Quantification of Arterial and Venous Morphologic Markers in Pulmonary Arterial Hypertension Using CT Imaging

Abstract

BackgroundPulmonary hypertension is a heterogeneous disease, and a significant portion of patients at risk for it have CT imaging available. Advanced automated processing techniques could be leveraged for early detection, screening, and development of quantitative phenotypes. Pruning and vascular tortuosity have been previously described in pulmonary arterial hypertension (PAH), but the extent of these phenomena in arterial vs venous pulmonary vasculature and in exercise pulmonary hypertension (ePH) have not been described.Research QuestionWhat are the arterial and venous manifestations of pruning and vascular tortuosity using CT imaging in PAH, and do they also occur in ePH?Study Design and MethodsA cohort of patients with PAH and ePH and control subjects with available CT angiograms were retrospectively identified to examine the differential arterial and venous presence of pruning and tortuosity in patients with precapillary pulmonary hypertension not confounded by lung or thromboembolic disease. The pulmonary vasculature was reconstructed, and an artificial intelligence method was used to separate arteries and veins and to compute arterial and venous vascular volumes and tortuosity.ResultsA total of 42 patients with PAH, 12 patients with ePH, and 37 control subjects were identified. There was relatively lower (median [interquartile range]) arterial small vessel volume in subjects with PAH (PAH 14.7 [11.7-16.5; P < .0001]) vs control subjects (16.9 [15.6-19.2]) and venous small vessel volume in subjects with PAH and ePH (PAH 8.0 [6.5-9.6; P < .0001]; ePH, 7.8 [7.5-11.4; P = .004]) vs control subjects (11.5 [10.6-12.2]). Higher large arterial volume, however, was only observed in the pulmonary arteries (PAH 17.1 [13.6-23.4; P < .0001] vs control subjects 11.4 [8.1-15.4]). Similarly, tortuosity was higher in the pulmonary arteries in the PAH group (PAH 3.5 [3.3-3.6; P = .0002] vs control 3.2 [3.2-3.3]).InterpretationLower small distal pulmonary vascular volume, higher proximal arterial volume, and higher arterial tortuosity were observed in PAH. These can be quantified by using automated techniques from clinically acquired CT scans of patients with ePH and resting PAH. Pulmonary hypertension is a heterogeneous disease, and a significant portion of patients at risk for it have CT imaging available. Advanced automated processing techniques could be leveraged for early detection, screening, and development of quantitative phenotypes. Pruning and vascular tortuosity have been previously described in pulmonary arterial hypertension (PAH), but the extent of these phenomena in arterial vs venous pulmonary vasculature and in exercise pulmonary hypertension (ePH) have not been described. What are the arterial and venous manifestations of pruning and vascular tortuosity using CT imaging in PAH, and do they also occur in ePH? A cohort of patients with PAH and ePH and control subjects with available CT angiograms were retrospectively identified to examine the differential arterial and venous presence of pruning and tortuosity in patients with precapillary pulmonary hypertension not confounded by lung or thromboembolic disease. The pulmonary vasculature was reconstructed, and an artificial intelligence method was used to separate arteries and veins and to compute arterial and venous vascular volumes and tortuosity. A total of 42 patients with PAH, 12 patients with ePH, and 37 control subjects were identified. There was relatively lower (median [interquartile range]) arterial small vessel volume in subjects with PAH (PAH 14.7 [11.7-16.5; P < .0001]) vs control subjects (16.9 [15.6-19.2]) and venous small vessel volume in subjects with PAH and ePH (PAH 8.0 [6.5-9.6; P < .0001]; ePH, 7.8 [7.5-11.4; P = .004]) vs control subjects (11.5 [10.6-12.2]). Higher large arterial volume, however, was only observed in the pulmonary arteries (PAH 17.1 [13.6-23.4; P < .0001] vs control subjects 11.4 [8.1-15.4]). Similarly, tortuosity was higher in the pulmonary arteries in the PAH group (PAH 3.5 [3.3-3.6; P = .0002] vs control 3.2 [3.2-3.3]). Lower small distal pulmonary vascular volume, higher proximal arterial volume, and higher arterial tortuosity were observed in PAH. These can be quantified by using automated techniques from clinically acquired CT scans of patients with ePH and resting PAH. FOR EDITORIAL COMMENT, SEE PAGE 