Trum, Maximilian and Riechel, Johannes and Schollmeier, Elisa and Lebek, Simon and Hegner, Philipp and Reuthner, Kathrin and Heers, Silvia and Keller, Karoline and Wester, Michael and Klatt, Susanne and Hamdani, Nazha and Provaznik, Zdenek and Schmid, Christof and Maier, Lars and Arzt, Michael and Wagner, Stefan (2024) Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF. CARDIOVASCULAR RESEARCH, 120 (9). pp. 999-1010. ISSN 0008-6363, 1755-3245
Full text not available from this repository. (Request a copy)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. Graphical Abstract
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LATE SODIUM CURRENT; CARDIAC NA+/H+ EXCHANGER; PROTEIN-KINASE-II; PRESERVED EJECTION FRACTION; HEART-FAILURE; NATRIURETIC PEPTIDE; DIASTOLIC DYSFUNCTION; MOUSE CARDIOMYOCYTES; INTRACELLULAR SODIUM; SGLT2 INHIBITORS; Heart failure; HFpEF; Sodium; SGLT2i; Empagliflozin; Atrial remodelling |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Medicine > Lehrstuhl für Herz-, Thorax- und herznahe Gefäßchirurgie Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 17 Jul 2025 06:41 |
| Last Modified: | 17 Jul 2025 06:41 |
| URI: | https://pred.uni-regensburg.de/id/eprint/63617 |
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