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Pulmonary Vascular Morphology as an Imaging Biomarker in Chronic Thromboembolic Pulmonary Hypertension

Article Summary:

Background: Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a disease of chronic clot burden in the pulmonary vascular bed and associated pulmonary arterial hypertension.  Remodeling of the vasculature on CT imaging, such as distal pruning of the vascular bed and other findings, is frequently noted. However, developing a standardized method of quantifying these changes in vascular morphology and correlating them with hemodynamic parameters has been challenging.  In this study, Rahaghi et al. applied novel morphometric CT image processing techniques previously developed by the same group, and quantitatively analyzed the pulmonary vascular changes in subjects with CTEPH. 

Methods and Results: Patients who were referred to Brigham and Women’s Hospital for unexplained dyspnea and who underwent right heart catheterization (RHC) were retrospectively screened for inclusion. 18 subjects who were diagnosed with CTEPH by CT Pulmonary Angiogram (CTPA) and RHC were included for analysis. 15 subjects without evidence of CTEPH or other lung disease on CTPA and with normal RHC parameters were analyzed as controls.

The authors generated 3-dimensional trees of the pulmonary vascular bed of each subject from CTPA data, and used the following measures determined from this reconstruction for analysis:  Total Blood Volume (TBV); blood volume of vessels with a cross sectional area < or = to 5 mm2 (BV5); and blood volume of vessels with a cross sectional area of >10 mm2 (BV>10).  To correct for body size, the vessels were segmented by lungs and lobes and measures were normalized to the TBV for the region of interest (BV5/TBV, BV>10/TBV); in addition, BV5 and BV>10 were normalized for the lung volume of the region of interest (rBV5 and rBV>10).   Tortuosity of the vasculature was also assessed, which is described by the authors as “comparing the direct path versus the actual path a vessel takes between two endpoints.” The pulmonary arteries and veins were manually labelled at the segmental level so that arterial and venous vascular beds could be analyzed separately. These measures were used to compare CTEPH subjects to controls, and to assess whether any of these measures demonstrated correlation with hemodynamic measurements obtained by RHC. 

The main findings of this study include: 1) BV5/TBV and rBV5 were significantly reduced in CTEPH subjects, consistent with a pruning or loss of the smallest vessels in the lungs; 2) BV>10/TBV and rBV>10 were significantly increased in CTEPH subjects, consistent with engorgement of the larger proximal blood vessels, and this difference was seen only in the arterial vessels, as would be expected with pulmonary arterial hypertension; and 3) the tortuosity of arterial vessels in CTEPH subjects was significantly increased.  Interestingly, the BV5/TBV and BV>10/TBV measures did not correlate with hemodynamic measures obtained by RHC, but the global and right lung rBV5 were directly associated with cardiac indices.  Furthermore, higher right lung rBV5 was associated with RHC measures of increased vascular compliance and lower pulmonary vascular resistance, and this association was most pronounced in the right upper lobe. 

Conclusions: 3D reconstruction and analysis of the pulmonary vascular tree from CTPA of subjects with and without CETPH demonstrated significantly decreased blood volume of smaller blood vessels (with cross-sectional area <5 mm2) in CTEPH subjects.  Pruning of these smaller vessels, in addition to increased proximal vessel engorgement and tortuosity of vessels, is often noted on CTPA of CTEPH and other pulmonary arterial hypertension patients but this is the first study to systematically quantify these findings using novel image analysis techniques.   Some measures derived from this quantitative analysis were associated with hemodynamic measures obtained from invasive studies.  Further work with larger cohorts and subjects with other subsets of pulmonary arterial hypertension will be needed to determine the best imaging biomarkers derived from CTPA for diagnostic and prognostic evaluation of patients with pulmonary arterial hypertension.

