New developments in atrial antiarrhythmic drug therapy

Abstract

Atrial fibrillation (AF) is a growing clinical problem associated with increased morbidity and mortality. Currently available antiarrhythmic drugs (AADs), although highly effective in acute cardioversion of paroxysmal AF, are generally only moderately successful in long-term maintenance of sinus rhythm. The use of AADs is often associated with an increased risk of ventricular proarrhythmia, extracardiac toxicity, and exacerbation of concomitant diseases such as heart failure. AF is commonly associated with intracardiac and extracardiac disease, which can modulate the efficacy and safety of AAD therapy. In light of the multifactorial intracardiac and extracardiac causes of AF generation, current development of anti-AF agents is focused on modulation of ion channel activity as well as on upstream therapies that reduce structural substrates. The available data indicate that multiple ion channel blockers exhibiting potent inhibition of peak I(Na) with relatively rapid unbinding kinetics, as well as inhibition of late I(Na) and I(Kr), may be preferable for the management of AF when considering both safety and efficacy.

Figure 1

Current prominent investigational strategies for rhythm control of atrial fibrillation. Abbreviations: CA, constitutively active; Cx, connexin; I_K-ACh, acetylcholine-regulated inward rectifying potassium current; I_Kr, rapidly activating delayed rectified potassium current; I_Kur, ultra-rapid delayed rectifier potassium current; I_Na, early sodium current. Modified from Burashnikov, A. & Antzelevitch, C. Ann. Noninvasive Electrocardiol. 14, 290–300 (2009).

Figure 2

Opposite effect of I_Kur inhibition on the action potential in healthy and remodeled atria. Block of I_Kur with 4-aminopyridine (50 μM). APD₉₀ is abbreviated in a | ‘healthy’ (plateau-shaped action potential), but prolonged in b | ‘remodeled’ (triangular-shaped action potential) canine coronary-perfused atrial preparations. Abbreviations: 4-AP, 4-aminopyridine; APD₉₀, action potential duration at 90% repolarization; C, control. Modified from Burashnikov, A. & Antzelevitch, C. Heart Rhythm 5, 1304–1309 (2008) and Burashnikov, A. et al. Am. J. Physiol. Heart Circ. Physiol. 286, H2393–H2400 (2004).

Figure 3

Ranolazine induces atrial-selective prolongation of the ERP and development of PRR. The PRR is 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. Cycle length, 500 ms. Schematic illustration of induction of postrepolarization refractoriness with ranolazine in the atrium but not in the ventricle. a | The arrows 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. Summary data of the effect of ranolazine to induce PRR in atria but not in ventricles. b | *P <0.05 versus control. ^‡P <0.05 versus APD₇₅ values in atria and APD₉₀ in ventricles; (n = 5–18). Abbreviations: APD₉₀, action potential duration at 90% repolarization; C, control; CL, cycle length; ERP, effective refractory period. Modified from Burashnikov, A. et al. Circulation 116, 1449–1457 (2007).

Figure 4

Ranolazine produces a much greater rate-dependent inhibition of the maximal action potential upstroke velocity (V_max) in atria than in ventricles. Shown are V_max and action potential recordings obtained from coronary-perfused canine right atrium a | and left ventricle b | before (C) and after ranolazine (10 μM). Ranolazine prolongs late repolarization in the atria, but not in the ventricles (due to I_Kr inhibition) and acceleration of rate leads to elimination of the diastolic interval, during which much of the recovery from sodium-channel block occurs, contributing to the atrial selectivity of the drug. Abbreviations: AP, action potential; CL, cycle length. Modified from Antzelevitch, C. & Burashnikov, A. J. Electrocardiol. 42, 543–548 (2009).