1998Pulmonary hypertension is a heterogeneous group of conditions that results from pathologic processes affecting the arteries, capillaries, or veins of the pulmonary vascular tree. Although right heart catheterization remains the gold standard for disease diagnosis and classification, this procedure is invasive, does not scale easily for screening large numbers of patients, and is used sparingly to monitor disease progression. For these reasons, noninvasive biomarkers are highly sought after for all aspects of clinical care. Cardiopulmonary imaging continues to show great promise as a noninvasive biomarker, and CT imaging in particular has become part of the standard clinical evaluation of patients with suspected pulmonary vascular disease. Numerous investigations have shown that CT imaging-based measures of the main pulmonary artery size, both alone and normalized by the diameter of the aorta,1Ng C.S. Wells A.U. Padley S.P. A CT sign of chronic pulmonary arterial hypertension: the ratio of main pulmonary artery to aortic diameter.J Thorac Imaging. 1999; 14: 270-278Crossref PubMed Google Scholar are associated with the presence of pulmonary hypertension and are now commonly included in the clinical interpretation of a CT scan.2Johns C.S. Wild J.M. Rajaram S. Swift A.J. Kiely D.G. Current and emerging imaging techniques in the diagnosis and assessment of pulmonary hypertension.Expert Rev Respir Med. 2018; 12: 145-160Crossref PubMed Scopus (7) Google Scholar,3Devaraj A. Wells A.U. Meister M.G. Corte T.J. Wort S.J. Hansell D.M. Detection of pulmonary hypertension with multidetector CT and echocardiography alone and in combination.Radiology. 2010; 254: 609-616Crossref PubMed Scopus (143) Google Scholar Less is known about the intraparenchymal vasculature and how the morphology of those arteries and veins may differ according to disease type. FOR EDITORIAL COMMENT, SEE PAGE 1998 A lower area of functional small vessel lumen is a histologic characteristic of pulmonary arterial hypertension (PAH) that results in distal vascular pruning on pulmonary angiogram; this has been previously described by using taper and tree complexity measured by fractal dimension.4Reid L. The angiogram and pulmonary artery structure and branching (in the normal and with reference to disease).Proc R Soc Med. 1965; 58: 681-684PubMed Google Scholar, 5Rabinovitch M. Keane J.F. Fellows K.E. Castaneda A.R. Reid L. Quantitative analysis of the pulmonary wedge angiogram in congenital heart defects. Correlation with hemodynamic data and morphometric findings in lung biopsy tissue.Circulation. 1981; 63: 152-164Crossref PubMed Scopus (62) Google Scholar, 6Boxt L.M. Katz J. Liebovitch L.S. Jones R. Esser P.D. Reid L. Fractal analysis of pulmonary arteries: the fractal dimension is lower in pulmonary hypertension.J Thorac Imaging. 1994; 9: 8-13Crossref PubMed Scopus (41) Google Scholar Studies have shown that pruning can be objectively assessed by using CT imaging and that its presence is clinically significant in COPD,7Estépar R.S. Kinney G.L. Black-Shinn J.L. et al.COPDGene StudyComputed tomographic measures of pulmonary vascular morphology in smokers and their clinical implications.Am J Respir Crit Care Med. 2013; 188: 231-239Crossref PubMed Scopus (133) Google Scholar, 8Matsuoka S. Washko G.R. Yamashiro T. et al.Pulmonary hypertension and computed tomography measurement of small pulmonary vessels in severe emphysema.Am J Respir Crit Care Med. 2010; 181: 218-225Crossref PubMed Scopus (126) Google Scholar, 9Rahaghi F.N. Argemi G. Nardelli P. et al.Pulmonary vascular density: comparison of findings on computed tomography imaging with histology.Eur Respir J. 2019; 54Crossref PubMed Scopus (25) Google Scholar asthma,10Ash S.Y. Rahaghi F.N. Come C.E. et al.SARP InvestigatorsPruning of the pulmonary vasculature in asthma. The Severe Asthma Research Program (SARP) Cohort.Am J Respir Crit Care Med. 2018; 198: 39-50Crossref PubMed Scopus (33) Google Scholar and chronic thromboembolic disease.11Rahaghi F.N. Ross J.C. Agarwal M. et al.Pulmonary vascular morphology as an imaging biomarker in chronic thromboembolic pulmonary hypertension.Pulm Circ. 2016; 6: 70-81Crossref PubMed Scopus (28) Google Scholar In pulmonary hypertension, CT imaging-based sparsity of small vessels has also been characterized by using measures of tree complexity.12Moledina S. de Bruyn A. Schievano S. et al.Fractal branching quantifies vascular changes and predicts survival in pulmonary hypertension: a proof of principle study.Heart. 