The early metabolic cardiac targets of empagliflozin during the development of heart failure, independent of SGLT2 inhibition

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Background & purpose Cardiac metabolic changes are known early drivers of heart failure (HF). Recent preclinical research showed that protection against HF by sodium glucose transporter 2 inhibitors (SGLT2i) is independent of SGLT2 inhibition. Here, we unravel the SGLT2-independent metabolic effects of SGLT2i during early HF, to shed light on the early cardiac metabolic mechanisms through which SGLT2i may confer protection against HF. Methods Short-term HF was induced through transverse aortic constriction (TAC) and deoxycorticosterone (DOCA) administration in WT and SGLT2 KO mice, in the presence or absence of Empagliflozin (EMPA). Ten days post-surgery, following in vivo echocardiography, hearts were Langendorff-perfused. The SGLT2-independent metabolic effects of EMPA were determined by: 1) performing stable isotope tracer analysis for 13 C-glucose to asses relative glucose contribution to metabolic pathways via fluxomics ( 13 C-glucose perfusion), 2) quantifying metabolic intermediates using metabolomics (LC/MS), 3) evaluating metabolic regulators through Western blot analysis, and 4) analyzing gene expression of metabolic pathways via RNA sequencing. Results Independent of SGLT2 (i.e., being present in both genotypes), TAC/DOCA resulted in in vivo HF (systolic and diastolic dysfunction) that was prevented by EMPA. The early SGLT2-independent cardiac metabolic properties showed: 1) HF hearts used relatively less glucose for energy production through glycolysis and TCA cycle, with more glucose being diverted toward synthesis of glutamine. In contrast, EMPA enhanced glucose labeling of the distal part of glycolysis without affecting relative glucose contribution to acetyl CoA or TCA intermediates, 2) HF led to increased metabolic intermediates (malate, aspartate, 2-hydroxyglutarate) that are known to drive pathology, whereas EMPA reduced pathology-causing metabolic intermediates (malate, glucose-6-P), together with increased lactate release and ATP content, 3) EMPA increased the metabolic regulator SIRT3 and the insulin-sensitive glucose transporter (GLUT4) without affecting AMPK, and 4) HF decreased fatty acid metabolism gene expression, whereas EMPA increased multiple mitochondrial metabolic pathways (TCA cycle, branched-chained amino acid, fatty acid, mitochondrial respiratory chain complexes), possibly through increased ERRα signaling. Conclusion The early, SGLT2-independent, metabolic mechanism marking HF protection by SGLT2i entail 1) decreases in metabolic intermediates that drive hypertrophy (G6P, malate), 2) boosting glycolysis (GLUT4, distal part glycolysis, lactate release) without shifting glucose/fatty acid oxidation ratio, and 3) activating ERRα/SIRT3 pathway associated with increased gene expression of mitochondrial energy pathways and improved cardiac ATP levels.

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