Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF

Abstract

Aims Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodeling and atrial fibrillation is frequently observed in HFpEF. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial antiarrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin. Methods and Results Cardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green–2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs HFpEF: 0.21±0.02 vs 0.38±0.04 mmol/L/min (N=7 vs 18); p=0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment with the CaMKII inhibitor autocamtide-2 related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with NHE1 inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes. Conclusion We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to antiarrhythmic effects in patients with HFpEF.

CaMKIIδ-dependent dysregulation of atrial Na+ homeostasis promotes pro-arrhythmic activity in an obstructive sleep apnea mouse model

“…Recently, we showed for the first time that intracellular Na + entry and Na + concentration are higher in the atrial myocytes of patients with HFpEF, a condition in which SDB is very common, which could contribute to atrial contractile dysfunction and arrhythmias ( Trum et al, 2024 ). Interestingly, we also showed that patients with SDB have increased late Na + current in their remodeled atria, which could contribute to intracellular Na + overload ( Lebek et al, 2022 ).…”

“…It is also unclear whether myocardial Na + concentration is actually affected by the altered Na + currents in SDB. Recently, we demonstrated for the first time that intracellular Na + entry and Na + concentration were higher in the atrial myocytes of patients with heart failure and preserved ejection fraction—conditions in which SDB is very common ( Trum et al, 2024 ).…”