Author + information
- Received December 10, 2018
- Revision received January 11, 2019
- Accepted January 14, 2019
- Published online April 15, 2019.
- Carlos G. Santos-Gallego, MDa,∗∗ ( )(, )@IcahnMountSinai@SantosGallegoMD,
- Juan Antonio Requena-Ibanez, MDa,b,
- Rodolfo San Antonio, MDa,c,
- Kiyotake Ishikawa, MDd,
- Shin Watanabe, MDd,
- Belen Picatoste, PhDe,
- Eduardo Flores, MDa,c,
- Alvaro Garcia-Ropero, MDa,
- Javier Sanz, MDd,
- Roger J. Hajjar, MDd,
- Valentin Fuster, MD, PhDd and
- Juan J. Badimon, PhDa,∗ (, )@MountSinaiNYC
- aAtheroThrombosis Research Unit, Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- bCardiology Department, University Hospital of Ciudad Real, Ciudad Real, Spain
- cCardiology Department, Hospital Clinic de Barcelona, Barcelona, Spain
- dCardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- eBiochemistry Department, Weill Cornell Medical College, New York, New York
- ↵∗Address for correspondence:
Dr. Juan J. Badimon, Mount Sinai School of Medicine, Department of Cardiology, 1 Gustave L. Levy Place, Box 1030, New York, New York 10029-0310.
- ↵∗∗Dr. Carlos G. Santos-Gallego, Atherothrombosis Research Unit, Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, New York 10029.
Background Empagliflozin cardiac benefits in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial cannot be explained exclusively by its antihyperglycemic activity.
Objectives The hypothesis was that empagliflozin’s cardiac benefits are mediated by switching myocardial fuel metabolism away from glucose toward ketone bodies (KB), which improves myocardial energy production.
Methods Heart failure was induced in nondiabetic pigs (n = 14) by 2-h balloon occlusion of the proximal left anterior descending artery. Animals were randomized to empagliflozin or placebo for 2 months. Animals were evaluated with cardiac magnetic resonance imaging and 3-dimensional echocardiography. Myocardial metabolite consumption was analyzed by simultaneous blood sampling from coronary artery and coronary sinus. Myocardial samples were obtained for molecular evaluation. Nonmyocardial infarction animals served as comparison.
Results Despite similar initial ischemic myocardial injury in both groups, the empagliflozin group showed amelioration of adverse remodeling at 2 months (lower left ventricular [LV] mass, reduced LV dilatation, less LV sphericity) versus the control group. LV systolic function (LV ejection fraction and echocardiography-derived strains) was improved, as was neurohormonal activation. Compared with nonmyocardial infarction, control animals increased myocardial glucose consumption mainly through anaerobic glycolysis while reducing utilization of free fatty acid (FFA) and branched-chain amino acid (BCAA). Empagliflozin-treated pigs did not consume glucose (reduction in myocardial glucose uptake, and glucose-related enzymes) but instead switched toward utilization of KB, FFA, and BCAA (increased myocardial uptake of these 3 metabolites, and enhanced expression/activity of the enzymes implicated in the metabolism of KB/FFA/BCAA). Empagliflozin increased myocardial ATP content and enhanced myocardial work efficiency.
Conclusions Empagliflozin ameliorates adverse cardiac remodeling and heart failure in a nondiabetic porcine model. Empagliflozin switches myocardial fuel utilization away from glucose toward KB, FFA, and BCAA, thereby improving myocardial energetics, enhancing LV systolic function, and ameliorating adverse LV remodeling.
This research was supported by an independent grant from Boehringer Ingelheim Pharmaceuticals, which provided both drug and financial support for the study. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Nikolaus Marx, MD, served as Guest Associate Editor for this paper.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received December 10, 2018.
- Revision received January 11, 2019.
- Accepted January 14, 2019.
- 2019 American College of Cardiology Foundation