ArticleCardiovascular research2024
Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF.
Article in Cardiovascular research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Long-term effects of SGLT2 inhibitors on arrhythmias: a systematic review and meta-analysis.Frontiers in pharmacology · 2025Pooled it
- SGLT2 inhibitors: mechanisms, physiology and pharmacology, and clinical applications.Molecular biomedicine · 2026Review
- Revising NHE-1: From Cardiac Homeostasis to Heart Failure and Future Drug Development.Cell biochemistry and function · 2026Review
- Visinin-like protein 1 disrupts calcium homeostasis and promotes atrial fibrillation in human and rodent models.Signal transduction and targeted therapy · 2026Article
- Review
- Pathogenesis and Therapeutic Advances in Heart Failure with Preserved Ejection Fraction.Reviews in cardiovascular medicine · 2026Review
- Review
- Cardiac intermediary metabolism in heart failure: substrate use, signalling roles and therapeutic targets.Nature reviews. Cardiology · 2025Review
- Mechano-energetic uncoupling in heart failure.Nature reviews. Cardiology · 2025Review
- Cardiomyocyte-specific NHE1 overexpression confers protection against myocardial infarction during hyperglycemia.Cardiovascular diabetology · 2025Article
- MyocardialAntioxidants (Basel, Switzerland) · 2025Article
- [Atrial fibrillation in combination with severe mitral regurgitation : Which should be treated first, the atrial fibrillation or the mitral valve?]Herzschrittmachertherapie & Elektrophysiologie · 2024Review
- SGLT2 inhibitors protect against diabetic cardiomyopathy and atrial fibrillation through a CaMKII independent mechanism.bioRxiv : the preprint server for biology · 2024Article
- Effects of Heart Failure Therapies on Atrial Fibrillation: Biological and Clinical Perspectives.Antioxidants (Basel, Switzerland) · 2024Review
- CaMKIIδ-dependent dysregulation of atrial NaFrontiers in pharmacology · 2024Article
Corrections and comments
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Authors and funding
16 authors.
Funding
Abstract
aimsHeart 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
resultsCardiomyocytes 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.
conclusionWe 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.
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