Iborra-Egea, OriolSantiago-Vacas, EvelynYurista, Salva RLupón, JosepPacker, MiltonHeymans, StephaneZannad, FaiezButler, JavedPascual-Figal, Domingo ALax, AntonioNúñez, Juliode Boer, Rudolf ABayes-Genis, Antoni2020-04-212020-04-212019-11JACC Basic Transl Sci. 2019; 4(7):831-8402452-302Xhttp://hdl.handle.net/20.500.12105/9658The mechanism of action of empagliflozin in heart failure with reduced ejection fraction (HFrEF) was deciphered using deep learning in silico analyses together with in vivo validation. The most robust mechanism of action involved the sodium-hydrogen exchanger (NHE)-1 co-transporter with 94.7% accuracy, which was similar for diabetics and nondiabetics. Notably, direct NHE1 blockade by empagliflozin ameliorated cardiomyocyte cell death by restoring expression of X-linked inhibitor of apoptosis (XIAP) and baculoviral IAP repeat-containing protein 5 (BIRC5). These results were independent of diabetes mellitus comorbidity, suggesting that empagliflozin may emerge as a new treatment in HFrEF.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/ANN, artificial neural networkDM, diabetes mellitusHF, heart failureHFrEF, HF with reduced ejection fractionMI-HF, post-infarct heart failureNHE, sodium-hydrogen exchangerRNAseq, RNA sequencingSGLT2i, sodium-glucose co-transporter 2 inhibitorEmpagliflozinHeart failureMachine learningAttribution-NonCommercial-NoDerivatives 4.0 Internacional3199885147831-84010.1016/j.jacbts.2019.07.0102452-302XJACC. Basic to translational scienceopen access