Atrial-selective sodium channel block as a novel strategy for the management of atrial fibrillation

Abstract

Safe and effective pharmacologic management of atrial fibrillation (AF) is one of the greatest challenges facing an aging society. Currently available pharmacologic strategies for rhythm control of AF are associated with ventricular arrhythmias and in some cases multi-organ toxicity. Consequently, drug development has focused on atrial-selective agents such as IKur blockers. Recent studies suggest that IKur block alone may be ineffective for suppression of AF and may promote AF in healthy hearts. Recent experimental studies have demonstrated other important electrophysiologic differences between atrial and ventricular cells, particularly with respect to sodium channel function, and have identified sodium channel blockers that exploit these electrophysiologic distinctions. Atrial-selective sodium channel blockers, such as ranolazine and amiodarone, effectively suppress and/or prevent the induction of AF in experimental models, while producing little to no effect on ventricular myocardium. These findings suggest that atrial-selective sodium channel block may be a fruitful new strategy for the management of AF.

Figure 1

Ion channel differences between atrial and ventricular action potentials. The normal action potential in atria differs from that of the ventricle with respect to ion channel currents that contribute to resting membrane potential (RMP), phase 1, and phase 3 of the action potential. RMP in atria is more depolarized than in the atrial on account of a smaller I_K1. Phase 1 is more prominent in atria due to the presence of a prominent I_to and I_Kur. Both I_Kur and I_K–ACh are exclusive to atria. Phase 3 of the action potential is much slower to repolarize in atria because of weaker repolarizing currents I_Kr, I_Ks, and I_K1.

Figure 2

Ion channel currents in remodeled atria. Electrical remodeling of the atrial action potential. Rapid activation of the atria during AF results in a decrease in I_Ca, I_Kur, and I_to, but to an increase in I_K1 and constitutively active I_K–ACh. The abbreviation of action potential duration is due principally to the decrease in I_Ca and the increase in I_K1 and constitutively active -I_K–ACh.

Figure 3

Atrial-selective depression of maximal action potential upstroke velocity (V_max) by ranolazine. Ranolazine produces a much greater rate-dependent inhibition of the maximal V_max in atria than in ventricles. (A) Normalized changes in V_max of atrial and ventricular cardiac preparations paced at a cycle length (CL) of 500 ms. (C) Ranolazine prolongs late repolarization in atria, but not ventricles and acceleration of rate leads to elimination of the diastolic interval, resulting in a more positive take-off potential in atrium and contributing to atrial selectivity of ranolazine. The diastolic interval remains relatively long in ventricles. *P < 0.05 versus control. † P < 0.05 from respective values of M cell and Purkinje (n = 7–21). (From Burashnikov et al. Reproduced by permission.)

Figure 4

Atrial-selective development of post-repolarization refractoriness after exposure to ranolazine. Ranolazine-induced prolongation of effective refractory period (ERP) is much greater than prolongation of action potential duration (APD), resulting in the development of post-repolarization refractoriness in atria (PRR) but not ventricles. PRR is defined as the difference between ERP and APD₇₅ in atria and between ERP and APD₉₀ in the ventricles; ERP corresponds to APD₇₅ in atria and APD₉₀ in ventricles). *P < 0.05 versus control. ‡ = P < 0.05 versus APD₇₅ values in atria and APD₉₀ in ventricles; (n = 5–18). (From Burashnikov et al. Reproduced by permission.)

Figure 5

Ranolazine suppresses AF and/or prevents its induction in two experimental models involving isolated arterially perfused right atria at concentrations producing little to no effects in ventricles. Persistent acetylcholine (ACh)-mediated AF (A) and isoproterenol (Iso)- induced AF (C) are suppressed by ranolazine. In both models, ranolazine causes prominent use-dependent reduction of excitability and induction of PRR. (From Burashnikov et al. Reproduced by permission.)

Figure 6

Sodium channel block. A semi-quantitative assessment of atrial selectivity of I_Na blockers based on studies conducted in atrial and ventricular coronary-perfused (Cor-perfused) and superfused (Tissues) preparations, isolated myocytes, and in vivo. (From Burashnikov and Antzelevitch. Reproduced by permission.)