A new model of heart failure with preserved ejection fraction using external radiation therapy in male rats

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of heart failure cases and is characterized by diastolic dysfunction, myocardial fibrosis, inflammation, and endothelial alterations. However, relevant preclinical models remain limited. As chest radiotherapy induces cardiac fibrosis and endothelial injury, we hypothesized that targeted cardiac irradiation could reproduce key features of HFpEF. Male Sprague-Dawley rats were randomized to receive cardiac irradiation at 10 or 20 Gy, or no irradiation. Cardiac structure and function were assessed longitudina ly by echocardiography and invasive pressure-volume Disclaimer: This is a confidential document. analysis, and exercise capacity was evaluated using a treadmil test. Myocardial fibrosis, inflammation, and oxidative stress were analyzed by histological and biochemical methods. Irradiated rats preserved systolic function but developed significant diastolic dysfunction, with increased left ventricular end-diastolic pressure and prolonged relaxation time constant. Exercise tolerance was reduced by approximately 25% at 5 months. Histological analyses revealed increased interstitial and perivascular fibrosis with elevated co lagen I expression. CD68-positive macrophage infiltration was markedly increased, whereas CD163-positive ce ls were unchanged. Oxidative stress was evidenced by reduced superoxide dismutase activity and increased protein carbonylation. Targeted cardiac irradiation therefore induces a reproducible HFpEF-like phenotype, providing a relevant model to investigate HFpEF pathophysiology and radiation-induced cardiotoxicity.