Hegner Philipp, Drzymalski Marzena, Biedermann Alexander, Memmel Bernadette, Durczok Melanie, Wester Michael, Floerchinger Bernhard, Provaznik Zdenek, Schmid Christof, Zausig York, Maier Lars S, Wagner Stefan
Department of Internal Medicine II, University Medical Center Regensburg, 93053 Regensburg, Germany.
Department of Cardiothoracic Surgery, University Medical Center Regensburg, 93053 Regensburg, Germany.
Biomedicines. 2022 Aug 9;10(8):1932. doi: 10.3390/biomedicines10081932.
In reverse-mode, cardiac sodium-calcium exchanger (NCX) can increase the cytoplasmic Ca concentration in response to high intracellular Na levels, which may contribute to diastolic contractile dysfunction. Furthermore, increased spontaneous Ca 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.
We tested the antiarrhythmic, lusitropic and inotropic effects of a novel selective NCX-inhibitor (SAR296968) in human atrial myocardium.
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 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 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.
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.
在反向模式下，心脏钠钙交换体（NCX）可响应细胞内高钠水平增加细胞质钙浓度，这可能导致舒张期收缩功能障碍。此外，细胞内钙库自发钙释放增加可激活正向模式NCX。由此产生的瞬时内向电流会导致依赖延迟后去极化（DAD）的心律失常。此外，最近，NCX与射血分数保留的心力衰竭（HFpEF）患者的舒张功能受损和心脏功能降低有关。由于NCX在人类慢性心房颤动（AF）以及心力衰竭（HF）中上调，特异性抑制可能具有治疗潜力。
我们测试了一种新型选择性NCX抑制剂（SAR296968）对人心房肌的抗心律失常、舒张期正性肌力和收缩期正性肌力作用。
对46例择期心脏手术患者（主要为HFpEF队列，n = 24/46）的右心耳活检组织进行了研究。在分离的人心房肌细胞中，SAR296968降低了自发的肌浆网（SR）钙释放事件的频率，并增加了咖啡因诱发的钙瞬变幅度。相应地，在分离的心房小梁中，SAR296968在电刺激暂停30秒后增强了舒张期张力，这与舒张期肌浆网（SR）钙泄漏减少一致。此外，与载体相比，SAR296968降低了稳态舒张期张力（1 Hz时），而不损害收缩期舒张张力。重要的是，SAR296968不影响安全参数，如通过膜片钳测量的静息膜电位或动作电位持续时间。
新型选择性NCX抑制剂SAR296968可抑制人心房肌的促心律失常活性，并改善舒张期和收缩期功能，这可能具有治疗意义，特别是对于HFpEF的治疗。
