Investigation of the cardioprotective effects of dapagliflozin on doxorubicin andtrastuzumab cardiotoxicity

PURPOSE AND HYPOTHESIS: The main purpose of this study is to investigate the potential protective effects of dapagliflozin (DAPA), an SGLT2 inhibitor, in preventing cardiac injury caused by the sequential administration of doxorubicin (DOX) and trastuzumab (TRZ), which mimics a protocol carrying a high risk of cardiotoxicity in oncologic treatment. Although strong cardioprotective effects of DAPA alone against DOX toxicity have been demonstrated in the literature, this study specifically aimed to test the efficacy of DAPA in a complex combined toxicity model involving HER2 blockade. MATERIALS AND METHODS: In the study, a total of 40 adult female Wistar Albino rats, 10 in each group, were used to form four groups (Control, DAPA, DOX+TRZ, DAPA+DOX+TRZ). The cardiotoxicity model was induced by intraperitoneal (i.p.) administration of 3 mg/kg/week DOX for the first 4 weeks and 10 mg/kg/week TRZ for the following 4 weeks. DAPA was administered by oral gavage at a daily dose of 10 mg/kg/day for 8 weeks. The evaluation of cardiac injury was performed through Echocardiography (Ejection Fraction (EF), End-Systolic/End-Diastolic diameters), Electrocardiography (Heart Rate, QRS width), Biochemical analyses (Troponin I, CK-MB, BNP), and Histopathologically via TUNEL Apoptotic Index (TAI). RESULTS: Structural and Functional Findings: In the groups receiving toxic agents (DOX+TRZ and DAPA+DOX+TRZ), End-Systolic (ES) and End-Diastolic (ED) left ventricular diameters were found to be significantly higher compared to the Control group (ES: p=0.010; ED: p=0.002). This indicates that ventricular remodeling could not be prevented despite DAPA protection. No significant difference was detected among the groups in terms of EF values (p=0.418). Electrophysiological Findings: The QRS width of the DAPA+DOX+TRZ group, which received protective treatment, was found to be significantly higher compared to the Control and DOX+TRZ groups (p=0.011). xvi Cellular Injury: Contrary to expectations regarding the anti-apoptotic effect of DAPA, the TUNEL Apoptotic Index (TAI) of the DAPA+DOX+TRZ group reached the numerically highest value (Mean 21.89%), although this difference did not reach statistical significance (p=0.144). Biochemical Findings: CK-MB and BNP levels remained below measurable levels in all rats; no statistically significant difference was found between the groups in terms of Troponin I levels (p=0.799). CONCLUSION: The results of our study contradict the extensive literature findings showing that Dapagliflozin alone provides successful protection against Doxorubicin-induced cardiotoxicity. DAPA failed to prevent myocardial remodeling (increased ED/ES diameters) and cellular death (high TAI) caused by the sequential administration of DOX and TRZ. Our most striking and unique finding is the significant increase in QRS width in the group under DAPA protection, suggesting that DAPA may have entered into an unexpected or adverse interaction on electrophysiological conduction in this specific combined toxicity model. These data indicate that the cardioprotective benefits of DAPA may be limited against the complex cardiotoxicity mechanism exacerbated by Trastuzumab's HER2 signal blockade and reveal the need for further mechanistic research to develop protective strategies in the field of onco-cardiology.