How Rapidly Does the FAPI PET Signal Reverse Following Therapy? Assessing the FAPI PET Signal in Hypertensive Cardiac Injury and Fibrosis in Mice.

Abstract

Reactive fibrosis is a complex response to chronic myocardial insults, contributing to heart failure progression. Fibroblast activation protein inhibitor (FAPI) PET shows promise in distinguishing active from established fibrosis. Although antifibrotic therapies may improve left ventricular (LV) function in preclinical studies, their clinical application is limited by the lack of noninvasive imaging methods to assess fibrosis regression. This study investigates the potential of FAPI PET to track the therapeutic transition of activated fibroblast activation protein (FAP)-positive fibroblasts toward a FAP-negative phenotype. <b>Methods:</b> Mice were implanted with minipumps, infused with angiotensin-II/phenylephrine (Ang-II/PE) for 6 wk and scanned with ⁶⁸Ga-FAPI-46 PET/CT longitudinally. Control mice received saline. ⁶⁸Ga-FAPI-46 biodistribution studies were conducted at preselected time points, and FAPI uptake in the major organs was measured ex vivo. To assess the potential reversibility of the FAPI PET signal in the myocardium and liver, Ang-II/PE infusion was discontinued in a group of animals at 1 and 2 wk, respectively. LV structural and functional changes were assessed via echocardiography, tissue fibrosis via histology, and FAP expression via immunohistochemistry. <b>Results:</b> Significant ⁶⁸Ga-FAPI-46 uptake in the myocardium of treated mice peaked at 1 wk. An increase of ⁶⁸Ga-FAPI-46 uptake was also observed in the liver, peaking at 2 wk, and decreased significantly at 4 wk. The PET signal declined to an indiscernible level in the heart and liver early after Ang-II/PE withdrawal. Three weeks after the removal of the minipumps, the hearts of mice previously exposed to Ang-II/PE for 1 wk exhibited a significant reduction in fibrosis compared with mice that were sacrificed immediately after 1 wk of Ang-II/PE infusion, without the 3-wk recovery period. Coinjection with excess unlabeled FAPI-46 reduced uptake in the heart, liver, and kidneys. Despite an increase in LV wall thickness at 1 wk, the ejection fraction remained stable initially but dropped significantly by 4 wk. <b>Conclusion:</b> The rapid decline in PET signal after Ang-II/PE withdrawal shows that FAPI PET effectively visualizes dynamic changes in FAP expression, making it a valuable tool for quickly assessing treatment responses targeting activated fibroblasts. The cardiac FAPI signal precedes functional myocardial changes, indicating that FAPI PET could detect early fibrosis in cardiac remodeling leading to heart failure. FAPI PET may also visualize cardiac cirrhosis, a serious complication of cardiac disorders.