Illuminating Cardiac Remodeling: Insights From [18F]-Fluorodeoxyglucose Positron Emission Tomography Imaging in Plakoglobin-Associated Arrhythmogenic Cardiomyopathy

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is a genetic heart muscle disease, which presents with arrhythmias and sudden cardiac death, along with progressive cardiac remodeling and myocardial inflammation. This study aims to elucidate the patterns of [(18)F]-fluorodeoxyglucose ([(18)F]-FDG) uptake in a mouse model of plakoglobin-associated cardiac disease to better understand its diagnostic potential. METHODS AND RESULTS: Plakoglobin (Jup) knockout mice developed a cardiomyopathy that presented an ACM-like phenotype at 6 weeks of age. Flow cytometry experiments showed a significant increase of immune cells, for example, an expansion of proinflammatory and tissue-injury macrophages. In vivo positron emission tomography and ex vivo autoradiography showed increased [(18)F]-FDG uptake in genotype positive hearts. A correlative analysis between [(18)F]-FDG positivity and macrophage infiltration using CD68 and CD206 staining did not show colocalization. CD68 and CD206 positivity was primarily observed within the fibrotic scar, whereas [(18)F]-FDG uptake was predominantly identified in CD68 and CD206-negative tissue areas. Instead, [(18)F]-FDG signal seemed to originate from cardiomyocytes adjacent to areas of fibrotic remodeling. Morphometric analysis revealed hypertrophy of these cardiomyocytes, which may reflect metabolic remodeling as a compensatory response. CONCLUSIONS: In our murine model of Jup-related ACM, strong cardiac [(18)F]-FDG uptake was detected, which colocalized with regional hypertrophic cardiomyocytes rather than inflammatory cells. These findings indicate that [(18)F]-FDG positron emission tomography is a valuable tool for identifying and localizing hypermetabolic areas associated with cardiac remodeling in ACM, providing insights into disease mechanisms and potential diagnostic strategies.