94.6% (69.2-99.9%). The median number of vessel segments in the ranges of 8-10, 6-8, 4-6, and 2-4 mm diameter was 9, 34, 134, and 797, respectively. Number of vessel segments divided by the subject's lung volume was 206 vessels/L with arteries and veins contributing almost equally. In women this vessel density was about 15% higher than in men. Median arterial and venous volumes were 1.52 and 1.54% of the lung volume, respectively. Tortuosity was best described with the sum-of-angles metric and was 142.1 rad/m (138.3-144.5 rad/m). In conclusion, our fully-automatic artery/vein separation algorithm provided reliable measures of pulmonary arteries and veins with respect to age and gender. There was a large variation between subjects in all readouts. No relevant dependence on age, gender, or vessel type was observed. These data may provide reference values for morphometric analysis of lung vessels.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease in which the amount of emphysema and airway disease may be very different between individuals, even in end-stage disease. Emphysema formation may be linked to the involvement of the small pulmonary vessels. The NAPDH oxidase (Nox) family is emerging as a key disease-related factor in vascular diseases, but currently its role in hypoxia-induced pulmonary remodelling in COPD remains unclear.Here we investigate the role of p22phox, a regulatory subunit of Nox, in COPD lungs, hypoxic pulmonary vasoconstriction (HPV), hypoxia-induced pulmonary vascular remodelling and pulmonary hypertension.In COPD, compared to control lungs, p22phox expression was significantly reduced. The expression was correlated positively with mean pulmonary arterial pressure and oxygenation index and negatively with the diffusing capacity of the lung for carbon monoxide (p<0.02). This suggests a role of p22phox in ventilation/perfusion ratio matching, vascular remodelling and loss of perfused lung area. In p22phox -/- mice, HPV was significantly impaired. In the chronic hypoxic setting, lack of p22phox was associated with improved right ventricular function and decreased pulmonary vascular remodelling.p22phox-dependent Nox plays an important role in the COPD phenotype, by its action on phase II HPV and chronic vascular remodelling., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Automated computer-aided analysis of lung vessels has shown to yield promising results for non-invasive diagnosis of lung diseases. To detect vascular changes which affect pulmonary arteries and veins differently, both compartments need to be identified. We present a novel, fully automatic method that separates arteries and veins in thoracic computed tomography images, by combining local as well as global properties of pulmonary vessels. We split the problem into two parts: the extraction of multiple distinct vessel subtrees, and their subsequent labeling into arteries and veins. Subtree extraction is performed with an integer program (IP), based on local vessel geometry. As naively solving this IP is time-consuming, we show how to drastically reduce computational effort by reformulating it as a Markov Random Field. Afterwards, each subtree is labeled as either arterial or venous by a second IP, using two anatomical properties of pulmonary vessels: the uniform distribution of arteries and veins, and the parallel configuration and close proximity of arteries and bronchi. We evaluate algorithm performance by comparing the results with 25 voxel-based manual reference segmentations. On this dataset, we show good performance of the subtree extraction, consisting of very few non-vascular structures (median value: 0.9%) and merged subtrees (median value: 0.6%). The resulting separation of arteries and veins achieves a median voxel-based overlap of 96.3% with the manual reference segmentations, outperforming a state-of-the-art interactive method. In conclusion, our novel approach provides an opportunity to become an integral part of computer aided pulmonary diagnosis, where artery/vein separation is important., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The VESSEL12 (VESsel SEgmentation in the Lung) challenge objectively compares the performance of different algorithms to identify vessels in thoracic computed tomography (CT) scans. Vessel segmentation is fundamental in computer aided processing of data generated by 3D imaging modalities. As manual vessel segmentation is prohibitively time consuming, any real world application requires some form of automation. Several approaches exist for automated vessel segmentation, but judging their relative merits is difficult due to a lack of standardized evaluation. We present an annotated reference dataset containing 20 CT scans and propose nine categories to perform a comprehensive evaluation of vessel segmentation algorithms from both academia and industry. Twenty algorithms participated in the VESSEL12 challenge, held at International Symposium on Biomedical Imaging (ISBI) 2012. All results have been published at the VESSEL12 website http://vessel12.grand-challenge.org. The challenge remains ongoing and open to new participants. Our three contributions are: (1) an annotated reference dataset available online for evaluation of new algorithms; (2) a quantitative scoring system for objective comparison of algorithms; and (3) performance analysis of the strengths and weaknesses of the various vessel segmentation methods in the presence of various lung diseases., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The accuracy of pulmonary vascular pressure measurements is of great diagnostic and prognostic relevance. However, there is variability of zero leveling procedures, and the current recommendation of end-expiratory reading may not always be adequate. A review of physiological and anatomical data, supported by recent imaging, leads to the practical recommendation of zero leveling at the cross-section of three transthoracic planes, which are, respectively midchest frontal, transverse through the fourth intercostal space, and midsagittal. As for the inevitable respiratory pressure swings, end-expiratory reading at functional residual capacity allows for minimal influence of elastic lung recoil on pulmonary pressure reading. However, hyperventilation is associated with changes in end-expiratory lung volume and increased intrathoracic pressure, eventually exacerbated by expiratory muscle contraction and dynamic hyperinflation, all increasing pulmonary vascular pressures. This problem is amplified in patients with obstructed airways. With the exception of dynamic hyperinflation states, it is reasonable to assume that negative inspiratory and positive expiratory intrathoracic pressures cancel each other out, so averaging pulmonary vascular pressures over several respiratory cycles is most often preferable. This recommendation may be generalized for the purpose of consistency and makes sense, as pulmonary blood flow measurements are not corrected for phasic inspiratory and expiratory changes in clinical practice.

