Page 131 - Assessing right ventricular function and the pulmonary circulation in pulmonary hypertension Onno Anthonius Spruijt

Introduction
Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of the pulmonary vasculature leading to increased pulmonary artery pressure and progressive right heart dysfunction [1‐3]. Histopathology of lungs from PAH patients at the end stage of their disease show a complex pulmonary pathology including aberrant proliferation of pulmonary vascular cells, exuberant inflammatory cell infiltration and deposition of extra‐cellular matrix, but with a patchy distribution [4‐6]. The licensed treatments used in the clinic are based on restoration of an imbalance in vasoactive factors favoring vasoconstriction. While these drugs improve symptoms, they fail to halt the disease and have a limited effect on survival [7]. Innovative treatment strategies that inhibit the excessive proliferation of lung vascular cells, e.g. with the receptor tyrosine kinase inhibitor imatinib [8] and the metabolic modulator dichloroacetate (DCA) [9], show great promise in the preclinical setting. Disappointingly, imatinib was only partially efficacious in a larger PAH patient cohort [10]. A possible explanation for this failure to translate preclinical findings to patients may be the heterogeneity of pulmonary vascular remodeling in PAH, with some patients exhibiting profound active vascular proliferation but others a more quiescent state of end‐stage fixed pulmonary vascular remodeling. A new tool for assessing PAH pathology in vivo would greatly improve the potential to translate therapeutic strategies targeted at resolving pulmonary vascular remodelling into the clinic. Ideally, such a tool would allow a strategy of precision medicine with therapies tailored to individual patients.
Positron emission tomography (PET) with appropriate ligands allows for spatial detection and localization of pathophysiological processes in vivo. It is used in oncology to stratify patients and assess disease progression and response to treatment, and predict clinical outcomes. The radioactive ligand 18F‐3'‐fluoro‐3'‐deoxythymidine (18FLT) is a marker for cell proliferation [11,12] that correlates closely with histological markers, such as proliferating cell nuclear antigen (PCNA), Ki‐ 67 and S phase fraction [13‐16]. 18FLT is a fluorine‐modified thymidine analogue that is transported into the cell via passive diffusion and by nucleoside transporters, such as the equilibrative nucleoside transporter (ENT1), in a similar way as thymidine [17]. Thereafter, 18FLT is phosphorylated by thymidine kinase 1 (TK1) and trapped intracellularly at a rate proportional to TK1 activity, which is elevated during the S phase of the cell proliferation cycle but decreased or absent in quiescent cells [18‐21]. Importantly, 18FLT PET is recognized for evaluating whole tumor proliferation heterogeneity [22].
Chapter 8
129
8