Two concurrent mechanisms are responsible for the I increase produced by dapagliflozin and empagliflozin in healthy and heart failure cardiomyocytes.

Dapagliflozin and empagliflozin exert many cardiovascular protective actions in heart failure (HF) patients. HF-induced electrical remodelling decreases the expression of Nav1.5 channels (encoded by SCN5A) that generate the cardiac Na current (I) impairing excitability and promoting arrhythmias. We aimed to mechanistically decipher the peak I increase produced by dapagliflozin and empagliflozin in healthy and HF cardiomyocytes. We recorded macroscopic and single-channel currents and action potentials (AP) using the patch-clamp technique and generated a mouse model of HF with reduced ejection fraction by transverse aortic constriction (TAC). Single-channel recordings showed that dapagliflozin and empagliflozin (1 μM) increased the open probability (P) of Nav1.5 channels by augmenting channel re-openings and the number of traces with openings and by doubling the open time constant, respectively. Both drugs increased SCN5A mRNA levels and the membrane expression of Nav1.5 channels. Empagliflozin also enhanced the cytoplasmic mobility of Nav1.5 channels. Molecular modelling and site-directed mutagenesis analysis demonstrated that both drugs bind to a previously unknown site at the Nav1.5 DIII-DIV fenestration. Dapagliflozin and empagliflozin hyperpolarized the resting membrane potential and increased the action potential amplitude in human cardiomyocytes derived from induced pluripotent stem cells. Importantly, in TAC cardiomyocytes dapagliflozin and empagliflozin restored the HF-reduced peak I to control levels. Dapagliflozin and empagliflozin bind to a novel site within cardiac Nav1.5 increasing I by augmenting the P and the membrane expression of the channels. We hypothesized that this unique effects could be of interest for the treatment of arrhythmias associated with decreased Nav1.5 channel expression.