Serial cardiac MR assessment and histopathological evaluation of doxorubicin-induced cardiomyopathy in a miniature swine model

OBJECTIVE: Doxorubicin-induced cardiomyopathy remains challenging to detect at an early stage. This study aims to assess cardiac MR changes and their pathological correlates in a swine model of doxorubicin-induced cardiomyopathy. METHODS: Miniature pigs received repeated intravenous doxorubicin administration and underwent serial cardiac MR examinations from baseline to 32 weeks. Left ventricular function, global strain, and T2 relaxation time were assessed longitudinally. Histological and ultrastructural analyses were performed at predefined time points to evaluate myocardial injury. RESULTS: LVEF remained relatively preserved during doxorubicin administration and showed only a non-significant declining trend during follow-up. LVGLS showed a non-significant decreasing trend during the treatment (weeks 0-8, P = 0.068) and stabilized during the follow-up period (weeks 8-32, P = 0.35); GCS demonstrated deterioration (week 4: P = 0.006; week 32: P < 0.001); while GRS exhibited significant impairment, with maximal reduction at week 20 (β=-12.87, P = 0.04) that persisted through week 32 (P = 0.001). T2 mapping analysis showed significant elevation during active treatment (χ²=10.5, P = 0.033), followed by partial recovery by the final follow-up (week 32: 36.74 ± 2.80 ms, P = 0.020). Histopathological evaluation demonstrated mitochondrial swelling/vacuolization during treatment, with substantial resolution by week 32. However, persistent abnormalities in myocardial fiber architecture were observed at the study endpoint. CONCLUSIONS: In this miniature swine model, T2 prolongation during doxorubicin treatment was temporally associated with mitochondrial-related ultrastructural alterations and may reflect potentially reversible components of myocardial injury. Persistent strain abnormalities despite T2 normalization suggest incomplete structural recovery, mainly reflecting ultrastructural alterations rather than fibrotic progression. Combined T2 mapping and strain assessment may provide complementary information for characterizing doxorubicin-related myocardial injury in preclinical settings.