Novel imaging approaches in pulmonary hypertension patients

26 May 2021

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Academic Industry & roundtable

Chair and moderators

David Levin, Mayo Clinic, USA

Lan Zhao, Imperial College London, UK

David Kieley, University of Sheffield, UK

Agenda

  • Martine Remy // Update from the Fleischner Society Task Force for imaging in pulmonary hypertension
  • Jocelyn Dupuis // Molecular imaging of pulmonary vascular disease using microvascular endothelial cell ligands
  • Jens Vogel-Claussen // MRI to assess pulmonary vascular changes and PH progression
  • Sudarshan Rajagopal // Xenon magnetic resonance imaging signatures of PH
  • Karin Tran-Lundmark // Synchrotron-based phase contrast micro-CT imaging of pulmonary vascular disease in human tissue and animal models. 

A deeper look

Medical imaging is a rapidly advancing domain with new techniques, sequences and modalities constantly developed. In a highly heterogeneous condition such as pulmonary hypertension (PH), imaging plays a vital role in accurately phenotyping patients. This has implications for patient management, treatment and prognosis. There is great potential for novel imaging techniques to aid in the assessment for PH. This webinar series focuses on both the application and implementation of current imaging techniques, and novel techniques which show promise of clinical benefit.

The first talk by Martine Remy (University Centre of Lille, France) provides an update from the Fleischner Society Task force for imaging in pulmonary hypertension. The working group has been tasked with answering multiple salient questions regarding the role of imaging in pulmonary hypertension, and how to best use the technologies and resources currently at hand. 

The next talks by Jocelyn Dupuis (Montreal Heart Institute, Canada), Jens Vogel-Claussen (Hannover Medical School, Germany), Sudarshan Rajagopal (Duke University Medical Center, USA) and Karin Tran-Lundmark (Lund University, Sweden) each describe a novel imaging methodology for answering clinically relevant questions in PH. The spectrum of modalities covered include molecular imaging, magnetic resonance imaging (MRI), Xenon MRI, and synchrotron-based phase contrast micro-CT. Jocelyn Dupuis’s talk investigates molecular imaging using microvascular endothelial cell ligand in early detection in pulmonary vascular disease. Jens Vogel-Claussen’s talk focuses on MRI for Chronic thromboembolic pulmonary hypertension (CTEPH) and outlines the promise of radiation-free follow-up for patients that often undergo repeat scans for disease assessment. Sudarshan Rajagopal’s talk uses hyperpolarised Xenon gas to detect unique signals in pulmonary arterial hypertension (PAH), thereby providing a sensitive imaging biomarker for the disease. Karin Tran-Lundmark’s talk looks at using Synchrotron-based phase contrast micro-CT as a novel approach for interpreting the intricate and complex vascular branching patterns involved in pulmonary vascular. This enables analysis from samples to develop better understanding of disease pathophysiology.

 

Update from the fleischner society Task force for imaging in pulmonary hypertension

15:00-15:15 BST

Presenter: // Martine Remy, University Centre of Lille, France

The radiological community faces new challenges regarding PH evaluation. One important objective of this position paper is to share current imaging options with PH clinicians for an optimal use of available resources. It also appears important to share the clinical usefulness of technological advances with radiologists in order to update some scanning protocols used in daily practice. Whereas diagnosis and treatment of PH are optimally approached in specialized centers, all radiologists can play a more active role in the early recognition of this disease, helping to reduce the delay in diagnosis. In order to reach these objectives, this position paper focuses upon a series of questions relevant for both non-expert and expert centers, emphasizing non-invasive imaging (e.g., CT, MR and nuclear medicine) approaches in a target population of adult PH patients. Specific attention is directed toward imaging of chronic pre-capillary PH (Groups 1, 3, 4 and 5). The working group formed within the Fleischner Society identified key questions focusing on the utility of computed tomography, magnetic resonance imaging, and nuclear medicine in the evaluation of PH: (1) is noninvasive imaging capable of identifying PH? (2) what is the role of imaging in establishing the cause of PH? (3) how does imaging determine the severity and complications of PH? (4) how should imaging be used to assess CTEPH before treatment? (5) should imaging be performed after treatment of PH? (6) what are the perspectives in the field of imaging of pulmonary hypertension? This systematic review and position paper highlight the key role of imaging in the recognition, workup, treatment planning and follow-up of PH.

