SAR296968, a Novel Selective Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger Inhibitor, Improves Ca<sup>2+</sup> Handling and Contractile Function in Human Atrial Cardiomyocytes
Background: In reverse-mode, cardiac sodium-calcium exchanger (NCX) can increase the cytoplasmic Ca<sup>2+</sup> concentration in response to high intracellular Na<sup>+</sup> levels, which may contribute to diastolic contractile dysfunction. Furthermore, increased spontaneou...
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MDPI AG
2022-08-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/8/1932 |
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| author | Philipp Hegner Marzena Drzymalski Alexander Biedermann Bernadette Memmel Melanie Durczok Michael Wester Bernhard Floerchinger Zdenek Provaznik Christof Schmid York Zausig Lars S. Maier Stefan Wagner |
| author_facet | Philipp Hegner Marzena Drzymalski Alexander Biedermann Bernadette Memmel Melanie Durczok Michael Wester Bernhard Floerchinger Zdenek Provaznik Christof Schmid York Zausig Lars S. Maier Stefan Wagner |
| author_sort | Philipp Hegner |
| collection | DOAJ |
| description | Background: In reverse-mode, cardiac sodium-calcium exchanger (NCX) can increase the cytoplasmic Ca<sup>2+</sup> concentration in response to high intracellular Na<sup>+</sup> levels, which may contribute to diastolic contractile dysfunction. Furthermore, increased spontaneous Ca<sup>2+</sup> release from intracellular stores can activate forward mode NCX. The resulting transient inward current causes delayed afterdepolarization (DAD)-dependent arrhythmias. Moreover, recently, NCX has been associated with impaired relaxation and reduced cardiac function in heart failure with preserved ejection fraction (HFpEF). Since NCX is upregulated in human chronic atrial fibrillation (AF) as well as heart failure (HF), specific inhibition may have therapeutic potential. Objective: We tested the antiarrhythmic, lusitropic and inotropic effects of a novel selective NCX-inhibitor (SAR296968) in human atrial myocardium. Methods and Results: Right atrial appendage biopsies of 46 patients undergoing elective cardiac surgery in a predominant HFpEF cohort (n = 24/46) were investigated. In isolated human atrial cardiomyocytes, SAR296968 reduced the frequency of spontaneous SR Ca<sup>2+</sup> release events and increased caffeine transient amplitude. In accordance, in isolated atrial trabeculae, SAR296968 enhanced the developed tension after a 30 s pause of electrical stimulation consistent with reduced diastolic sarcoplasmic reticulum (SR) Ca<sup>2+</sup> leak. Moreover, compared to vehicle, SAR296968 decreased steady-state diastolic tension (at 1 Hz) without impairing developed systolic tension. Importantly, SAR296968 did not affect the safety parameters, such as resting membrane potential or action potential duration as measured by patch clamp. Conclusion: The novel selective NCX-inhibitor SAR296968 inhibits atrial pro-arrhythmic activity and improves diastolic and contractile function in human atrial myocardium, which may have therapeutic implications, especially for treatment of HFpEF. |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T10:00:55Z |
| publishDate | 2022-08-01 |
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| spelling | doaj.art-e8e11a5666a64d56aa6f189c8b32711f2023-12-01T23:27:59ZengMDPI AGBiomedicines2227-90592022-08-01108193210.3390/biomedicines10081932SAR296968, a Novel Selective Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger Inhibitor, Improves Ca<sup>2+</sup> Handling and Contractile Function in Human Atrial CardiomyocytesPhilipp Hegner0Marzena Drzymalski1Alexander Biedermann2Bernadette Memmel3Melanie Durczok4Michael Wester5Bernhard Floerchinger6Zdenek Provaznik7Christof Schmid8York Zausig9Lars S. Maier10Stefan Wagner11Department of Internal Medicine II, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Internal Medicine II, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Internal Medicine II, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Internal Medicine II, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Internal Medicine II, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Internal Medicine II, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Cardiothoracic Surgery, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Cardiothoracic