Objectives: In this pilot study we explored whether contrast-material bolus propagation time and speed in the pulmonary arteries (PAs) determined by dynamic contrast-enhanced computed tomography (DCE-CT) can distinguish between patients with and without pulmonary hypertension (PH)., Methods: Twenty-three patients (18 with and 5 without PH) were examined with a DCE-CT sequence following their diagnostic or follow-up right-sided heart catheterisation (RHC). X-ray attenuation over time curves were recorded for regions of interest in the main, right and left PA and fitted with a spline fit. Contrast material bolus propagation speeds and time differences between the peak concentrations were compared with haemodynamic parameters from RHC., Results: Bolus speed correlated (ρ = -0.55) with mean pulmonary arterial pressure (mPAP) and showed a good discriminative power between patients with and without PH (cut-off speed 317 mm/s; sensitivity 100%/specificity 100%). Additionally, time differences between peaks correlated with mPAP (ρ = 0.64 and 0.49 for right and left PA, respectively) and discrimination was achieved with sensitivity 100%/specificity 100% (cut-off time 0.15 s) and sensitivity 93 %/specificity 80% (cut-off time 0.45 s), respectively., Conclusions: Bolus propagation speed and time differences between contrast material peaks in the PA can identify PH. This method could be used to confirm the indication for RHC in patients screened for pulmonary hypertension., Key Points: • Dynamic contrast-enhanced computed tomography (CT) can identify patients with pulmonary hypertension. • Bolus propagation speed in the pulmonary artery is reduced in pulmonary hypertension. • Peak-contrast propagation times provide a practical surrogate for speed. • This non-invasive technique could serve as a screening method for pulmonary hypertension. • Invasive right-sided heart catheterisations might be restricted to a smaller group of patients.

Unlabelled: Pulmonary hypertension (PH) can result in vascular pruning and increased tortuosity of the blood vessels. In this study we examined whether automatic extraction of lung vessels from contrast-enhanced thoracic computed tomography (CT) scans and calculation of tortuosity as well as 3D fractal dimension of the segmented lung vessels results in measures associated with PH. In this pilot study, 24 patients (18 with and 6 without PH) were examined with thorax CT following their diagnostic or follow-up right-sided heart catheterisation (RHC). Images of the whole thorax were acquired with a 128-slice dual-energy CT scanner. After lung identification, a vessel enhancement filter was used to estimate the lung vessel centerlines. From these, the vascular trees were generated. For each vessel segment the tortuosity was calculated using distance metric. Fractal dimension was computed using 3D box counting. Hemodynamic data from RHC was used for correlation analysis. Distance metric, the readout of vessel tortuosity, correlated with mean pulmonary arterial pressure (Spearman correlation coefficient: ρ = 0.60) and other relevant parameters, like pulmonary vascular resistance (ρ = 0.59), arterio-venous difference in oxygen (ρ = 0.54), arterial (ρ = -0.54) and venous oxygen saturation (ρ = -0.68). Moreover, distance metric increased with increase of WHO functional class. In contrast, 3D fractal dimension was only significantly correlated with arterial oxygen saturation (ρ = 0.47). Automatic detection of the lung vascular tree can provide clinically relevant measures of blood vessel morphology. Non-invasive quantification of pulmonary vessel tortuosity may provide a tool to evaluate the severity of pulmonary hypertension., Trial Registration: ClinicalTrials.gov NCT01607489.

Cardiac output (CO) is an important diagnostic and prognostic factor in the haemodynamic evaluation of patients. The gold standard for CO measurement, thermodilution, requires an invasive right-heart catheterisation (RHC). In this pilot study we aimed to determine the accuracy of non-invasive CO determination from dynamic contrast-enhanced computed tomography (CT) compared to thermodilution. Patients who underwent diagnostic or follow-up RHC due to suspected or known pulmonary vascular disease at our department and required a thoracic CT between June 2011 and August 2012 were included. CO was determined from CT attenuation-time curves in the pulmonary artery and the ascending aorta using a dynamic contrast-enhanced CT sequence. CO determined in N = 18 patients by dynamic CT in the pulmonary artery was in very good agreement with thermodilution data (r = 0.84). Bland-Altman analysis showed a systematic overestimation of 0.7 ± 0.6 l/min compared to thermodilution. Data from the ascending aorta also showed a good correlation, but with a larger scattering of the values. The average effective dose for the dynamic investigation was 1.2 ± 0.7 mSv. CO determined with dynamic contrast-enhanced CT in the main pulmonary artery reliably predicts the values obtained by thermodilution during RHC. This non-invasive technique might provide an alternative for repeated invasive right-heart catheter investigations in the follow-up of pulmonary arterial hypertension patients.