Late Sodium Current in Atrial Cardiomyocytes Contributes to the Induced and Spontaneous Atrial Fibrillation in Rabbit Hearts

Abstract

Increased late sodium current (INa) induces long QT syndrome 3 with increased risk of atrial fibrillation (AF). The role of atrial late INa in the induction of AF and in the treatment of AF was determined in this study. AF parameters were measured in isolated rabbit hearts exposed to late INa enhancer and inhibitors. Late INa from isolated atrial and ventricular myocytes were measured using whole-cell patch-clamp techniques. We found that induced-AF by programmed S1S2 stimulation and spontaneous episodes of AF were recorded in hearts exposed to either low (0.1–3 nM) or high (3–10 nM) concentrations of ATX-II (n = 10). Prolongations in atrial monophasic action potential duration at 90% completion of repolarization and effective refractory period by ATX-II (0.1–15 nM) were greater in hearts paced at slow than at fast rates (n = 5–10, P < 0.05). Both endogenous and ATX-II-enhanced late INa density were greater in atrial than that in ventricular myocytes (n = 9 and 8, P < 0.05). Eleclazine and ranolazine reduced AF window and AF burden in association with the inhibition of both endogenous and enhanced atrial late INa with half maximal inhibitory concentrations (IC50) of 1.14 and 9.78, and 0.94 and 8.31 μM, respectively. The IC50s for eleclazine and ranolazine to inhibit peak INa were 20.67 and 101.79 μM, respectively, in atrial myocytes. In conclusion, enhanced late INa in atrial myocytes increases the susceptibility for AF. Inhibition of either endogenous or enhanced late INa, with increased atrial potency of drugs is feasible for the treatment of AF.

Study on the role and mechanism of lncRNA in the remodeling of atrial energy metabolism in rabbits with atrial fibrillation based on nano sensor technology

“…Recently, the critical role of atrial energy metabolism remodeling in the occurrence of AF has received attention gradually. The establishment of AF rabbit models here is consistent with the experimental object selected by Chu et al [ 18 ], suggesting the feasibility of taking New Zealand white rabbits as the experimental object. lncRNA sequencing based on nano sensor technology is performed by taking the right atrial muscle tissue of AF/control rabbit model.…”

Ranolazine exerts atrial antiarrhythmic effects in a rat model of monocrotaline‐induced pulmonary hypertension

“…In an experimental model of atrial fibrillation induced by ATX-II, a toxin able to enhance I Nalate , it was found that atrial fibrillation was induced by programmed S1-S2 stimulation, and spontaneous episodes of atrial fibrillation were recorded in left atrial tissue exposed to ATX-II, and it was associated with prolonged AP duration in atrial cells, with ranolazine at 10 μM being able to fully eliminate atrial fibrillation. 32 l Nalate is an arrhythmogenic component of the sodium current involved in the genesis of arrhythmias in several animal models of atrial and ventricular heart diseases. 33 In another study, using RA appendages from patients with atrial fibrillation compared with patients with sinus rhythm, it was found that RA cardiomyocytes presented enhanced level of I Nalate .…”

Cardiac mechanisms of the beneficial effects of SGLT2 inhibitors in heart failure: Evidence for potential off-target effects

“…The resultant sodium influx through late-I Na leads to AP prolongation, and an increase in cytoplasmic sodium concentration [95]. The subsequent sodium/ calcium exchanger (NCX1.1) reverse-mode activity leads to calcium loading within cardiomyocytes [89][90][91][92] resulting in contractile dysfunction, impaired relaxation, activation of pro-hypertrophic gene transcription pathways [96] and ventricular arrhythmias [91,97,98] and AF [99,100] (Fig. 2).…”