Atrial-selective sodium channel block for the treatment of atrial fibrillation

Abstract

The pharmacological approach to therapy of atrial fibrillation (AF) is often associated with adverse effects resulting in the development of ventricular arrhythmias. As a consequence, much of the focus in recent years has been on development of atrial-selective agents. Atrial-selective sodium channel blockers have recently been shown to exist and be useful in the management of AF. This review summarizes the available data relative to current therapies, focusing on our understanding of the actions of atrial selective sodium channel blockers in suppressing and preventing the induction of AF and electrophysiological properties that confer atrial-selectivity to these antifibrillatory drugs.

Figure 1. Ranolazine specifically induces prolongation of the ERP and development of post-repolarization refractoriness in atria (the difference between ERP and APD₇₅ in atria and between ERP and APD₉₀ in ventricles; ERP corresponds to APD₇₅ in atria and APD₉₀ in ventricles)

CL= 500 ms. The arrows in panel A illustrate the position on the action potential corresponding to the end of the ERP in atria and ventricles and the effect of ranolazine to shift the end of the ERP in atria but not ventricles. Panel B includes summary data for the ranolazine induced changes in ERP and APD in atria and ventricles. From Burashnikov et al. [5] with permission. Copyright of the American Heart Association. *p < 0.05 versus control.^‡p < 0.05 versus APD₇₅ values in atria and APD₉₀ in ventricles; (n = 5 – 18). APD: Action potential duration; C: Control; CL: Cycle length; ERP: Effective refractory period.

Figure 2. 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 ACh-mediated AF (A.) and Iso-induced AF (C.) are suppressed by ranolazine. B. Ranolazine prevents rapid-pacing induction of AF following pretreatment with ACh (0.5 μmol/l). ERP is 140 ms at a CL of 500 ms (left panel). Acceleration of pacing rate from a CL of 500 to 200 ms permits a 1:1 response only during the first seven beats (right panel). In both models, ranolazine causes prominent use-dependent reduction of excitability and induction of PRR. From Burashnikov et al. [5] with permission. Copyright of the American Heart Association. Ach: Acetylcholine; AF: Atrial fibrillation; CL: Cycle length; ERP: Effective refractory period; Iso: Isoproterenol; PRR: Post-repolarization refractoriness.

Figure 3. Ranolazine produces a much greater rate-dependent inhibition of the maximal action potential upstroke velocity (V_max) in atria than in ventricles

A. Normalized changes in V_max of atrial and ventricular cardiac preparations paced at a CL of 500 ms. B. 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. “Atria” represent combined crista terminalis and pectinate muscle data. “Ventricles” represent combined epicardial and M-cell data from left ventricular wedge preparations. From Burashnikov et al. [5] with permission. Copyright of the American Heart Association. *p < 0.05 versus control.*p < 0.05 versus respective values of ventricles and Purkinje (n = 7 – 21). CL: Cycle length.

Figure 4. A semi-quantitative assessment of atrial selectivity of l_Na blockers based on studies conducted in atrial and ventricular Cor-perfused and superfused (tissues) preparations, isolated myocytes and in vivo.

Reproduced from Burashnikov A, Antzelevitch C, Atrial-selective sodium channel blockers: do they exist? J Cardiovasc Pharmacol 2008;52:12l-8 [47] with permission. Copyright © 2009 Lippincott Williams & Wilkins. Cor-perfused: Coronary-perfused.

Figure 5. Activation and steady-state inactivation in atrial versus ventricular myocytes

A. Current-voltage relation in ventricular and atrial myocytes. Voltage of peak l_Na is more positive and current density is larger in atrial versus ventricular myocytes. B. Summarized steady-state inactivation curves. C. Steady-state inactivation curves before and after addition of 15 μM ranolazine. From Burashnikov et al. [5] with permission. Copyright of the American Heart Association.