PulmoBind Imaging Measures Reduction of Vascular Adrenomedullin Receptor Activity with Lack of effect of Sildenafil in Pulmonary Hypertension

Nassiba Merabet,Myriam Letourneau,Yan Fen Shi,Jocelyn Dupuis,Jean-Claude Tardif,Alain Fournier,François Harel,Quang Trinh Nguyen,Mohamed Jalloul Nsaibia

doi:10.1038/s41598-019-43225-3

Abstract

Endothelial dysfunction is a core pathophysiologic process in pulmonary arterial hypertension (PAH). We developed PulmoBind (PB), a novel imaging biomarker of the pulmonary vascular endothelium. 99mTechnetium (99mTc)-labelled PB binds to adrenomedullin receptors (AM1) densely expressed in the endothelium of alveolar capillaries. We evaluated the effect of sildenafil on AM1 receptors activity using 99mTc-PB. PAH was induced in rats using the Sugen/hypoxia model and after 3 weeks, animals were allocated to sildenafil (25 or 100 mg/kg/day) for 4 weeks. 99mTc-PB uptake kinetics was assessed by single-photon emission computed tomography. PAH caused right ventricular (RV) hypertrophy that was decreased by low and high sildenafil doses. Sildenafil low and high dose also improved RV function measured from the tricuspid annulus plane systolic excursion. Mean integrated pulmonary uptake of 99mTc-PB was reduced in PAH (508% · min ± 37, p < 0.05) compared to controls (630% · min ± 30), but unchanged by sildenafil at low and high doses. Lung tissue expressions of the AM1 receptor components were reduced in PAH and also unaffected by sildenafil. In experimental angio-proliferative PAH, sildenafil improves RV dysfunction and remodeling, but does not modify pulmonary vascular endothelium dysfunction assessed by the adrenomedullin receptor ligand 99mTc-PB.

Highlights

Pulmonary arterial hypertension (PAH), or group I pulmonary hypertension (PH), is a rare but fatal disease characterized by progressive elevation in pulmonary artery pressure
It is still unclear whether the effects are primarily mediated by a vasodilatory action with secondary improvement in right ventricular (RV) function or whether sildenafil can directly impact on the pathophysiologic process of pulmonary vascular disease (PVD)
Pathological RV hypertrophy (RVH) was confirmed by the Fulton index showing severe RVH in the Sugen/hypoxia model (SUHx) animals

Summary

Introduction

Pulmonary arterial hypertension (PAH), or group I pulmonary hypertension (PH), is a rare but fatal disease characterized by progressive elevation in pulmonary artery pressure. Macroaggregates are retained within the pulmonary arterioles in relation to their diameter (50–150 μm) and in proportion to the distribution of flow This “physical” tracer cannot diagnose non-anatomical abnormalities associated with pulmonary vascular disease (PVD) and its capacity to reveal small resistance arteries obstruction is limited by the size of the particles and by spatial resolution. This is relevant to PAH that affects lung arterioles and explains why human subjects with PAH can have apparently normal 99mTc-MAAs lung perfusion scans. The primary aims of this study were: (1) to evaluate the capacity of the endothelial cell tracer 99mTc-PB to detect the presence of angio-proliferative PVD by imaging the AM1 receptor in the SUHx of PAH and (2) to investigate the potential therapeutic effects of two doses of sildenafil on angio-proliferative PVD by assessing 99mTc-PB uptake kinetics

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