Empagliflozin improved cardiac function in diabetic HFpEF patients by upregulating the NO-sGC-cGMP-PKG pathway and reducing inflammation and myocardial stiffness.
Does in vitro treatment with empagliflozin improve protein quality control, inflammation, and cardiomyocyte stiffness in myocardial biopsies from HFpEF patients with diabetes?
Empagliflozin improves cardiomyocyte stiffness and reduces inflammation in diabetic HFpEF myocardial biopsies via the NO-sGC-cGMP-PKG pathway, providing mechanistic insights into its clinical benefits.
Abstract Background Heart failure with preserved ejection fraction (HFpEF) is frequently associated with comorbidities such as type 2 diabetes mellitus (T2DM), which induces distinct molecular alterations. T2DM, among other conditions, exerts detrimental effects on cardiomyocyte metabolism through mechanisms including the formation of advanced glycation end products (AGE), the accumulation of reactive oxygen species (ROS), mitochondrial damage, apoptosis, endothelial dysfunction linked to inflammation, reduced nitric oxide (NO) bioavailability. These pathological changes adversely influence contractile performance and thereby contribute substantially to diastolic dysfunction and cardiac remodeling in HFpEF. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) like empagliflozin (EMPA) is primarily anti-diabetic drugs. Recently, these agents have shown promise as treatments for HFpEF, though the exact mechanisms remain unclear. Aim In this study, we aimed to investigate the effect of T2DM on protein quality control mechanisms, myocardial oxidation, apoptosis, and inflammation. We also sought to elucidate the cardioprotective effects of EMPA on metabolic and inflammatory signaling pathways in HFpEF patients, both with and without DM. Methods We used left ventricular myocardial biopsies and investigated whether diminished protein quality control contributes to cardiac dysfunction in the context of diabetes and whether this dysfunction can be ameliorated through in vitro treatment with EMPA. We conducted a comparative analysis of patients with HFpEF and DM versus those without DM. Results Inflammasome markers were all upregulated in the hearts of diabetic HFpEF patients, indicating markedly increased inflammation. Reduced activation of NO-sGC-cGMP-PKG signalling pathway, increased oxidative stress, and decreased NO bioavailability contribute to increased inflammation in the HFpEF-DM group. Dysregulated insulin signalling was associated with reduced AKT phosphorylation and compromised autophagy in the HFpEF-DM group. Furthermore, decreased expression of HSP27 and HSP70, which were associated with increased cardiomyocyte passive stiffness, indicated PQC dysfunction. Our findings showed that EMPA upregulates the NO-sGC-cGMP-PKG pathway, decreases the inflammatory marker, and corrects the cardiomyocytes’ stiffness in HFpEF-DM groups. Conclusion Chronic catecholamine overload in the context of diabetes leads to impaired protein quality control mechanisms, inflammation, oxidative stress, and dysfunctional cardiomyocytes. EMPA may counteract these detrimental effects by mitigating sympathetic overactivation and promoting the recovery of the NO-sGC-cGMP-PKG pathway and inflammatory pathways. These synergistic effects offer a promising therapeutic strategy for HFpEF, particularly in patients with diabetes. Keywords HFpEF, Diabetes mellitus, Empagliflozin, protein quality control, oxidative stress, inflammation.
Delalat et al. (2026) studied this question. Empagliflozin improved cardiac function in diabetic HFpEF patients by upregulating the NO-sGC-cGMP-PKG pathway and reducing inflammation and myocardial stiffness.