Unraveling the Molecular Mechanism of Action of Empagliflozin in Heart Failure With Reduced Ejection Fraction With or Without Diabetes

Oriol Iborra-Egea; Evelyn Santiago-Vacas; Salva R Yurista; Josep Lupón; Milton Packer; Stephane Heymans; Faiez Zannad; Javed Butler; Domingo Pascual-Figal; Antonio Lax; Julio Núñez; Rudolf A de Boer; Antoni Bayés-Genís

doi:10.1016/j.jacbts.2019.07.010

Unraveling the Molecular Mechanism of Action of Empagliflozin in Heart Failure With Reduced Ejection Fraction With or Without Diabetes

JACC Basic Transl Sci. 2019 Oct 23;4(7):831-840. doi: 10.1016/j.jacbts.2019.07.010. eCollection 2019 Nov.

Authors

Oriol Iborra-Egea^{1

2

3}, Evelyn Santiago-Vacas^{1

2

3}, Salva R Yurista⁴, Josep Lupón^{1

2

3}, Milton Packer⁵, Stephane Heymans⁶, Faiez Zannad⁷, Javed Butler⁸, Domingo Pascual-Figal⁹, Antonio Lax⁹, Julio Núñez¹⁰, Rudolf A de Boer⁴, Antoni Bayés-Genís^{1

2

3}

Affiliations

¹ Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
² Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
³ Centro de Investigación Biomédica en Red Enfermedades Cardiovascualres (CIBERCV), Madrid, Spain.
⁴ Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁵ Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas.
⁶ Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
⁷ Centre d'Investigation Clinique Plurithématique 1433, INSERM U1116, Université de Lorraine, Centre Hospitalier Régional et Universitaire de Nancy, French Clinical Research Infrastructure Network (F-CRIN), Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists (INI-CRCT), Nancy, France.
⁸ Department of Medicine, University of Mississippi, Jackson, Mississippi.
⁹ Domingo Hospital Universitario Virgen de la Arrixaca, University of Murcia, Centro Nacional de Investigaciones Cardiovasculares, CIBERCV, Murcia, Spain.
¹⁰ Cardiology Department, Hospital Clínico Universitario, CIBERCV, INCLIVA, Universitat de València, València, Spain.

Abstract

The 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.

Keywords: ANN, artificial neural network; DM, diabetes mellitus; HF, heart failure; HFrEF, HF with reduced ejection fraction; MI-HF, post-infarct heart failure; NHE, sodium-hydrogen exchanger; RNAseq, RNA sequencing; SGLT2i, sodium-glucose co-transporter 2 inhibitor; empagliflozin; heart failure; machine learning.