Protective effect of a chronic hypobaric hypoxic environment at high altitude on cardiotoxicity induced by doxorubicin in rats: a 7 T magnetic resonance study.

Abstract

Doxorubicin (DOX)-induced cardiotoxicity (DIC), a major clinical problem, has no effective preventive therapies. We hypothesized that left ventricular (LV) systolic function would be improved in a chronic hypobaric hypoxia environment at high altitude. The purpose of this study was to investigate whether cardiovascular magnetic resonance could reveal the cardioprotective effect of chronic hypobaric hypoxia on DIC. In total, 60 rats were randomly assigned to 1 of 6 groups (n=10 per group): the P group (plain), PD group (plain + DOX), HH group (high altitude), HHD4 group (high altitude + DOX for 4 weeks), HHD8 group (high altitude + DOX for 8 weeks), and HHD12 group (high altitude + DOX for 12 weeks). The rats were transported to either Yushu (altitude: 4,250 m) or Chengdu (altitude: 500 m) where they underwent intraperitoneal injection of DOX (5 mg/kg/week for 3 weeks) or saline. Preclinical 7 T cardiovascular magnetic resonance was performed at weeks 4, 8, and 12. Tissue tracking was used to measure LV cardiac function and to analyze global and segmental strains. Subsequently, histological and oxidative stress tests were performed to evaluate the protective effect of a high-altitude environment on DIC. The left ventricular ejection fraction (LVEF) and global and regional strains in the middle, apical, anterior, septal, inferior, and lateral segments (all P<0.05) were improved in the HHD4 group compared with the PD group. The global strain was significantly greater in absolute value in the HHD8 and HHD12 groups than in the HHD4 group (all P<0.05). Additionally, histological and enzyme-linked immunosorbent assay evaluations supported the in vivo results. A chronic hypobaric and hypoxic environment at high altitude partially prevented cardiac dysfunction and increased global and regional strain in DIC rat models, thereby minimizing myocardial injury and fibrosis. In addition, by increasing the total duration of chronic hypobaric hypoxia, the global strain was further increased, which was likely due to reduced oxidative stress.