Cardiac late Na+ current: Proarrhythmic effects, roles in long QT syndromes, and pathological relationship to CaMKII and oxidative stress

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

“…Furthermore, elevation of the H 2 O 2 concentration for up to 2 mM (N=5) in the young/adult hearts still failed to promote EADs and/or atrial ectopic activity consistent with our previous findings [1,7,22] and by Lin CS et al [24]. The discrepancy between the ease of oxidative EAD formation at the single myocyte level isolated from young/adult atria [18,25] and the resistance to EAD formation at the atrial tissue level in young/adult hearts, suggests that atrial tissue factor(s) must have been responsible in the aged tissue to readily promote EAD and EAD-mediated triggered activity. These findings suggest that increased atrial tissue fibrosis observed in the aged atria may indeed be a key factor in facilitating the formation EADs and EAD-mediated AF.…”

“…This suggests a synergistic interaction between oxidative stress and increased atrial tissue fibrosis in the promotion of spontaneous AF [27]. Indeed young/adult isolated atrial myocytes readily manifest EADs and TA at the isolated atrial myocyte level [18,28] however, not at tissue level as shown in this study. Simulation studies [29] have convincingly demonstrated the importance of electrotonic repolarizing “sink” effect caused by well-coupled cells that prevents initiation of EAD-mediated arrhythmias in normal well-coupled atrial tissue.…”

“…Indeed inhibition of the I Na-L with the highly potent (IC 50 =0.143 μM) and selective inhibitor GS-967 [18] suppresses EADs in isolated atrial myocytes [18,19]. The purpose of this study is to test the following two hypotheses; 1) oxidative stress-mediated activation of CaMKII signaling with hydrogen peroxide (H 2 O 2 ) in structurally remodeled atria characterized with increased atrial tissue fibrosis promotes AF by the mechanism of EAD and DAD-mediated triggered activity; and 2) selective inhibition of the enzymatic activity of CaMKII or its distal target, the I Na-L with the specific I Na-L blocker, GS-967, [18] suppresses the oxidative AF.…”

Late sodium current dysregulation as a causal factor in arrhythmia

“…long QT 3), and in acquired forms of disease (e.g. heart failure, atrial fibrillation (AF)) [9][10][11][12][13]. I Na,L likely promotes arrhythmogenesis by (1) increasing a depolarizing current that prolongs the AP and increases susceptibility to secondary depolarizations (afterdepolarizations) that serve as potential arrhythmia triggers and (2) increasing intracellular Na + that promotes intracellular Ca 2+ accumulation via altered activity of Na + /Ca 2+ exchanger [2,6].…”

Ranolazine in Cardiac Arrhythmia

“…7 On the other side, several electrophysiological mechanisms result in the initiation of ventricular arrhythmias, including triggered activity (which is either early after depolarization [EAD] or delayed after depolarization [DAD]), abnormal automaticity, and reentry. 10 Patients with cardiomyopathies may have increased transmural dispersion of repolarization (TDR), which is considered one of the Figure 1. Phases of cardiac action potential in nonpacemaker cells.…”