Atorvastatin treatment affects atrial ion currents and their tachycardia-induced remodeling in rabbits

Abstract

Aims

Atrial fibrillation (AF) leads to electrical atrial remodeling including alterations of various ion channels early after arrhythmia onset. The beneficial effects of statins in AF treatment due to their influence on oxidative stress and inflammation are discussed. Our hypothesis was that statins might also alter atrial ion currents and their early tachycardia-induced remodeling.

Main methods

Effects of an atorvastatin treatment (7 days) on atrial ion currents and their tachycardia-induced alterations were studied in a rabbit model of tachycardia-induced electrical remodeling (rapid atrial pacing (600 min) for 24 and 120 h). Ion currents (L-type calcium channel [I_Ca,L], transient outward current [I_to]) were measured using whole cell patch clamp method and were compared with previous experiments in untreated but also tachypaced animals.

Key findings

Atorvastatin treatment alone decreased I_Ca,L similar to rapid atrial pacing alone, currents were also further reduced by additional atrial tachypacing. I_to and its pacing-induced down-regulation after 24 h were not influenced by atorvastatin treatment. However, I_to was still reduced after 120 h in atorvastatin-treated animals and did not return to control values as expected.

Significance

The present study establishes that an atorvastatin treatment can affect atrial ion currents and their tachycardia-induced remodeling in a rabbit model. These results show that—amongst other positive effects on oxidative stress and inflammation—the impact of statins on ion currents and their tachycardia-induced alterations might also play a role in “upstream” treatment of AF with HMG-CoA reductase inhibitors.

Introduction

Atrial fibrillation (AF) is the most common sustained arrhythmia in humans (Fuster et al. 2006). It is characterized by a variety of electrophysiological, mechanical and structural changes caused by the arrhythmia itself. This process termed “atrial remodeling in AF” is a time-dependent adaptive regulation mechanism promoting the maintenance of cell homeostasis after arrhythmia onset (Allessie et al., 2002, Wijffels et al., 1995). Progressive shortening, reduced rate-adaption and increased heterogeneity of the atrial effective refractory period are characteristic features of in vivo electrophysiological alterations in AF which have been studied extensively in several animal models and humans (Allessie et al., 2002, Nishidal et al., 2010, Workman et al., 2008). Many of these observations can be explained by the influence of AF on atrial ion channels and their regulative mechanisms (Nattel et al. 2008). Atrial remodeling begins within a few hours after arrhythmia onset, as shown by our group using a rabbit model of tachycardia-induced electrical remodeling (Bosch et al., 2003, Laszlo et al., 2008).

Recent studies report an association between AF and various endogenous states including oxidative stress and inflammation (Adam et al., 2008, Issac et al., 2007, Korantzopoulos et al., 2003, Korantzopoulos et al., 2007, Savelieva & Camm, 2008). Oxidative stress refers to a situation when formation and bonding of reactive oxygen species are imbalanced. By reacting with macromolecules like lipids, nucleic acids and proteins including ion channels, free radicals provoke fibrosis and inflammation (Korantzopoulos et al. 2007). In addition to the well-known cholesterol- and triglyceride-lowering effects, HMG-CoA reductase inhibitors (statins) possess so-called “pleiotropic” effects such as inhibition of inflammation and amelioration of oxidative stress (Beltowski et al. 2009). Thus, “upstream” therapy of AF with statins is discussed (Hadi et al., 2009, Koebe & Kirchhof, 2008, Korantzopoulos & Kokkoris, 2004, Korantzopoulos et al., 2007, Kostapanos et al., 2007, Lozano et al., 2005, Meinertz & Willems, 2008, Nattel et al., 2002, Savelieva & Camm, 2008, Smit & Van Gelder, 2009, Tamargo et al., 2007).

There is evidence that statins can directly affect cardiac ion currents (Vaquero et al. 2007). However, these acute effects cannot fully explain the influence of statins on atrial in vivo electrophysiology which has been reported recently (Shiroshita-Takeshita et al. 2004). Therefore, we studied the effects of an atorvastatin treatment in our rabbit model of early tachycardia-induced atrial electrical remodeling (which is closer to clinical settings than the effects of acute application on atrial ion currents in vitro) and also compared the time-course of ion current remodeling of atorvastatin-treated animals with the corresponding time-course of untreated animals already obtained in previous experiments of our group (Bosch et al., 2003, Laszlo et al., 2008).