Page 143 - Assessing right ventricular function and the pulmonary circulation in pulmonary hypertension Onno Anthonius Spruijt

A.
100 80 60 40 20
Musculariza on
* **
B.
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Prolifera on Ki‐67 score
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DCA
C. RV Hypertrophy
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MCT IMA DCA
Chapter 8
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00
C 4W_MCT DCA IMA
Lung 18FLT uptake E.
C
4W_MCT
IMA
F. *
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C
D.
0.15 0.10 0.05 0.00
(phosphoryla
on rate k3)
18FLT uptake (Tissue count)
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TK1 ENT1 GAPDH
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4W_MCT
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DCA
0.3 0.2 0.1
IMA 0.0
C 4W_MCT
DCA IMA
Figure 4. A. Treatment with dichloroacetate (DCA) and imatinib (IMA) attenuated pulmonary vascular muscularization. B. Effect of treatments on Ki‐67–positive nuclei surrounding remodelled peripheral pulmonary vessels. C. Effect of treatments on attenuation of right ventricular hypertrophy in the monocrotaline (MCT) rat. D and E. Treatment with DCA and imatinib attenuated lung 18FLT uptake in MCT rats. %ID/gm indicates percentage of injected dose per gram of tissue. F. Summary data and representative western blot for TK1 and ENT1 expression in whole lung homogenate. Both TK1 and ENT1 expression, normalized to GAPDH, were increased in the MCT rat and attenuated by DCA and imatinib treatment. Data are expressed as mean±SEM; n≥5 in each group. ***P<0.001, **P<0.01, *P<0.05.
Discussion
This is the first study to explore dynamic 18FLT PET imaging in PAH patients to track pulmonary vascular pathology. We found that lung 18FLT uptake was increased in IPAH patients compared with control subjects, and that there is heterogeneity in the lung 18FLT signal in IPAH, both between patients and within the lungs of each patient. The MCT rat model allowed us to investigate this signal in more depth. Increased lung 18FLT uptake in this model responded to drugs that reduce pulmonary vascular remodeling in animal models. Further in depth kinetic 2T4k modelling of the lung 18FLT signal showed an increased rate of 18FLT phosphorylation k3. Together with gene expression studies in pulmonary arterial fibroblasts isolated from IPAH patients, our data support
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8
min-1
% of muscularization
%ID/gm
Positive nuclei per vessel