Several studies highlight the potential for SGLT2 inhibitors (i) to exert their cardioprotective effects by shifting myocardial fuel utilization towards ketone oxidation. However, direct in vivo measurements of cardiac mitochondrial substrate oxidation in awake rodents during heart failure are lacking, and whether SGLT2i-mediated increases in ketone availability and oxidation are able to improve cardiac efficiency remains unclear. Here, we examined the effect of acute SGLT2 inhibition with dapagliflozin (dapa) on cardiac function and mitochondrial metabolism in awake male Sprague Dawley rats 2 weeks after induction of heart failure by permanent ligation of the left anterior descending coronary artery. Echocardiography and in vivo metabolic flux studies were performed 4-6 h after oral dapa (1.5 mg/kg) or vehicle treatment in sham-surgerized rats and rats with myocardial infarction (MI) . Acute dapa treatment caused a 15% decrease in fasting plasma glucose concentrations and 50% increase in fasting plasma NEFAs, whole-body βOHB turnover and plasma βOHB levels in sham and MI rats (all P<0.05 vs. VEH) . Dapa treatment decreased left ventricular (LV) [14C]deoxyglucose uptake and relative rates of pyruvate oxidation to total mitochondrial oxidation (VPDH/VCS) by 40-60%. Dapa treatment also caused a 60% increase in relative rates of LV ketone oxidation to total mitochondrial oxidation (VβOHB/VCS) in sham and MI rats (all P<0.05 vs. VEH) , independently of changes in cardiac metabolic gene expression. Interestingly, the dramatic shift in substrate utilization caused by acute dapa treatment did not significantly alter cardiac output or LV ejection fraction. Acute dapa treatment also did not significantly alter myocardial acetyl-CoA content, malonyl-CoA content, ATP/ADP ratios or ATP/AMP ratios in the LV myocardium remote from the infarct.
Conclusion: Taken together, these results demonstrate that single-dose dapa treatment, which acutely decreased LV myocardial pyruvate oxidation and increased LV ketone oxidation, was not sufficient to alter cardiac output or LV ejection fraction.
L. Goedeke: Other Relationship; The Liver Company, Inc. . G. I. Shulman: Advisory Panel; 89bio, Inc., AstraZeneca, Equator Therapeutics, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Consultant; DiCerna Pharmaceuticals, Inc., Novo Nordisk, Other Relationship; Generian Pharmaceuticals, iMetabolic Biopharma Corporation, Maze Therapeutics, The Liver Company, Stock/Shareholder; Levels Health, Inc. . Y. Ma: None. J. Zhang: n/a. N. Guerrera: None. X. Wu: None. D. Zhang: None. M. Kahn: None. X. Zhang: None. L. H. Young: None.
NIH (P30 DK045735 and K99 HL150234) , AstraZeneca (NCR-19-20028)