Dapagliflozin (DAPA) has been reported to have significant cardiac protective effects on heart failure (HF). However, the dose and time, as well as the underlying mechanisms, for DAPA treatment in acute myocardial infarction (AMI) remain controversial. The aim of this study aimed to assess the efficacy and safety of DAPA treatment along with an increased concentration gradient for AMI and explore the potential mechanisms. Methods: Non-diabetic Sprague-Dawley rats were used for establishing AMI models and then were treated with three different concentrations of DAPA [0.5 mg/kg, 1 mg/kg and 1.5 mg/kg, described as AMI+DAPA Low, AMI+DAPA Medium (Med) and AMI +DAPA High, respectively] for six weeks from the onsetting of AMI. Echocardiography, histological staining and Western blot were performed to assess the relevant cardiac protective effects. Mitochondrial biogenesis and myocardial apoptosis were evaluated via the electron microscopy and TUNEL assay, respectively, as well as the Immunoblotting. In vitro, H9c2 cells were subjected to hypoxic treatment to assess the efficacy of DAPA on mitochondrial biogenesis and apoptosis. Results: The medium dose of DAPA treatment could significantly reduce the infarct size (P < 0.01) and the echocardiography results showed that the MI-induced damage in cardiac function got partly repaired, showing no significant difference in left ventricle ejection fraction (LVEF) versus the Sham group (Sham vs AMI+DAPA Med group: 70.47% vs 61.73%). The Western blotting results confirmed the relevant benefits and the underlying mechanisms might be through the activation of PGAM5/Drp1 signaling pathway to normalize the mitochondrial fission and reduce cardiomyocyte apoptosis. Moreover, a medium dose of DAPA treatment could avoid increased damage to the bladder endothelium following higher treatment doses. Conclusion: Appropriate dose of DAPA treatment could improve the cardiac remodeling and reduce the cardiomyocyte apoptosis after AMI, without increased damage to bladder endothelium, which might be more preferred for MI patients without diabetes.

Background: Dynamin-related protein 1 (Drp1) has been demonstrated as a crucial role in mediating the programed cell death and cardiac metabolism through its regulatory of mitophagy in animal studies. However, the clinical values of Drp1 for human cardiac disease remain unknown. This study is aimed to evaluate the diagnostic and prognostic values of serum Drp1 in these patients with heart failure (HF). Methods: The enzyme linked immunosorbent assay (ELISA) was used for measuring serum Drp1 concentrations in 85 cases of HF with preserved ejection fraction (HFpEF) and 86 cases of HF with reduced ejection fraction (HFrEF). The diagnostic value of Drp1 was evaluated using the receiver operating characteristic (ROC) analysis. The composite endpoint was consisted of cardiac death and rehospitalization for HF, and the association between Drp1 and clinical outcomes were further determined. Results: Serum Drp1 concentrations were much higher in HFpEF than that in HFrEF (4.2 ± 3.7 ng/mL vs. 2.6 ± 2.2 ng/mL, p = 0.001) and the ROC analysis demonstrated it as a potential diagnostic biomarker for distinction of the HF phenotypes, with an optimal cutoff point of 3.5 ng/mL (area under the curve (AUC) = 0.659, sensitivity: 45.9%, specificity: 83.7%). Kaplan-Meier survival analysis indicated that a low serum concentration of Drp1 (cut-off value = 2.5 ng/mL, AUC = 0.738) was in relation to poor prognosis of HF. Moreover, binary logistic regression analysis identified the low serum concentration of Drp1 as an independent risk predictor for rehospitalization (odds ratio (OR) = 6.574, p = 0.001) and a composite endpoint (OR = 5.927, p = 0.001). Conclusions: Our findings suggested that low serum concentrations of Drp1 might serve as a predicting biomarker for distinction of HF phenotypes and overall prognosis of HF.