Metabolic Changes Precede Radiation‐Induced Cardiac Remodeling in Beagles: Using Noninvasive (18)F‐FDG ((18)F‐Fludeoxyglucose) and (13)N‐Ammonia Positron Emission Tomography/Computed Tomography Scans

BACKGROUND: This study was performed to characterize the metabolic, functional, and structural cardiac changes in a canine model of radiation‐induced heart disease by serial in vivo imaging and ex vivo analyses. METHODS AND RESULTS: Thirty‐six dogs were randomly assigned to control or irradiated groups at 3 time points (months 3, 6, and 12 after radiation; each group comprised 6 dogs). The left anterior myocardium of dogs in irradiated groups was irradiated locally with a single dose of 20‐Gy X‐ray. The irradiated myocardial regions showed increased myocardial uptake of (18)F‐FDG ((18)F‐fludeoxyglucose) in the irradiated beagles, but the increased uptake area decreased at months 6 and 12 compared with month 3 after radiation. Abnormality of myocardial perfusion and cardiac function were detected at month 6 after radiation. Compared with the control groups, the protein expression of GLUT4 (glucose transporter 4) was upregulated in the irradiated groups, correlating with significantly decreased CPT1 (carnitine acyltransferase 1) expression. Mitochondria degeneration, swelling, and count reduction in the irradiated groups were observed. The difference in CD68 of macrophage markers and the inflammatory cytokines (IL‐6 [interleukin 6], TNF‐α [tumor necrosis factor α]) between the irradiation and control groups was not significant. Furthermore, the progressive aggravation of apoptosis and fibrosis was displayed. CONCLUSIONS: Elevated (18)F‐FDG uptake occurred after irradiation and subsequently led to ventricular perfusion defects and dysfunction. The process was associated with myocardial metabolic substrate remodeling, cardiac muscle cell apoptosis, and myocardial fibrosis rather than inflammation.