2011; 97: 1245-1249Crossref PubMed Scopus (44) Google Scholar, 13Haitao S. Ning L. Lijun G. Fei G. Cheng L. Fractal dimension analysis of MDCT images for quantifying the morphological changes of the pulmonary artery tree in patients with pulmonary hypertension.Korean J Radiol. 2011; 12: 289-296Crossref PubMed Scopus (14) Google Scholar, 14Helmberger M. Pienn M. Urschler M. et al.Quantification of tortuosity and fractal dimension of the lung vessels in pulmonary hypertension patients.PloS One. 2014; 9e87515Crossref PubMed Scopus (64) Google Scholar Increases in transmural pressure in the pulmonary vasculature due to elevated pulmonary vascular resistance may also lead to central vascular dilation,6Boxt L.M. Katz J. Liebovitch L.S. Jones R. Esser P.D. Reid L. Fractal analysis of pulmonary arteries: the fractal dimension is lower in pulmonary hypertension.J Thorac Imaging. 1994; 9: 8-13Crossref PubMed Scopus (41) Google Scholar,12Moledina S. de Bruyn A. Schievano S. et al.Fractal branching quantifies vascular changes and predicts survival in pulmonary hypertension: a proof of principle study.Heart. 2011; 97: 1245-1249Crossref PubMed Scopus (44) Google Scholar,15Reid L.M. Structure and function in pulmonary hypertension. New perceptions.Chest. 1986; 89: 279-288Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar much like the dilation of the main pulmonary artery or increased tortuosity.11Rahaghi F.N. Ross J.C. Agarwal M. et al.Pulmonary vascular morphology as an imaging biomarker in chronic thromboembolic pulmonary hypertension.Pulm Circ. 2016; 6: 70-81Crossref PubMed Scopus (28) Google Scholar,14Helmberger M. Pienn M. Urschler M. et al.Quantification of tortuosity and fractal dimension of the lung vessels in pulmonary hypertension patients.PloS One. 2014; 9e87515Crossref PubMed Scopus (64) Google Scholar However, the extent to which many of these morphologic changes differentially affect arteries and veins in patients with PAH has not yet been quantified in CT imaging. Characterization of the similarities and differences between arterial and venous changes in the lung parenchyma may enhance their utility as diagnostic markers and further improve the understanding of pulmonary vascular remodeling in PAH. The goal of the was to the changes in the pulmonary arterial and venous vasculature in patients with PAH pulmonary automated arterial and venous using an artificial intelligence that lower small vessel volume, proximal vascular and higher vascular tortuosity be in the arteries but not veins of patients with PAH with control sought to those in patients with PAH were also in those with exercise pulmonary hypertension which may be a of PAH in for this were identified a of subjects right heart catheterization between and shown in subjects were identified CT with lung and with the imaging right heart this of subjects ePH, and control were identified. with a resting pulmonary arterial pressure and pulmonary vascular resistance were for in the PAH cohort were an pulmonary arterial pressure CT of or clinical diagnosis of lung G. et and clinical of pulmonary Respir J. 2019; PubMed Scopus Google Scholar The subjects by pulmonary hypertension as disease (PAH) disease presence of the PAH were for in the ePH or control group they a resting pulmonary arterial pressure and exercise to by a heart of or a ratio were they lung disease according to or available heart disease by or < or or aortic or significant with the subjects the of Agarwal M. et of normal for exercise pulmonary Respir J. 2016; PubMed Scopus Google Scholar were included an elevated exercise pulmonary arterial pressure for for a in pulmonary vascular resistance at exercise for and of elevated wedge arterial wedge pressure at exercise for and for The subjects with exercise of ePH or wedge were included as control subjects in this for a analysis clinical was by the at A of automated used for lung vascular vascular as and of are in A of the used is in the with the were used to a of the lung parenchyma and vascular using the Ross Washko imaging an and for quantitative imaging. New and R. A. et an and for quantitative J 2016; Scholar which described in R.S. Kinney G.L. Black-Shinn J.L. et al.COPDGene StudyComputed tomographic measures of pulmonary vascular morphology in smokers and their clinical implications.Am J Respir Crit Care Med. 2013; 188: 231-239Crossref PubMed Scopus (133) Google J.C. R.S. A. et and assessment for quantitative analysis on computed tomography 12: Google Scholar, J.C. G.L. et al.Pulmonary on and 2013; PubMed Scopus Google Scholar, G.L. R. and with PubMed Scopus Google Scholar, R.S. Ross J.C. T. Washko G.R. G.L. vascular for the assessment of pulmonary vascular disease on Imaging. Google Scholar The vasculature was as arterial and venous by using a P. et al.Pulmonary in CT images using Imaging. 