Page 144 - Assessing right ventricular function and the pulmonary circulation in pulmonary hypertension Onno Anthonius Spruijt

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the contention that the lung 18FLT PET signal reflects pulmonary vasculature cellular proliferation in PAH.
We have previously shown that 18FDG uptake is increased in the lungs of IPAH patients [9]. A limitation of this approach is the challenge of distinguishing inflammation from proliferation. In the field of oncology, the 18FLT ligand has been used for imaging tumor cell proliferation [22], especially for improving the accuracy of anti‐proliferative target delineation. 18FLT has been shown to correlate better than 18FDG with cell proliferation markers in excised tumors and has potential to better differentiate growing tumors from inflammation [32,33]. In addition, background activity of 18FLT is low in the thorax as shown in studies of lung cancer [34‐36]. In the current study, dynamic PET scanning data from IPAH patients allowed us to perform the in‐depth kinetic analysis of the rates of 18FLT transportation in the lung by 2T4k modeling [29]. We found a significantly higher rate of 18FLT phosphorylation k3 in a proportion of IPAH patient lungs.
The 18FLT phosphorylation reaction, denoted by k3, is the TK1 rate‐limiting step during the cell cycle S‐phase, determining the uptake and retention of 18FLT in tissue. TK1 overexpression has been described in various tumour tissues including brain, breast and lung tumors and TK1 expression is correlated closely with Ki67 expression as well as 18FLT uptake [18‐21]. The measurement of intracellular levels of phosphorylated thymidine (as a surrogate of TK1 activation level) is regarded as an accurate method for estimating cellular growth [37]. Direct correlation of 18FLT uptake with vascular remodeling in humans is not possible. We employed pulmonary fibroblasts, an active contributor to vascular remodeling in IPAH, that we isolated from IPAH patients to explore the biology in vitro. Consistent with increased lung uptake of 18FLT PET and phosphorylation of 18FLT in IPAH patients, we observed a significantly increased expression of thymidine metabolism enzymes TK1 and TP, as well as thymidine transporter ENT1,in these hyper‐proliferative cells. These data are consistent with a lung 18FLT signal that depicts the hyper‐proliferative vascular pathology documented in the pulmonary hypertensive lung.
There was considerable variation in the distribution of lung 18FLT uptake within the IPAH study group. Some patients exhibited a more than 2‐fold increase in 18FLT phosphorylation, k3, above the control group, whereas others were in the range of controls. This is not surprising as vascular proliferation is unlikely to be constant throughout the course of the disease. Little is known about