 

Molecular imaging of pulmonary vascular disease using microvascular endothelial cell ligands

15:24-15:39 BST

Presenter: // Jocelyn Dupuis, Montreal Heart Institute, Canada 

There is great need for a non-invasive imaging modality enabling detection of pulmonary vascular disease (PVD) at an early stage and allowing surveillance of its evolution and the effect of therapy. Pulmonary vascular endothelium dysfunction is a recognized early event in the pathophysiology of PVD leading to pulmonary hypertension (PH). Our work has focused on developing molecular ligands able to specifically and safely probe the integrity of the pulmonary vascular endothelium. We identified the adrenomedullin receptor has a promising target, principally because it is densely distributed on the pulmonary microvascular endothelium, mostly in alveolar capillaries. The lead adrenomedullin receptor ligand we developed is called PulmoBind. A nuclear medicine kit for labelling of PulmoBind with 99mTechnetium (Tc) was developed to perform SPECT-CT imaging of PVD. Proof-of-concept studies in animal models of group I (monocrotaline and hypoxa-Sugen), group III (Bleomycin lung fibrosis), and group IV PH confirmed the capacity of PulmoBind to detect and grade the severity of PVD in relation with a reduced lung expression of the adrenomedullin receptor. In a phase I clinical study of 20 normal human subjects, PulmoBind SPECT-CT was safe and provided excellent quality lung imaging with 60% uptake. Furthermore, PulmoBind allowed dynamic and quantitative analysis of lung uptake as well as evaluation of spatial distribution of this molecular tracer, demonstrating a normal predominant dorso-ventral gradient in supine subjects. A phase II clinical study of PulmoBind was completed in 23 patients with group I PH (PAH) and 7 patients with CTEPH (group IV) compared to 15 healthy human subjects. The SPECT-CT studies were independently evaluated by blinded nuclear medicine specialists. Segmental perfusion defects compatible with pulmonary embolism were read in 7/7 CTEPH patients and in 2/23 PAH patients, but in none of the controls. Most of the PAH patients showed markedly abnormal distribution of PulmoBind with moderate to severe heterogeneity of distribution (drop-out zones) of moderate to severe extent. The perfusion abnormalities were generally unevenly distributed between the right and left lung as well as within lung. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p = 0.0003). Interestingly, in the only patient with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution and quantitative analysis confirming good testing reproducibility. In parallel, we are also developing an adrenomedullin receptor ligand, called DHF-17, that is labelled with AL-18F enabling PET imaging of PVD. Pre-clinical studies with DFH-17 were successfully completed and phase I clinical trials are in preparation. In conclusion, using ligands of the adrenomedullin receptor is a promising strategy for early non-invasive detection and evaluation of the severity of PVD. This strongly supports further clinical development of these agents.

 

MRI to assess pulmonary vascular changes and PH progression

15:48-16:03 BST

Presenter: // Jens Vogel-Claussen, Hannover Medical School, Germany

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, life-threatening disease. Its primary treatment promising cure is pulmonary endarterectomy (PEA). Three-year survival after PEA is 89% compared to only 70% for non-surgical treatment. Following the latest diagnostic algorithm proposed in the”2015 guidelines for the diagnosis and treatment of pulmonary hypertension” of the European Respiratory Society, CTEPH should be diagnosed in specialized centers. Magnetic resonance imaging (MRI) has been proposed for CTEPH assessment. Regarding the evaluation of pulmonary hypertension and CTEPH in particular, MRI has made distinct advances in the past decade and therefore has become part of our routine perioperative CTEPH patient workup. So far, MRI has shown improved regional and global cardiac function and pulmonary parenchymal perfusion after PEA. In a recent study two-dimensional (2D) phase-contrast (PC) MRI was able to detect hemodynamic changes due to increased pulmonary pressures in CTEPH patients. MRI furthermore offers a choice for radiation-free follow-up.

