Clin Res Cardiol (2021) DOI DOI https://doi.org/10.1007/s00392-021-01843-w |
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"Increased Na-Influx in isolated atrial cardiomyocytes of patients with Heart Failure with preserved Ejection Fraction (HFpEF) can be completely normalized by treatment with Empagliflozin" | ||
J. Riechel1, M. Trum1, S. Lebek1, L. Rupprecht2, C. Schmid2, M. Creutzenberg3, L. S. Maier1, S. Wagner1 | ||
1Klinik und Poliklinik für Innere Med. II, Kardiologie, Universitätsklinikum Regensburg, Regensburg; 2Herz-, Thorax- und herznahe Gefäßchirurgie, Universitätsklinikum Regensburg, Regensburg; 3Anästhesiologie, Universitätsklinikum Regensburg, Regensburg; | ||
Objective: SGLT2-inhibitors (SGLT2i) have been shown to exert cardioprotective effects in patients with heart failure with reduced ejection fraction (HFrEF) and clinical trials investigating SGLT2i as a treatment strategy for heart failure with preserved ejection fraction (HFpEF) are ongoing. Interestingly, we have shown that empagliflozin inhibits cardiac Ca-calmodulin-dependent kinase II (CaMKII) in HFrEF and mouse models leading to reduced intracellular Na concentration and improved Ca handling. However, it remains unclear, which pathways mediate the Na lowering effect and if this observation can be transferred to HFpEF.
Methods and Results: Human atrial tissue was obtained from patients undergoing heart surgery requiring heart-lung apparatus after informed consent. Chunk-isolated human atrial cardiomyocytes were immobilized on laminin-coated cover slips and preincubated with empagliflozin (1 µM), tetrodotoxin (TTX, 1 µM), an inhibitor of the late Na current (late INa), or DMSO-containing Tyrode solution for 30 minutes. The cells were loaded with the sodium dye Asante-Na-Green 2 (ANG2) and mounted on a confocal microscope. Na influx was assessed as the slope of the rise in intracellular Na concentration during inhibition of Na/K-ATPase by superfusion with K-free solution for 10 minutes (Fig. A). Intriguingly, Na-influx was significantly increased in atrial cardiomyocytes of HFpEF patients compared to atrial myocytes isolated from non-failing hearts (Δ[Na+] mM/s 0.003858±0.0005058 vs. 0.006295±0.001062, p=0.0463). Interestingly, compared to NF, CaMKII-dependent phosphorylation of the cardiac Na channel pNaV1.5 was significantly increased in HFpEF patients (Fig. B). CaMKII-dependent regulation NaV1.5 is known to stimulate late INa and cellular Na overload. For NF vs. HFpEF, densitometric expression of pNaV1.5/GAPDH were 0.7325±0.1069 vs. 1.192±0.1750 (p=0.0115, Western blotting, Fig. B). Importantly, the increased Na influx was completely abolished by pretreatment with either empagliflozin or TTX (Δ[Na+] mM/s 0.003439±0.0003121 and 0.003335±0.0003518 for empagliflozin and TTX, respectively, p=0.0456 and p=0.0335, each vs. vehicle, respectively, Fig. C). In contrast, preincubation with the Na/H exchanger inhibitor cariporide did not affect Na influx. Conclusion: Na influx is increased in isolated atrial cardiomyocytes of HFpEF patients, potentially due to increased late INa as a consequence of enhanced phosphorylation of NaV 1.5. Intriguingly, pretreatment with empagliflozin mimicked the TTX effect, suggesting direct or indirect inhibition of late INa (via CaMKII) in atrial myocytes of HFpEF patients.
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https://dgk.org/kongress_programme/jt2021/aP79.html |