Page 191 - Assessing right ventricular function and the pulmonary circulation in pulmonary hypertension Onno Anthonius Spruijt

Future perspectives
Non-invasive quantification of pulmonary vascular remodeling
In chapter 2 we investigated the usage of 3’-[18F]fluoro-3’-deoxythymidine ([18F]-FLT) positron emission tomography (PET/CT) for quantitative assessment of proliferation in the pulmonary vasculature of patients with idiopathic pulmonary arterial hypertension (IPAH). In this study we found an increased uptake of [18]-FLT in the lungs of patients with IPAH compared to control subjects. Furthermore, [18F]-FLT was able to track the pulmonary vascular remodeling in a monocrotaline ratmodel and the reverse remodeling after treating the animals with targeted therapies.
An important next study would be a test-retest study to assess repeatability of the uptake of [18F]- FLT in IPAH patients. Good repeatability is essential to be able to use [18F]-FLT PET/CT in the future to select patients with a hyperproliferative state that may benefit from anti-proliferative agents and to assess treatment responses. Current pulmonary hypertension therapies mainly have vasodilatory effects and thus may not influence proliferation rate. Therefore, application of [18F]-FLT should be assessed with future anti-proliferative compounds that directly target the pulmonary vascular remodeling.
In addition to the further development of [18F]-FLT, alternative tracers to quantify pulmonary vascular remodeling should be investigated. The increased expression of growth factor receptors may be reflected by enhanced uptake of radio-labeled tyrosine kinase inhibitors. It has been shown that there is an increased expression of the epidermal growth factor receptor (EGF-R) in the intima and media of pulmonary arteries of patients with pulmonary arterial hypertension [1]. In a pilot study we tested the tracer [11C]-Erlotinib (unpublished data), which binds to the EGF-R. We found that the uptake of [11C]-Erlotinib was not increased in patients with idiopathic pulmonary arterial hypertension compared to control subjects.
Other growth factors are upregulated as well in pulmonary arterial hypertension (platelet derived growth factor receptor (PDGF-R), vascular endothelial growth factor receptor (VEGF-R) and fibroblast growth factor receptor (FGF-R)) [2] and can potentially be used to quantify the pulmonary vascular remodeling using PET/CT. Nintedanib is a tyrosine kinase inhibitor targeting the PDGF-R, VEGF-R and FGF-R. Moreover, in preclinical studies Nintedanib showed potential to reverse pulmonary vascular remodeling [3]. Therefore, development of a Nintedanib tracer would be of interest to quantify pulmonary vascular remodeling in patients with pulmonary hypertension.
Chapter 11
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