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

Author:

Trum Maximilian1ORCID,Riechel Johannes1,Schollmeier Elisa1,Lebek Simon1ORCID,Hegner Philipp1ORCID,Reuthner Kathrin1,Heers Silvia1,Keller Karoline1,Wester Michael1ORCID,Klatt Susanne1,Hamdani Nazha2ORCID,Provaznik Zdenek3ORCID,Schmid Christof3,Maier Lars1ORCID,Arzt Michael1,Wagner Stefan1ORCID

Affiliation:

1. Department of Internal Medicine II, University Hospital Regensburg , Regensburg , Germany

2. Department of Cellular and Translational Physiology, Ruhr-University Bochum , Bochum , Germany

3. Department of Cardiothoracic Surgery, University Hospital Regensburg , Regensburg , Germany

Abstract

Abstract Aims Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodelling and atrial fibrillation are 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 anti-arrhythmic 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 not only with the CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with sodium/hydrogen exchanger 1 (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 anti-arrhythmic effects in patients with HFpEF.

Funder

Else Kröner-Fresenius-Stiftung

German Cardiac Society

DGK

Deutsche Forschungsgemeinschaft

Philips Respironics

University of Regensburg ReForM A Program

ReForM C Program

Publisher

Oxford University Press (OUP)

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