SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy

Figures

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  Fig. 1.. Study design (a): 8-week-old male C57BL/6J mice were fed a control (CD) or high fat, high sucrose diet (HFHS) for six months. Ertugliflozin (ERTU) was added to HFHS in the last month. Left ventricular contractile function and energetics were measured in isolated hearts by 31P NMR spectroscopy at baseline (2 mM Ca2+, paced at 450 bpm) and high work demand (4 mM Ca2+, 600 bpm). Myocardial [Na+]i was measured by 23Na NMR spectroscopy. CD in black, HFHS in red, HFHS + ERTU in green. ERTU improves cardiac function (b): HFHS hearts showed diastolic dysfunction (increased left ventricular end-diastolic pressure, LVEDP) and decreased contractile reserve, assessed by rate pressure product, RPP. ERTU improves cardiac energetics (c): Phosphocreatine (PCr) concentration and PCr/ATP were lower in HFHS during all workloads. ERTU treatment normalized LVEDP, contractile reserve and energetics in HFHS. n = 6 (CD), 9 (HFHS), and 4 (HFHS + ERTU). ***P < 0.001 vs. CD, †††P < 0.001 vs. HFHS. 2-way ANOVA followed by Tukey’s multiple comparisons test.

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  Fig. 2.. ERTU decreases elevated [Na+]i in DCMP: [Na+]i was elevated 2-fold in HFHS, and normalized by ERTU treatment. n = 4 (CD), 5 (HFHS), and 3 (HFHS + ERTU). 1-way ANOVA followed by Tukey’s multiple comparisons test.

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  Fig. 3.. Elevated [Na+]i contributes to impaired cardiac energetics: Perfusion with 1 μmol/l CGP 37157, an NCXMITO inhibitor, improved the PCr/ATP ratio in HFHS hearts to the level of CD, implying a detrimental effect of elevated myocardial [Na+]i on [Ca2+]MITO-dependent ATP production in DCMP. n = 5 (CD), and 6 (HFHS). *P < 0.05 vs. CD. 2-way ANOVA followed by Bonferroni’s multiple comparisons test.

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  Fig. 4.. Schematic representation of ERTU’s effect on intracellular sodium, cardiac energetics and function in DCMP. (Created with BioRender.com).