2018; PubMed Scopus Google Scholar The and total arterial and venous volumes were computed by using a previously used of as a area large from small R.S. Kinney G.L. Black-Shinn J.L. et al.COPDGene StudyComputed tomographic measures of pulmonary vascular morphology in smokers and their clinical implications.Am J Respir Crit Care Med. 2013; 188: 231-239Crossref PubMed Scopus (133) Google S. Washko G.R. Yamashiro T. et al.Pulmonary hypertension and computed tomography measurement of small pulmonary vessels in severe emphysema.Am J Respir Crit Care Med. 2010; 181: 218-225Crossref PubMed Scopus (126) Google G.R. Nardelli P. S.Y. et vascular right size, and clinical in chronic pulmonary disease. A J Respir Crit Care Med. 2019; PubMed Scopus (41) Google G.R. Nardelli P. S.Y. et at CT is associated with lower in PubMed Scopus Google Scholar volumes were normalized by the lung volume from the from the was computed and as a with the at the that the and the and the volume was as a function of this for The method of tortuosity is in the lower of was computed for as previously F.N. Ross J.C. Agarwal M. et al.Pulmonary vascular morphology as an imaging biomarker in chronic thromboembolic pulmonary hypertension.Pulm Circ. 2016; 6: 70-81Crossref PubMed Scopus (28) Google Scholar and the tortuosity for both the arterial and venous In with tortuosity were in both the arterial and venous and the arterial was normalized by the venous are as and for between were measured by using the P are and < were analysis was in R for The included patients, with 42 subjects in the PAH 12 subjects in the ePH and 37 subjects in the control and resting for group are in The of PAH, the diagnosis associated with control and function results are described in the CT imaging are described in and For patients in the control and ePH exercise and from exercise are also in The PAH and ePH were the control and the PAH and control included subjects the ePH and of PAH and ePH and = = = between and CT control subjects and subjects with ePH by exercise patients with resting of PAH not exercise exercise exercise exercise are as or for which is as a ePH = exercise pulmonary = pulmonary arterial PAH = pulmonary arterial = pulmonary arterial wedge = pulmonary vascular = right heart = = control subjects and subjects with ePH by exercise patients with resting of PAH not exercise in a are as or for which is as a ePH = exercise pulmonary = pulmonary arterial PAH = pulmonary arterial = pulmonary arterial wedge = pulmonary vascular = right heart = = and were by using the procedure as in of the of the pulmonary vasculature and from the artificial intelligence of the arterial and venous for a with PAH, a with ePH, and a control are shown in vascular volume as a function of vessel for the subjects are shown in in these lower distal vascular volume and proximal arterial dilation with disease. CT imaging-based measures of lung and vascular volumes are in The lung volumes and total vascular volumes of arteries and small and large normalized by lung volume were between patients with PAH and control However, the small vessel volumes normalized by lung volume were lower in the PAH group with the control the large vessel volumes normalized by lung volume were higher in the PAH group with the control The lung volumes and total vascular volumes were also between the ePH and control and to the PAH the ePH group lower small vessel volumes with control but the of higher large vessel volume not of by on = = = vs from the vs from the volume, vessel vascular volumes are normalized by lung The by lung volume is a of vessel of vessel vessel vascular measures arterial arterial arterial vascular measures venous venous venous by venous vessel vessel are as ratio = the ratio of arterial to venous ePH = exercise pulmonary PAH = pulmonary arterial P from the vascular volumes are normalized by lung The by lung volume is a of vessel of in a are as ratio = the ratio of arterial to venous ePH = exercise pulmonary PAH = pulmonary arterial hypertension. of the arterial and venous vasculature by vessel are in with of arterial and venous