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

Abstract

<b>Rationale:</b> Diagnosis and monitoring of patients with pulmonary artery hypertension (PAH) is currently difficult.<b>Objectives:</b> 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, ⁶⁸Ga-2-(<i>p</i>-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) mannosylated human serum albumin (MSA), that targets the mannose receptor (MR).<b>Methods:</b> We induced PAH in rats by monocrotaline injection. Tissue analysis, echocardiography, and ⁶⁸Ga-NOTA-MSA PET were performed weekly in rats after monocrotaline injection and in those treated with either sildenafil or macitentan. The translational potential of ⁶⁸Ga-NOTA-MSA PET was explored in patients with PAH.<b>Measurements and Main Results:</b> 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 ⁶⁸Ga-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 ⁶⁸Ga-NOTA-MSA on PET was significantly lower than that of the PAH-only group. The pulmonary uptake of ⁶⁸Ga-NOTA-MSA was significantly higher in patients with PAH than normal subjects (<i>P</i> = 0.009) or than those with pulmonary hypertension by left heart disease (<i>P</i> = 0.019) (<i>n</i> = 5 per group).<b>Conclusions:</b>⁶⁸Ga-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 ⁶⁸Ga-NOTA-MSA PET has the potential to be used as a novel noninvasive diagnostic and monitoring tool of PAH.