Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway.

Empagliflozin significantly improved cardiac function in wild-type mice after myocardial infarction, while untreated wild-type mice showed progressive systolic dysfunction.

• Untreated WT mice demonstrated progressive systolic dysfunction with a change in ejection fraction (ΔEF) of -11.6 ± 6.3%
• Empa-treated WT mice showed significant improvement with ΔEF of 9.9 ± 4.3%
• Treatment was administered at 10 mg/kg/day for 4 weeks following confirmation of reduced ejection fraction
• Myocardial infarction was surgically induced prior to randomization to empagliflozin or saline

The cardioprotective benefit of empagliflozin was completely abolished in cardiomyocyte-specific BDH1 knockout mice.

• BDH1-KO mice treated with Empa showed ΔEF of -10.5 ± 2.8%, similar to untreated WT mice (-11.6 ± 6.3%)
• BDH1 (beta-hydroxybutyrate dehydrogenase 1) is the primary enzyme responsible for ketone body oxidation in cardiomyocytes
• The knockout was cardiomyocyte-specific, isolating the role of cardiac ketone oxidation from systemic metabolic effects
• These results indicate that cardiomyocyte ketone oxidation is required for Empa cardioprotection

The cardioprotective benefit of empagliflozin was completely abolished in liver-specific FGF21 knockout mice.

• Liver-specific FGF21-KO mice failed to show improvement in post-MI cardiac function with Empa treatment
• This demonstrates that hepatic production of Fibroblast Growth Factor-21 (FGF21) is required for Empa's cardiac benefit
• The use of liver-specific knockouts isolates the contribution of the liver to the cardioprotective mechanism
• Results suggest empagliflozin acts through a liver-heart metabolic axis rather than directly on the heart

Empagliflozin increased cardiac BDH1 expression in wild-type mice but not in hepatocyte-specific FGF21-deficient mice after one week of treatment.

• Experiments were conducted in both WT and hepatocyte-specific FGF21-KO mice
• One week of Empa treatment was sufficient to detect changes in cardiac BDH1 expression
• BDH1 upregulation in the heart was absent when hepatic FGF21 was genetically deleted
• This finding links liver-derived FGF21 to downstream regulation of cardiac ketone metabolism machinery

In human iPSC-derived cardiomyocytes, FGF21 induced BDH1 expression, whereas empagliflozin had no direct effect on BDH1.

• Experiments were performed in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-cardiomyocytes)
• FGF21 treatment directly upregulated BDH1 expression in these cells
• Empagliflozin alone did not directly increase BDH1 expression in cardiomyocytes
• These results support the conclusion that Empa's effect on cardiac BDH1 is indirect, mediated through liver-derived FGF21 rather than a direct drug effect on heart cells

In HepG2 liver cells, empagliflozin increased both FGF21 and BDH1 expression.

• Experiments were conducted in HepG2 human hepatocyte cell line
• Empa treatment upregulated expression of both FGF21 and BDH1 in liver cells
• This provides a cellular mechanism by which SGLT2 inhibition in the liver could initiate the liver-heart signaling axis
• These findings are consistent with the in vivo data showing liver-specific FGF21 production as a required mediator of Empa cardioprotection

The study identifies a liver-heart metabolic axis involving FGF21 and ketone body oxidation as a key mechanism of SGLT2 inhibitor cardioprotection after myocardial infarction.

• The proposed pathway is: empagliflozin stimulates hepatic FGF21 production → FGF21 acts on cardiomyocytes to upregulate BDH1 → increased ketone oxidation supports cardiac recovery post-MI
• Loss of either component (cardiomyocyte BDH1 or hepatic FGF21) is sufficient to completely abolish the cardioprotective effect
• Both in vivo mouse models and in vitro human cell models were used to support this mechanism
• The study addresses an incompletely understood mechanism of SGLT2 inhibitor benefit in heart failure