Carlos G Santos-Gallego1, Juan Antonio Requena-Ibanez2, Rodolfo San Antonio3, Kiyotake Ishikawa4, Shin Watanabe4, Belen Picatoste5, Eduardo Flores3, Alvaro Garcia-Ropero6, Javier Sanz4, Roger J Hajjar4, Valentin Fuster4, Juan J Badimon7. 1. AtheroThrombosis Research Unit, Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: carlos.santos-gallego@mssm.edu. 2. AtheroThrombosis Research Unit, Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Cardiology Department, University Hospital of Ciudad Real, Ciudad Real, Spain. 3. AtheroThrombosis Research Unit, Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Cardiology Department, Hospital Clinic de Barcelona, Barcelona, Spain. 4. Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 5. Biochemistry Department, Weill Cornell Medical College, New York, New York. 6. AtheroThrombosis Research Unit, Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 7. AtheroThrombosis Research Unit, Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: juan.badimon@mssm.edu.
Abstract
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.
BACKGROUND:Empagliflozin cardiac benefits in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes MellitusPatients) 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.
Authors: Valeria E Duarte; Julia A Graf; Kimberlee Gauvreau; Sarah Rae Easter; Sheila C Drakeley; Matthew R Carazo; Katherine E Economy; Anne Marie Valente; David M Harrild Journal: Pediatr Cardiol Date: 2020-09-11 Impact factor: 1.655
Authors: Mark C Petrie; Subodh Verma; Kieran F Docherty; Silvio E Inzucchi; Inder Anand; Jan Belohlávek; Michael Böhm; Chern-En Chiang; Vijay K Chopra; Rudolf A de Boer; Akshay S Desai; Mirta Diez; Jaroslaw Drozdz; Andre Dukát; Junbo Ge; Jonathan Howlett; Tzvetana Katova; Masafumi Kitakaze; Charlotta E A Ljungman; Béla Merkely; Jose C Nicolau; Eileen O'Meara; Pham Nguyen Vinh; Morten Schou; Sergey Tereshchenko; Lars Køber; Mikhail N Kosiborod; Anna Maria Langkilde; Felipe A Martinez; Piotr Ponikowski; Marc S Sabatine; Mikaela Sjöstrand; Scott D Solomon; Per Johanson; Peter J Greasley; David Boulton; Olof Bengtsson; Pardeep S Jhund; John J V McMurray Journal: JAMA Date: 2020-04-14 Impact factor: 56.272
Authors: Yi Tan; Zhiguo Zhang; Chao Zheng; Kupper A Wintergerst; Bradley B Keller; Lu Cai Journal: Nat Rev Cardiol Date: 2020-02-20 Impact factor: 32.419