Canagliflozin Ameliorates Myocardial Fibrosis and Cardiac Function in Chronic Heart Failure: A Dose‐Independent Therapeutic Approach

The myocardial fibrosis leading to cardiac remodelling is a key factor in the progression of chronic heart failure. The present study aims to investigate the mechanism of canagliflozin's improvement of cardiac fibrosis in chronic heart failure rats and the effect of dose on efficacy. Chronic heart failure models were established by intraperitoneal injection of isoproterenol to rats for 10 days. The rats were then randomised into five groups: control rats, chronic heart failure rats, rats treated with a low dose of canagliflozin, rats treated with a high dose of canagliflozin and rats treated with enalapril. Canagliflozin was administered once daily for 4 weeks by gastric feeding. The rats were then euthanised after cardiac function analysis by echocardiography. Detection of chronic heart failure markers from serum was performed using enzyme-linked immunosorbent assay kits. The tissue sections were examined by histological staining to assess the cardioprotective effect of canagliflozin in chronic heart failure rats. Myocardial interstitial fibrosis was evaluated by specific immunostaining. The control, chronic heart failure and low dose of canagliflozin groups were sequenced and analysed to identify differentially expressed genes, and the expression of selected genes was verified by qRT-PCR. Echocardiographic measurements provided evidence supporting the ability of canagliflozin to improve cardiac function. Canagliflozin treatment reduced the chronic heart failure marker N-terminal pro-B-type natriuretic peptide. HE staining and Masson's trichrome staining demonstrated that canagliflozin effectively reduced collagen deposition and alleviated myocardial fibrosis. The immunohistochemical staining revealed that treatment with canagliflozin inhibited the expression of fibrosis markers Collagen I, Collagen III and fibronectin 1. The differentially expressed genes identified through RNA sequencing were found to be enriched in the ECM-receptor interaction pathway. The results of qRT-PCR demonstrated that canagliflozin reduced the level of differentially expressed genes involving collagen type I alpha 1 chain, collagen type I alpha 2 chain, collagen type III alpha 1 chain and fibronectin 1. Interestingly, the results did not show a trend toward better efficacy of high-dose compared with low-dose canagliflozin in the treatment of chronic heart failure. In summary, canagliflozin could directly improve myocardial fibrosis to control the progression of chronic heart failure. Canagliflozin may not be dose-dependent in the treatment of chronic heart failure.