Combined inhibition of HMG-CoA reductase and the renin-angiotensin system attenuates doxorubicin-induced cardiotoxicity in an albino rat model

Objective
Doxorubicin-associated cardiotoxicity remains a significant clinical challenge in clinical settings. This study aimed to investigate the synergistic cardioprotective effects of combined simvastatin and losartan against doxorubicin-induced cardiac injury.
Materials and methods
A total of 42 Albino Wistar rats were enrolled in the preset study and subdivided into, control male and female groups (received distilled water orally for 7 days and IP normal saline dose at day 14), doxorubicin male and female groups (received distilled water orally for 13 days and single IP dose of doxorubicin 15mg/kg at day 14), and simvastatin+losartan+doxorubicin male and female groups (received oral simvastatin dose of 10 mg/kg/day and losartan dose of 10mg/kg/day for 13 days and single IP dose of doxorubicin 15 mg/kg at day 14). The sampling for all group were conducted at day 16, including blood collection and tissue harvesting after the animal sacrificed. Initial blood sample collected at day 0 before starting any interventional products. Cardiac injury was assessed through histological examination and biochemical analysis of cardiac biomarkers including tumor necrosis factor-alpha (TNF-α), cardiac troponin (TNNI3), and heart-type fatty acid-binding protein (FABP3).
Results
Histological analysis revealed that combination therapy significantly attenuated doxorubicin-induced cardiac damage, showing only slight vascular congestion compared to severe endocardial congestion, inflammatory cell infiltration, and myocyte necrosis observed in the doxorubicin-only group. The combination therapy group demonstrated localized thin fibrous tissue formation between muscle bundles and mild interstitial edema, suggesting active tissue remodeling and healing processes. Biochemically, control groups maintained stable baseline levels throughout the study (TNF-α: 49.3±2.5 to 48.5±1.2; troponin: 11±0.3 to 11.7±0.5; FABP3: 0.55±0.09 to 0.66±0.09). The combination therapy provided remarkable cardioprotection in both sexes, with male rats showing non-significant changes in TNF-α (56.3±4.1 to 59.4±6.3, p=0.53), troponin (12.2±1 to 11.8±0.9, p=0.22), and FABP3 (0.67±0.1 to 0.74±0.05, p=0.63). Female rats demonstrated similar protection with TNF-α levels (60.9±7.4 to 56.2±11.3, p=0.6), troponin (10.8±0.7 to 11.7±0.8, p=0.1), and FABP3 (0.6±0.11 to 0.68±0.08, p=0.9) remaining within normal ranges.
Conclusions
The combination of simvastatin and losartan demonstrated synergistic cardioprotective effects against doxorubicin-induced cardiotoxicity through dual mechanisms involving statin-mediated pleiotropic protection and angiotensin receptor blockade. This combination therapy preserved cardiac function, prevented elevation of cardiac injury biomarkers, and promoted beneficial tissue remodeling. These findings suggest that simvastatin-losartan combination therapy represents a promising cardioprotective strategy for patients receiving doxorubicin chemotherapy, potentially allowing for optimal oncological treatment while minimizing cardiac complications.