Assessment of Inflammation in Pulmonary Artery Hypertension by 68Ga-Mannosylated Human Serum Albumin

Abstract

Rationale: Diagnosis and monitoring of patients with pulmonary artery hypertension (PAH) is currently difficult. Objectives: We aimed to develop a noninvasive imaging modality for PAH that tracks the infiltration of macrophages into the pulmonary vasculature, using a positron emission tomography (PET) agent, Ga-68-2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) mannosylated human serum albumin (MSA), that targets the mannose receptor (MR). Methods: We induced PAH in rats by monocrotaline injection. Tissue analysis, echocardiography, and Ga-68-NOTA-MSA PET were performed weekly in rats after monocrotaline injection and in those treated with either sildenafil or macitentan. The translational potential of Ga-68-NOTA-MSA PET was explored in patients with PAH. Measurements and Main Results: Gene sets related to macrophages were significantly enriched on whole transcriptome sequencing of the lung tissue in PAH rats. Serial PET images of PAH rats demonstrated increasing uptake of Ga-68-NOTA-MSA in the lung by time that corresponded with the MR-positive macrophage recruitment observed in immunohistochemistry. In sildenafil- or macitentan-treated PAH rats, the infiltration of MR-positive macrophages by histology and the uptake of Ga-68-NOTA-MSA on PET was significantly lower than that of the PAH-only group. The pulmonary uptake of Ga-68-NOTA-MSA was significantly higher in patients with PAH than normal subjects (P = 0.009) or than those with pulmonary hypertension by left heart disease (P = 0.019) (n = 5 per group). Conclusions: Ga-68-NOTA-MSA PET can help diagnose PAH and monitor the inflammatory status by imaging the degree of macrophage infiltration into the lung. These observations suggest that Ga-68-NOTA-MSA PET has the potential to be used as a novel noninvasive diagnostic and monitoring tool of PAH.