Integrated [18F]mFBG PET/CMR Reveals Early Sympathetic Dysfunction Preceding Myocardial Fibrosis and Pharmacotherapy Response in Heart Failure with Preserved Ejection Fraction Model

Abstract Aims We aimed to explore the assessment of heart failure with preserved ejection fraction (HFpEF) and intervention drug efficacy with integrated [ 18 F]-meta-fluorobenzylguanidine ([ 18 F]mFBG) positron emission tomography/cardiac magnetic resonance imaging (PET/CMR). Methods This study included 20 adult swine of 8 months and 20–30 kg, and randomly assigned to subgroups: control group and model group with non-intervention, early and late intervention. The HFpEF models were induced by deoxycorticosterone acetate sustained-release tablets (DOCA), angiotensin II sustained-release pump, and a high-fat diet. Early and late drugs interventions of metoprolol tartrate and enalapril maleate were administered at 9 days and 13weeks post-modeling, respectively. Echocardiography was utilized at 4, 8, 12, and 16 weeks post-modeling for dynamic assessment of cardiac function and structural alterations to confirm successful model establishment. Concurrently, serum lipids, norepinephrine (NE), serum B-type natriuretic peptide (BNP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were measured to evaluate the progression of the HFpEF model and the effectiveness of drug intervention. [ 18 F]mFBG PET/CMR was conducted to assess sympathetic nerve activity and myocardial fibrosis in HFpEF models dynamically. Linear regression analyzed the correlations between retention index (RI)/extracellular volume (ECV) and tyrosine hydroxylase (TH) antibody immunofluorescence, Masson staining. Results [ 18 F]mFBG uptake showed that RI and target-to-background ratio (TBR) were significantly lower in non-intervention group than control group after modeling ( P < 0.05). RI and TBR were significantly higher in early intervention group than non-intervention group and late intervention group ( P < 0.05). ECV were significantly higher in non-intervention group than control group and were significantly higher in non-intervention group and late intervention group than early intervention group at 8, 12, and 16 weeks ( P < 0.05). Further analysis revealed strong positive correlations between RI and myocardial nerve fiber ( P < 0.001), ECV and myocardial collagen ( P < 0.0001), and strong negative correlations between RI and myocardial collagen ( P < 0.001), ECV and myocardial nerve fiber ( P < 0.0001). Conclusions [ 18 F]mFBG PET/CMR could assess sympathetic nerve function in HFpEF models. Furthermore, this study preliminarily indicated that sympathetic nerve dysfunction preceded myocardial fibrosis. In addition, early intervention drugs reversed sympathetic nerve dysfunction and reduced myocardial fibrosis. Therefore, [ 18 F]mFBG PET/CMR would be sensitive and non-invasive method for early diagnosis, treatment plan, prognostic evaluation of HFpEF patients.