 

Xenon magnetic resonance imaging signatures of PH

16:12-16:27 BST

Presenter: // Sudarshan Rajagopal, Duke University Medical Center, USA

The diagnosis and management of pulmonary hypertension (PAH) is limited by the lack of specific biomarkers. While PAH is a disease of the pulmonary arterioles, it is monitored by a number of biomarkers that only indirectly report on its underlying pathology, such as hemodynamics from right heart catheterization, echocardiography, NTproBNP and six minute walk testing. Many of those biomarkers are not specific to PAH, and could represent left heart failure, chronic lung disease or other systemic limitations. An alternative strategy is to visualize the abnormal pulmonary vascular remodeling that underlies PAH using functional lung imaging. Our research focuses on using hyperpolarized 129Xe (Xe) magnetic resonance imaging (MRI) for functional lung imaging in PAH. Xe MRI has been primarily used for characterizing ventilatory defects in obstructive lung disease, but its unique properties allow it to image three phases, with different Xe signals in airspace, barrier (lung parenchyma) and red blood cells (where it binds hemoglobin). Therefore, in a single breath-hold, functional imaging of gas exchange throughout the lung can be visualized. This of potential relevance to pulmonary vascular diseases, which are commonly associated with abnormal gas exchange, e.g., the classic finding of an isolated decrease in DLCO on pulmonary function tests in patients with PAH and marked abnormalities in DLCO in patients with pulmonary veno-occlusive disease.

 Here we review our initial studies in characterizing patients with PAH with Xe MRI. By integrating Xe MR imaging with spectroscopy, we found that patients with PAH have a unique signature compared to patients with different chronic heart and lung diseases. Specifically, in PAH we observed lower RBC signal (consistent with a lower pulmonary capillary blood volume) with small amplitude cardiogenic oscillations on Xe MRI spectroscopy, differentiating it from other diseases associated with RBC signal. Notably, Xe MRI spectroscopy was sensitive to pulmonary vascular hemodynamics, reporting on changes in pulmonary capillary blood volume with each cardiac cycle. In our current studies, we are now testing how well these parameters correlate with same day right heart catheterization results, i.e., whether Xe MRI could be used for the noninvasive diagnosis of PAH. We are also testing the change in Xe MRI parameters to acute treatment with PAH therapies, i.e., whether Xe MRI could be used to follow response to treatment. Xe MRI also provides important pathophysiological insights into other disease states such as chronic thromboembolic PH (CTEPH). The largest impact of Xe MRI may be in the evaluation of patients with unexplained dyspnea, as it provides important information on lung gas exchange and function beyond currently available studies.

 

Synchrotron-based phase contrast micro-CT imaging of pulmonary vascular disease in human tissue and animal models. 

16:36-16:51 BST

Presenter: // Karin Tran-Lundmark, Lund University, Sweden

The microanatomy of the lung is highly complex with intricate vascular branching patterns and histological tissue sections are therefore often difficult to interpret. We have started to use synchrotron-based phase contrast micro-CT to analyze the pulmonary vascular tree in 3D with micrometer resolution. The method is non-destructive and therefore allows analysis of rare and unique samples of various lung pathologies from different biobanks. Radiopaque dye can also be injected prior to embedding to facilitate visualization. Following the scan, digital serial sections and 3D reconstructions can be generated from infinite angles which enables better understanding of the microstructures of the vascular pathology. The digital sections can be used to localize interesting regions within the tissue blocks and to guide actual sectioning for histology, immunohistochemistry, and in situ hybridization. Detected molecular processes with these latter methods can then be accurately assigned to its location in 3D space within the lesions. Recruited intrapulmonary bronchopulmonary anastomoses have previously been described in several forms of pulmonary hypertension and 3D imaging is ideal for studying this type of connections. Digital sectioning and 3D reconstructions of vascular changes in human pulmonary arterial hypertension, with focus on plexiform lesions and connections between pulmonary arteries and the bronchial circulation will be presented, as well as three-dimensional imaging of some of the commonly used animal models.

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