using as described in and The lung total arterial volume was in the PAH cohort with the control a lower lung small arterial vessel volume and higher lung arterial large vessel volume with control Although was a for the higher total and large vessel and lower small vessel arterial volume subjects with ePH vs control these findings not A analysis of the venous vasculature a lower lung total venous volume in subjects with PAH with control from a lower lung venous small vessel The lung large vessel volumes were between the PAH and control in the PAH was also lower lung venous small vessel volume in the ePH group with the control The venous total and large vessel volumes not a between subjects with ePH and control The findings from the arterial and venous volume vessel analysis are in of the arterial vascular volume by venous vascular volume is described in The ratio of arterial to venous vascular volume was higher in subjects with PAH with control which a higher ratio both for small vessels and large the ePH group vs the control was a higher total only the in large vessel ratio that and vessel is an of distal and proximal in the vascular the arterial and venous vasculature was on from the as shown in volume was as a function of the from the for all patients, and the in vascular volume identified as described in and in The in vascular volume in PAH was the in both the arterial and venous The the was subjects with ePH vs control of on = = = vs from vs from are as ePH = exercise pulmonary PAH = pulmonary arterial P from in a are as ePH = exercise pulmonary PAH = pulmonary arterial hypertension. vascular tortuosity was computed as described in for both arteries and veins The tortuosity was higher in patients with PAH not with the control the tortuosity for the venous vasculature was the of the arterial tree with vessel on for as as a of vessel are shown in in part by the relatively higher of in the of this the ratio of the of arterial with to the of venous ratio tortuosity as shown in which was higher in subjects with PAH and ePH with control analysis of with for and are in of and = = = vs from the vs from the arterial tortuosity tortuosity is the of the be a the that a have a tortuosity of venous tortuosity by venous ratio are as ePH = exercise pulmonary PAH = pulmonary arterial P from the tortuosity is the of the be a the that a have a tortuosity of in a are as ePH = exercise pulmonary PAH = pulmonary arterial hypertension. In this of right heart catheterization identified a group of patients with PAH, a group with ePH, and patients of pulmonary vascular disease by exercise as control CT of the intraparenchymal pulmonary arterial and pulmonary venous vascular were and from those were to objectively their of vascular volumes as as volume measures as a function of from the distal arterial and venous pruning in patients with PAH and proximal arterial dilation was to those with PAH. further vascular tortuosity and those in the arterial but not venous vasculature to be higher in subjects with PAH with control or sparsity of the small or distal has been previously described in patients with pulmonary vascular disease. used to this in the arterial and venous vascular The measures of vessel volume < in have been described in in R.S. Kinney G.L. Black-Shinn J.L. et al.COPDGene StudyComputed tomographic measures of pulmonary vascular morphology in smokers and their clinical implications.Am J Respir Crit Care Med. 2013; 188: 231-239Crossref PubMed Scopus (133) Google F.N. Argemi G. Nardelli P. et al.Pulmonary vascular density: comparison of findings on computed tomography imaging with histology.Eur Respir J. 2019; 54Crossref PubMed Scopus (25) Google R.S. Ross J.C. T. Washko G.R. G.L. vascular for the assessment of pulmonary vascular disease on Imaging. Google Scholar but the using the of vessel volume as a function of from the is to this this to the in vessel volume to the central vasculature in disease but also measures of small vessel volume may the of disease on vascular For as pruning of the vascular tree distal vessels may in size, and their area their to the small vessel volume volume measures in this is by the of small vessels they the of of clinical CT and volume measures in this is only vascular the of vessels that the volume by small vessels measured distal pruning by the vascular volume as a function of from the in a vascular this to the as the distal vessels volume and the proximal vessels due to increased resistance to