Expert commentary:

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a disease defined by the presence of chronic clot accompanied by vascular remodeling and pulmonary arterial hypertension. CTEPH, one of the increasingly recognized causes of Pulmonary Artery Hypertension (PAH), follows a single or recurrent event of acute Pulmonary Embolism (PE). The exact incidence of this disease is uncertain, although various studies have suggested that it may occur after approximately 0.57% to 3.8% of acute pulmonary embolic events and in up to 10% of patients with recurrent PE (1).  CTEPH is one of the potentially curable causes of pulmonary hypertension and is definitively treated with pulmonary thromboendarterectomy. CTEPH can be easily overlooked, as its symptoms are nonspecific and can be mimicked by a wide range of diseases that can cause pulmonary hypertension. The survival rate without intervention in CTEPH is poor and fairly similar to rates seen with other forms of PAH (2).  Early diagnosis of CTEPH and prompt evaluation for surgical candidacy are paramount factors in determining future outcomes.

Imaging plays a central role in the diagnosis of CTEPH and patient selection for pulmonary thromboendartectomy and balloon pulmonary angioplasty. CT morphologic features of PAH have long been described such as pruning of the distal vasculature, dilation of the more central vasculature, and vessel tortuosity. These descriptive findings have been used to suggest the presence of PAH in different settings such as CTEPH but have not been use to quantitate the physiologic abnormality. In this study, the investigators measured markers of distal-vessel pruning, proximal-vessel dilation, differential distribution of volume between arterial and venous beds, and changes in vessel tortuosity. They demonstrated that these biomarkers differ significantly between patients with CTEPH and controls and that they correlate with invasive hemodynamic measurements. The regional lobar data further suggests that their proposed vascular metrics may provide insight into the heterogeneity of disease within different lung regions that may not only complement but offer additional insights to measures such as echocardiography and Right Heart Catheterization which measures the composite effect of all regions.

This study is limited by the retrospective nature of the data, and a relatively large number of missing data due to the absence of appropriate imaging for some CTEPH patients, resulting in their exclusion. The imaging data was not standardized and as such is likely a significant source of variability in each group. The impact of image acquisition protocols on quantitative CT measures cannot be over emphasized and the authors clearly are aware of this limitation as they highlight this in their discussion relating to limitations of their study. It is possible that the significant difference demonstrated between the CTEPH and control groups could have been due to differences in imaging protocols and not due to disease itself. However, this is hopefully not the case. Nevertheless, a prospective study powered sufficiently using a standardized CT acquisition protocol, is needed to confirm the findings of this study. In such a study, acquiring CT and RHC on the same day would also strength the analysis. In this study, the studies were not performed on the same day, so opening the possibility that the cardiovascular system was not in fact measured in the same condition by the two techniques. Although the median difference was only two days in this study, the range was large and may well have weakened the association due to other factors impacting the regional vascular physiology. A final caveat that should be considered is that the control cohort were not definitively free of cardiopulmonary disease. While they did not have abnormal pulmonary vascular measures on invasive hemodynamic measures, the possibility of early regional disease cannot be excluded, given that they were being investigated for unexplained cardiopulmonary symptoms.

Currently, various imaging tools are used in concert: techniques such as Computed Tomography (CT) and conventional pulmonary angiography providing detailed structural information; tests such as ventilation-perfusion (V/Q) scanning providing functional data; and magnetic resonance imaging providing a combination of morphologic and functional information. Emerging techniques such as dual-energy CT, single photon emission computed tomography-CT V/Q scanning, and quantitative CT measures to provide both anatomic and functional information on a regional and whole lung basis in a single test may change the way we image and assess these patients in the near future.

Article summary by: Heather Jones, MD, Assistant Professor of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Expert commentary by: Jonathan Goldin, MD, PhD, Professor of Radiology, Medicine and Biomedical Physics, University of California, Los Angeles.


  • Pengo V, Lensing AW, Prins MH, et al. Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350:2257–2264).
  •  Held M, Kolb P, Grün M, et al. Functional characterization of patients with chronic thromboembolic disease. Respiration. 2016;91:503–509).
Last Reviewed: November 2017