Decoding empagliflozin’s molecular mechanism of action in heart failure with preserved ejection fraction using artificial intelligence

Abstract

The use of sodium-glucose co-transporter 2 inhibitors to treat heart failure with preserved ejection fraction (HFpEF) is under investigation in ongoing clinical trials, but the exact mechanism of action is unclear. Here we aimed to use artificial intelligence (AI) to characterize the mechanism of action of empagliflozin in HFpEF at the molecular level. We retrieved information regarding HFpEF pathophysiological motifs and differentially expressed genes/proteins, together with empagliflozin target information and bioflags, from specialized publicly available databases. Artificial neural networks and deep learning AI were used to model the molecular effects of empagliflozin in HFpEF. The model predicted that empagliflozin could reverse 59% of the protein alterations found in HFpEF. The effects of empagliflozin in HFpEF appeared to be predominantly mediated by inhibition of NHE1 (Na+/H+ exchanger 1), with SGLT2 playing a less prominent role. The elucidated molecular mechanism of action had an accuracy of 94%. Empagliflozin’s pharmacological action mainly affected cardiomyocyte oxidative stress modulation, and greatly influenced cardiomyocyte stiffness, myocardial extracellular matrix remodelling, heart concentric hypertrophy, and systemic inflammation. Validation of these in silico data was performed in vivo in patients with HFpEF by measuring the declining plasma concentrations of NOS2, the NLPR3 inflammasome, and TGF-β1 during 12 months of empagliflozin treatment. Using AI modelling, we identified that the main effect of empagliflozin in HFpEF treatment is exerted via NHE1 and is focused on cardiomyocyte oxidative stress modulation. These results support the potential use of empagliflozin in HFpEF.

Impact of dapagliflozin treatment on renal function and diuretics use in acute heart failure: a pilot study

“…This decision was made, first, according to the paradigm of role of inflammation and oxidative stress in HFpEF, where SGLT2i can benefit through the blockade of NH1 receptors. 43 Second, it was shown that SGLT2i improves the diastolic function of the LV and the LV mass index. 44 We also had data from the SOLOIST-WHF study, where sotagliflozin was shown to have a beneficial effect, although 20.1% of patients had LVEF>50%.…”

“…Our study included patients regardless of LVEF. This decision was made, first, according to the paradigm of role of inflammation and oxidative stress in HFpEF, where SGLT2i can benefit through the blockade of NH1 receptors 43. Second, it was shown that SGLT2i improves the diastolic function of the LV and the LV mass index 44.…”

SGLT2 Inhibitors and Their Antiarrhythmic Properties

“…Therefore, big data analysis using deep learning artificial intelligence seems to be a reasonable approach to reveal the most likely targets. An algorithm that analyzed publicly available databases showed that empagliflozin could reverse 59% of all known protein alterations in heart failure with preserved ejection fraction (HFpEF) with a predominance of the effect via the sodium hydrogen antiporter 1 (NHE1) receptor and the impact on oxidative stress modulation, myocardial stiffness, myocardial extracellular matrix remodeling, and systemic inflammation [102]. None such analysis has been performed for another SGLT2 inhibitor so far.…”

Clinical Evidence and Proposed Mechanisms of Sodium–Glucose Cotransporter 2 Inhibitors in Heart Failure with Preserved Ejection Fraction: A Class Effect?

“…Increasing evidence supports SGLT2is' inhibition of NHE1 in the heart, either directly and/or indirectly, explaining some of the cardioprotective mechanisms in HFpEF ( Figure 2 ). [ 38 , 109 , 110 ] Enhanced activity of NHE1 has been detected in HFpEF pathology, such as in pressure overload and hypertensive hypertrophy. [ 111 – 113 ] When pathologically activated in cardiomyocytes, NHE1 exchanges hydrogen for an intrusion of sodium with reversal of the Na + /Ca2 + exchanger, resulting in sodium-dependent calcium overload, pH alterations and oxidative stress.…”

“…[ 114 ] A mechanistic study using artificial intelligence also showed empagliflozin-mediated NHE1 inhibition appears to modulate cardiomyocyte stiffness, myocardial extracellular matrix remodelling, systemic inflammation and concentric hypertrophy mechanisms. [ 110 ] Validation of the data was performed by measuring declining plasma concentrations of inducible nitric oxide synthase, NLR family pyrin domain containing 3 inflammasome and TGF-β1 during 12 months of empagliflozin treatment. [ 110 ]…”