The influence of sacubitril and sacubitril/valsartan on echocardiographic and electrocardiographic parameters in a rodent model of anthracycline-induced cardiotoxicity

Anthracycline-induced cardiotoxicity (AIC) poses a clinical challenge in the management of cancer patients. Sacubitril/valsartan (Sac/Val), recently incorporated into the management of heart failure with reduced ejection fraction, was shown to provide an additive cardioprotective effect over Val monotherapy in preclinical models of AIC. However, Sac monotherapy was not assessed in this setting. Thus, we hypothesized that the administration of Sac will provide independent cardioprotective effects in a rodent model of AIC.We aimed to investigate the efficacy of Sac and Sac/Val in the primary prevention of AIC.Male 12-week-old Sprague-Dawley rats received doxorubicin (DOX) intraperitoneally (4 milligrams (mg)/kg weekly) over 4 weeks. The animals were randomly divided into 3 groups (control, Sac/Val, and Sac). Starting on the day of the first DOX injection, animals were gavaged daily with either saline, Sac/Val (20 mg/kg), or Sac (10 mg/kg) for 4 weeks. Echocardiography and electrocardiography (ECG) were performed at baseline and at 4 weeks.The echocardiographic parameters of the left ventricle (LV) systolic function in the control group depicted a DOX-induced deterioration, with a significant decrease of LV ejection fraction (EF) (76.91±2.58% vs. 66.33±5.91; p<0.05), stroke volume/tibial length ratio (0.078±0.009 milliliters (ml)/centimetre (cm) vs 0.058±0.02; p<0.05), and cardiac output/tibial length ratio (20.51±2.43 ml/min/cm vs 12.54±4.11; p<0.05). Additionally, treatment with DOX was associated with prolongation of the QRS complex (25.50±2.81 milliseconds (ms) vs 27.92±4.08, p<0.05) and QTc (64.19±5.42 vs 69.61±3.85; p<0.05). In the treatment groups, a decrease in EF was prevented only in the Sac-treated group (EF: 77.56±2.91 vs 78.67± 4.16; p=0.24), which was not observed in the Sac/Val group (EF: 77.52±1.37 vs 69.57±5.09; p<0.05). Both treatments were effective in preventing deterioration of the stroke volume/tibial length ratio (Sac: 0.075±0.008 vs 0.071±0.012; p=0.48; Sac/Val: 0.068±0.008 vs 0.068±0.008; p=0.36), while only Sac monotherapy prevented a decrease in the cardiac output/tibial length ratio (Sac: 22.81±2.74 vs 17.30±3.11; p=0.11; Sac/Val: 18.36±1.96 vs 15.34±1.15; p<0.05). In both treatment groups, there were no changes in the duration of the QRS complex (Sac: 27.50±3.96 vs 28.00±1,00; p=0.15; Sac/Val: 25.29±3.15ms vs 26.25±0.43; p=0.09), and QTc (Sac: 65.15±3.43 vs 66.16±4.05; p=0.38; Sac/Val: 66.12±5.88 vs 70.18±6.87; p=0.09). Additionally, Sac monotherapy prevented DOX-associated weight loss (319±13.08g vs 309±21.62; p=0.31), which was not observed in the Sac/Val group (314±10,11 vs 275±20,44; p<0.05).Both Sac and Sac/Val offered some protection against deterioration of echocardiographic parameters of LV systolic function and ECG changes in a rodent model of AIC. However, this effect was more pronounced in the group receiving Sac monotherapy, which prevented a decrease in all of the assessed parameters, including weight loss. This study was supported by the MD-PhD program No. 93/FS228/2020 based on cooperation between the Medical University of Warsaw and the National Centre for Research and Development (Poland). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.