Abstract
Based on recent findings, an increased late sodium current (INa,late) plays an important pathophysiological role in cardiac diseases, including rhythm disorders. The article first describes what is INa,late and how it functions under physiological circumstances. Next, it shows the wide range of cellular mechanisms that can contribute to an increased INa,late in heart diseases, and also discusses how the upregulated INa,late can play a role in the generation of cardiac arrhythmias. The last part of the article is about INa,late inhibiting drugs as potential antiarrhythmic agents, based on experimental and preclinical data as well as in the light of clinical trials.
Highlights
During the non-pacemaker action potential (AP) in the heart, depolarization of the cell membrane opens voltage gated sodium channels (Nav) for a short period of time (Scanley et al, 1990; Mitsuiye and Noma, 2002) giving rise to the early sodium current peak (INa,early)
Adrenergic stimulation on one hand further activates CaM Dependent Protein Kinase II (CaMKII) (Hegyi et al, 2018) but on the other hand, it reduces or even diminishes [Na+]i loading of the cells by enhancing Na+/K+ pump (NKP) activity (Cheung et al, 2010). This makes the role of INa,late in delayed afterdepolarization (DAD)-mediated arrhythmias occurring at high heart rates questionable
Experimental data about ranolazine shows an effective reduction of atrial fibrillation (AF) burden (AFB) only at concentrations that potently inhibit both INa,early (Burashnikov et al, 2007; Kumar et al, 2009; Burashnikov et al, 2014) and IKr (Burashnikov et al, 2007) Suppressing IKr reduces the diastolic interval between APs promoting rate-dependent INa,early inhibition
Summary
Balázs Horváth 1,2*, Tamás Hézso 1, Dénes Kiss 1, Kornél Kistamás 1, János Magyar 1,3, Péter P. An increased late sodium current (INa,late) plays an important pathophysiological role in cardiac diseases, including rhythm disorders. The article first describes what is INa,late and how it functions under physiological circumstances. It shows the wide range of cellular mechanisms that can contribute to an increased INa,late in heart diseases, and discusses how the upregulated INa,late can play a role in the generation of cardiac arrhythmias. The last part of the article is about INa,late inhibiting drugs as potential antiarrhythmic agents, based on experimental and preclinical data as well as in the light of clinical trials
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