Page 130 - Assessing right ventricular function and the pulmonary circulation in pulmonary hypertension Onno Anthonius Spruijt

8
Abstract
Introduction: Pulmonary vascular cell hyperproliferation is characteristic of pulmonary vascular remodelling in pulmonary arterial hypertension (PAH). A non‐invasive imaging biomarker is needed to track the pathology and assess the response to treatments targeted at resolving the structural changes. Here we evaluate the application of radioligand 3'‐deoxy‐3'‐[18F]‐fluorothymidine (18FLT) using positron emission tomography (PET).
Methods & results: We performed dynamic 18FLT PET scanning in 8 idiopathic PAH patients (IPAH) and applied in‐depth kinetic analysis with a reversible 2‐compartment 4k model. Our results show significantly increased lung 18FLT phosphorylation k3 in IPAH patients compared with non‐PAH controls (0.086±0.034 min‐1 vs 0.054±0.009 min‐1; P<0.05). The lung 18FLT signals are variable both between IPAH patients and within the lungs of each patient, compatible with histopathological reports of lungs from IPAH patients. Consistent with 18FLT PET data, hyperproliferative pulmonary vascular fibroblasts isolated from IPAH patients exhibited upregulated expression of the key thymidine metabolism enzymes TK1 and thymidine transporter ENT1. In the monocrotaline rat PAH model, increased lung 18FLT uptake was strongly associated with peripheral pulmonary vascular muscularization and the proliferation Ki‐67 score, along with the prominent thymidine kinase TK1 and transporter ENT1 in the remodeled vessels. Importantly, lung 18FLT measurements responded to two anti‐proliferative treatments, dicholoroacetate and tyrosine kinase inhibitor imatinib. Conclusions: Dynamic 18FLT PET imaging can be used to report hyperproliferation in pulmonary hypertension and merits further study to evaluate response to treatment in IPAH patients.