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

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

JACC: Basic to Translational Science (Nov 2019)

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

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

Affiliations

Oriol Iborra-Egea, MSc: Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovascualres (CIBERCV), Madrid, Spain
Evelyn Santiago-Vacas, MD: Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovascualres (CIBERCV), Madrid, Spain
Salva R. Yurista, MD: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Josep Lupón, MD, PhD: Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovascualres (CIBERCV), Madrid, Spain
Milton Packer, MD: Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
Stephane Heymans, MD: Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands
Faiez Zannad, MD: 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
Javed Butler, MD: Department of Medicine, University of Mississippi, Jackson, Mississippi
Domingo Pascual-Figal, MD: Domingo Hospital Universitario Virgen de la Arrixaca, University of Murcia, Centro Nacional de Investigaciones Cardiovasculares, CIBERCV, Murcia, Spain
Antonio Lax, PhD: Domingo Hospital Universitario Virgen de la Arrixaca, University of Murcia, Centro Nacional de Investigaciones Cardiovasculares, CIBERCV, Murcia, Spain
Julio Núñez, MD, PhD: Cardiology Department, Hospital Clínico Universitario, CIBERCV, INCLIVA, Universitat de València, València, Spain
Rudolf A. de Boer, MD, PhD: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Antoni Bayés-Genís, MD, PhD: Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovascualres (CIBERCV), Madrid, Spain; Address for correspondence: Dr. Antoni Bayes-Genis, Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, 08916 Barcelona, Spain.

Journal volume & issue: Vol. 4, no. 7
pp. 831 – 840

Abstract

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Summary: 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. Key Words: empagliflozin, heart failure, machine learning

Published in JACC: Basic to Translational Science

ISSN: 2452-302X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the circulatory (Cardiovascular) system
Website: https://www.journals.elsevier.com/jacc-basic-to-translational-science/

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