Author + information
- Received May 20, 2019
- Revision received July 9, 2019
- Accepted July 9, 2019
- Published online November 25, 2019.
- Oriol Iborra-Egea, MSca,b,c,
- Evelyn Santiago-Vacas, MDa,b,c,
- Salva R. Yurista, MDd,
- Josep Lupón, MD, PhDa,b,c,
- Milton Packer, MDe,
- Stephane Heymans, MDf,
- Faiez Zannad, MDg,
- Javed Butler, MDh,
- Domingo Pascual-Figal, MDi,
- Antonio Lax, PhDi,
- Julio Núñez, MD, PhDj,
- Rudolf A. de Boer, MD, PhDd and
- Antoni Bayés-Genís, MD, PhDa,b,c,∗ ()
- aHeart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- bDepartment of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- cCentro de Investigación Biomédica en Red Enfermedades Cardiovascualres (CIBERCV), Madrid, Spain
- dDepartment of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- eBaylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
- fMaastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands
- gCentre 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
- hDepartment of Medicine, University of Mississippi, Jackson, Mississippi
- iDomingo Hospital Universitario Virgen de la Arrixaca, University of Murcia, Centro Nacional de Investigaciones Cardiovasculares, CIBERCV, Murcia, Spain
- jCardiology Department, Hospital Clínico Universitario, CIBERCV, INCLIVA, Universitat de València, València, Spain
- ↵∗Address for correspondence:
Dr. Antoni Bayes-Genis, Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, 08916 Barcelona, Spain.
• Using artificial intelligence, followed by in vivo validation, this study identified the key cardiac mechanism of action of empagliflozin in heart failure in patients with or without diabetes mellitus.
• The most robust mechanism of action involved the NHE-1 co-transporter with 94.7% accuracy.
• NHE-1 blockade by empagliflozin administration in rats restored the antiapoptotic activity of XIAP and BIRC5.
• The beneficial reduction in cardiomyocyte cell death after empagliflozin treatment is independent of the presence of diabetes mellitus.
• Empagliflozin could emerge as a new treatment for heart failure patients regardless of their glycemic status.
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.
Dr. Yurista is supported by Indonesia Endowment Fund for Education grant LPDP 20150722083422. Dr. Packer is a consultant with Abbvie, Amgen, Akcea, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Gilead, Johnson and Johnson, NovoNordisk, Pfizer, Sanofi, Synthetic Biologics, Relypsa, and Theravance. Dr. Zannad is a member of the Boehringer Ingelheim steering committee; and is a consultant for AstraZeneca, Mundipharma, NovoNordisk, and Merck. Dr. Butler is a consultant with Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, BerlinCures, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiocell, Corvidia, CVRx, G3 Pharmaceutical, Innolife, Janssen, Lantheus, LinaNova, Luitpold, Medscape, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, StealthPeptide, SC Pharma, V-Wave Limited, Vifor, and ZS Pharma. Dr. Núñez has received speaker fees from Boehringer Ingelheim. Dr. De Boer holds equity in scPharmaceuticals; has received honoraria from Mandalmed, Novartis, and Servier; and has received research support through his institution from AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Roche, Trevena, and ThermoFisher GmbH. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received May 20, 2019.
- Revision received July 9, 2019.
- Accepted July 9, 2019.
- 2019 The Authors