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CT-scan Analysis on Microfil Perfused Lungs Represents a Novel and Interesting Approach to Measure Distal Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension in Different Animals Models

M Barrier

A Courboulin

M Chapolard

MH Jacob

M Bisserier

C Lambert

S Bonnet

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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 07.06.2012

Presentation Type: Abstracts

BACKGROUND: Pulmonary arterial hypertension (PAH) is a vascular disease affecting distal pulmonary arteries (PA). Indeed, PAH is characterized by distal PA remodeling that elevates pulmonary vascular resistance, and decreases blood lung perfusion. This is responsible for the main non-specific symptoms of PAH, i.e. dyspnea and syncopes. This also causes right ventricular compensatory hypertrophy, which ultimately leads to right ventricular heart failure and premature death. This distal PA remodeling is mainly caused by pulmonary arterial smooth muscle cells phenotype of proliferation and resistance to apoptosis. In addition, plexiform lesions, a specific pathological finding in PAH, are usually found at branch points, often distal to an occluded arteriole and further decrease lung perfusion. Current treatments lack of efficiency and don’t yet target the vascular remodeling accounting for PAH. Thus, improvement regarding preclinical research is more than required. Indeed, in vivo assessment of lung perfusion abnormalities in PAH remains limited, indirect or restrictive to lung histology. We hypothesize that CT-scan-derived Microfil-perfused lung angiograms are an efficient way in assessing lung perfusion and thus overall lung vascular remodeling accounting for PAH.

METHODS/RESULTS: Lung angiograms were performed in control, chronic hypoxic (limited vascular remodeling), Monocrotaline or MCT (medium vascular remodeling) and Sugen5416 rats (severe vascular remodeling) using Microfil contrast agent. Perfusion was made in the rightventricle to access pulmonary vasculature. Lungs were then scanned to obtain CT angiograms and perfusion was calculated as the amount of PA signal/total lung signal. We have observed that the total lung perfusion decreases with histologically assessed PA remodeling severity (r2=0,9932; p=0,0526). Indeed, the hypoxic model (less remodeled model) has the smallest lung perfusion decrease (-5.35%; n=4), followed by the Monocrotaline model (-9.24%; n=7, p<0.001)

and the Sugen5416 model (-11.37%; n=3, p<0.001), compared to control rats. Moreover, perfused medium arteries quantity (300 to 500 m) is only decreased in Sugen5416 model compared to the control and the MCT model (p<0.05). However, perfused distal arteries quantity (200 to 300 m) is significantly decreased between controls and MCT, MCT and Sugen5416 and control and Sugen5416 (p<0.05). To assess whether CT-angiograms-derived lung perfusion measurement is a good PAH surrogate, we correlated this new parameter with others usually evaluated in PAH patients, which are known to correlate with PAH severity. Thus, the mean PA pressure, pulmonary artery acceleration time, right ventricle hypertrophy, and pulmonary vascular resistance measured by Echo-Doppler all correlate with CT-derived lung perfusion measurements (respectively: r=-0.7081, p<0.0001, n=31; r=0.7830, p<0.0001, n=32; r=-0,7816, p<0.0001, n=29; r=-0.7345, p<0.0001, n=28).

CONCLUSIONS: We have shown that CT lung angiograms performed on PAH animals model is an interesting and powerful approach in assessing lung perfusion associated with vascular remodeling. Indeed, it can represent a strong tool to evaluate efficiency of new drugs that target the remodeling in PAH animal models in pre-clinical research and may be used in PAH patients in the future.