Surgery, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Cardiothoracic Surgery, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Anesthesiology, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Internal Medicine II, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Internal Medicine II, University Medical Center Regensburg, 93053 Regensburg, GermanyBackground: In reverse-mode, cardiac sodium-calcium exchanger (NCX) can increase the cytoplasmic Ca<sup>2+</sup> concentration in response to high intracellular Na<sup>+</sup> levels, which may contribute to diastolic contractile dysfunction. Furthermore, increased spontaneous Ca<sup>2+</sup> release from intracellular stores can activate forward mode NCX. The resulting transient inward current causes delayed afterdepolarization (DAD)-dependent arrhythmias. Moreover, recently, NCX has been associated with impaired relaxation and reduced cardiac function in heart failure with preserved ejection fraction (HFpEF). Since NCX is upregulated in human chronic atrial fibrillation (AF) as well as heart failure (HF), specific inhibition may have therapeutic potential. Objective: We tested the antiarrhythmic, lusitropic and inotropic effects of a novel selective NCX-inhibitor (SAR296968) in human atrial myocardium. Methods and Results: Right atrial appendage biopsies of 46 patients undergoing elective cardiac surgery in a predominant HFpEF cohort (n = 24/46) were investigated. In isolated human atrial cardiomyocytes, SAR296968 reduced the frequency of spontaneous SR Ca<sup>2+</sup> release events and increased caffeine transient amplitude. In accordance, in isolated atrial trabeculae, SAR296968 enhanced the developed tension after a 30 s pause of electrical stimulation consistent with reduced diastolic sarcoplasmic reticulum (SR) Ca<sup>2+</sup> leak. Moreover, compared to vehicle, SAR296968 decreased steady-state diastolic tension (at 1 Hz) without impairing developed systolic tension. Importantly, SAR296968 did not affect the safety parameters, such as resting membrane potential or action potential duration as measured by patch clamp. Conclusion: The novel selective NCX-inhibitor SAR296968 inhibits atrial pro-arrhythmic activity and improves diastolic and contractile function in human atrial myocardium, which may have therapeutic implications, especially for treatment of HFpEF.https://www.mdpi.com/2227-9059/10/8/1932Na<sup>+</sup>/Ca<sup>2+</sup> exchangerNCXHFpEFSAR296968 |
| spellingShingle | Philipp Hegner Marzena Drzymalski Alexander Biedermann Bernadette Memmel Melanie Durczok Michael Wester Bernhard Floerchinger Zdenek Provaznik Christof Schmid York Zausig Lars S. Maier Stefan Wagner SAR296968, a Novel Selective Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger Inhibitor, Improves Ca<sup>2+</sup> Handling and Contractile Function in Human Atrial Cardiomyocytes Biomedicines Na<sup>+</sup>/Ca<sup>2+</sup> exchanger NCX HFpEF SAR296968 |
| title | SAR296968, a Novel Selective Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger Inhibitor, Improves Ca<sup>2+</sup> Handling and Contractile Function in Human Atrial Cardiomyocytes |
| title_full | SAR296968, a Novel Selective Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger Inhibitor, Improves Ca<sup>2+</sup> Handling and Contractile Function in Human Atrial Cardiomyocytes |
| title_fullStr | SAR296968, a Novel Selective Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger Inhibitor, Improves Ca<sup>2+</sup> Handling and Contractile Function in Human Atrial Cardiomyocytes |
| title_full_unstemmed | SAR296968, a Novel Selective Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger Inhibitor, Improves Ca<sup>2+</sup> Handling and Contractile Function in Human Atrial Cardiomyocytes |
| title_short | SAR296968, a Novel Selective Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger Inhibitor, Improves Ca<sup>2+</sup> Handling and Contractile Function in Human Atrial Cardiomyocytes |
| title_sort | sar296968 a novel selective na sup sup ca sup 2 sup exchanger inhibitor improves ca sup 2 sup handling and contractile function in human atrial cardiomyocytes |
| topic | Na<sup>+</sup>/Ca<sup>2+</sup> exchanger NCX HFpEF SAR296968 |
| url | https://www.mdpi.com/2227-9059/10/8/1932 |
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