observed pruning of the distal arterial and venous vascular in patients with PAH. however, was this of vascular pruning in patients with Pruning of the distal arterial vasculature is a in PAH, and the lower area of precapillary vessels or of vascular remodeling the of clinical for these The presence of distal arterial pruning in patients with ePH that ePH may an early of PAH. proximal arterial dilation is to the dilation of the main pulmonary artery also observed in this cohort The presence of proximal arterial dilation vascular in PAH but not ePH that the in pulmonary vascular resistance and lower arterial associated with pruning on CT in the is not great at to in of transmural pressure and proximal vascular is that of the CT exercise show proximal dilation of the arterial vasculature in to in pulmonary arterial pressure Pruning of the distal venous vasculature in patients with both PAH and ePH on CT imaging is to a a as venous remodeling in pulmonary disease. A of the arterial and venous vascular may the of distal venous volume is to the changes in the and CT imaging-based investigations have higher tortuosity of the intraparenchymal pulmonary vasculature in patients with M. Pienn M. Urschler M. et al.Quantification of tortuosity and fractal dimension of the lung vessels in pulmonary hypertension patients.PloS One. 2014; 9e87515Crossref PubMed Scopus (64) Google Scholar in patients with chronic thromboembolic pulmonary hypertension that this was to the arterial vascular F.N. Ross J.C. Agarwal M. et al.Pulmonary vascular morphology as an imaging biomarker in chronic thromboembolic pulmonary hypertension.Pulm Circ. 2016; 6: 70-81Crossref PubMed Scopus (28) Google Scholar but an has not been in patients with PAH. In the vessel tortuosity was measured in the arterial and venous pulmonary and to chronic thromboembolic pulmonary hypertension, patients with PAH have higher arterial but not venous vascular tortuosity. the ratio of arterial to venous vascular that patients with ePH may have higher arterial vascular tortuosity with control There are of this that be was a and the analysis was to the of patients CT images available for The of the available is for the analysis of subjects with ePH, a the control and PAH and a higher between CT imaging and right heart also a clinical that the subjects scans were those in a the was for clinical which may affect the of In the small and a of it that the was to of the differences between Although the control cohort of pulmonary vascular disease they were for and be as control CT scans were used they were acquired the of right heart which for PAH may have been The of on vascular morphology is but it is that with in be an of the differences between control subjects and subjects with PAH. is that disease to changes in the of imaging to that could affect the results of this In lung disease and lung disease PAH, in the of disease. A analysis this is in CT scans were in the which is from the conditions used to this many and the of the of is to these findings and their utility in clinical pruning and proximal dilation as as higher tortuosity of the arterial vasculature are all on the CT scans of patients with PAH. pruning is also in patients with ePH, that in at this may an early of PAH. that CT imaging-based of the pulmonary vasculature may be used to of pulmonary vascular disease. is to the and of as as their for and to What are the arterial and venous manifestations of pruning and vascular tortuosity using CT imaging in PAH and arterial and venous volume proximal arterial and increased arterial tortuosity are observed on CT scans of patients with PAH and using CT imaging can a noninvasive method for of PAH and What are the arterial and venous manifestations of pruning and vascular tortuosity using CT imaging in PAH and ePH? arterial and venous volume proximal arterial and increased arterial tortuosity are observed on CT scans of patients with PAH and using CT imaging can a noninvasive method for of PAH and R. is the of the for the of the as a from to P. A. J. A. A. R. and G. R. were in the and P. G. S. J. S. and A. R. were in data and in and of the The have to the from the of and the of the from and from and from G. R. from the of and from and from Quantitative and from and the and for and G. R. are also and of Quantitative which is a that and to P. G. J. R. S. J. S. A. R. A. J. A. A. of The in the of the the and analysis of the or the of the The and can be in the of the with

Topics & Concepts