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

Diagnosis and monitoring of patients with pulmonary artery hypertension (PAH) is currently difficult. 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-2-( -isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) mannosylated human serum albumin (MSA), that targets the mannose receptor (MR). We induced PAH in rats by monocrotaline injection. Tissue analysis, echocardiography, and Ga-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-NOTA-MSA PET was explored in patients with PAH. 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-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-NOTA-MSA on PET was significantly lower than that of the PAH-only group. The pulmonary uptake of Ga-NOTA-MSA was significantly higher in patients with PAH than normal subjects ( = 0.009) or than those with pulmonary hypertension by left heart disease ( = 0.019) ( = 5 per group). Ga-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-NOTA-MSA PET has the potential to be used as a novel noninvasive diagnostic and monitoring tool of PAH.