Abstract Body: Background: Anthracycline cardiotoxicity disproportionately affects older patients, yet mechanisms beyond cardiomyocyte injury remain poorly defined. Cardiac lymphatic vessels regulate interstitial fluid homeostasis and immune cell clearance, suggesting a potential role in cardiotoxicity.
Objective: To determine whether aging exacerbates doxorubicin-induced cardiotoxicity through cardiac lymphatic remodeling and immune dysregulation.
Methods: Young (4-month) and aged (18-month) C57BL/6J mice received doxorubicin (5 mg/kg/week x 4; cumulative 20 mg/kg). Cardiac function was assessed longitudinally by echocardiography (E/e', fractional shortening [FS]). Cardiac lymphatic architecture was analyzed by immunostaining and 3D reconstruction. Lymphatic function was evaluated by fluorescent tracer clearance. Immune cell dynamics were assessed by flow cytometry and spatial imaging. Fibrosis and edema were quantified by histology.
Results: Aged mice developed early diastolic dysfunction prior to overt systolic impairment. With cumulative exposure, aged mice exhibited greater systolic decline (reduced FS). This was accompanied by pronounced lymphatic remodeling, including vessel rarefaction, reduced open lymphatic density, decreased branching, and pathological dilation, along with impaired lymphatic drainage. Doxorubicin-treated aged hearts showed increased neutrophil accumulation, with marked peri-lymphatic retention. Spatial analyses revealed localized cardiomyocyte injury adjacent to dysfunctional lymphatic vessels. Histological analyses demonstrated increased myocardial edema and interstitial fibrosis.
Conclusions: Aging exacerbates anthracycline cardiotoxicity through early cardiac lymphatic dysfunction, impaired drainage, and immune cell retention. These findings identify lymphatic remodeling as a previously underappreciated mechanism and potential therapeutic target in cardio-oncology.