Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling

Abstract

Atrial fibrillation (AF) results in a remodeling of the electrical and structural characteristics of the cardiac tissue which dramatically reduces the efficacy of pharmacological and catheter-based ablation therapies. Recent experimental and clinical results have demonstrated that the complexity of the fibrillatory process significantly differs in paroxysmal versus persistent AF; however, the lack of appropriate research models of remodeled atrial tissue precludes the elucidation of the underlying AF mechanisms and the identification of appropriated therapeutic targets. Here, we summarize the different research models used to date, highlighting the lessons learned from them and pointing to the new doors that should be open for the development of innovative treatments for AF.

Keywords:

• atrial fibrillation
• electrophysiological properties
• persistent AF
• rotors
• tissue remodeling

Atrial fibrillation & atrial tissue remodeling

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. The initiation of an episode of AF requires the involvement of a trigger event and a cardiac substrate that allows the perpetuation of the reentrant electrical activity [1]. The elimination of the atrial trigger could be sufficient to successfully treat patients with paroxysmal AF with a healthy atrial tissue [2,3]; however, in persistent AF patients both pharmacological and catheter-based ablation therapies have a limited value. Although this lack of success may be related, in part, with a poor ablation technique, the progression of electrical and structural remodeling that takes place in persistent AF patients plays an important role. The term remodeling refers to the changes in the atrial tissue properties following periods of sustained AF [4] or as a result of other cardiovascular diseases (e.g., congestive heart failure, valvular heart disease, genetic determinants, etc.) [5]. These changes include electrical remodeling during the first stages of the fibrillatory process; mainly shortening of the atrial action potential duration and refractoriness. In case of AF episodes lasting for several weeks or months, alterations in the expression of ion channels are followed by a structural and contractile remodeling that includes increased fibrosis, chamber dilatation and a reduction of atrial mechanical function [6,7]. As a consequence, the atrial substrate is heterogeneous, with regions of short effective refractory period and a decreased conduction velocity, which dramatically increases the susceptibility to maintain AF. However, all the efforts made to date aiming to treat persistent AF by counteracting this tissue remodeling and restoring normal electrophysiological properties have achieved limited success.

Atrial tissue remodeling & fibrillatory process characteristics

Both experimental [8] and mathematical [9] models have suggested that the main determinants of electrical remodeling are a reduction in the density of the depolarizing inward L-type Ca2+ current (I_CaL) and an increased activity of the inward rectifier current, I_K1. These two modifications explain both the shortening of the action potential duration and the reduction of the effective refractory period observed in chronically remodeled atrial myocytes. Regarding the structural remodeling of long-term AF, the adaptation to calcium overload and metabolic stress due to a fast activation rate promotes cardiomyocyte dedifferentiation, producing an increment in cell size which is associated with the modification of main subcellular structures [6]. In addition to atrial cell dilatation, extracellular matrix remodeling produces a profibrotic environment which stimulates fibroblast proliferation and differentiation into myofibroblasts [6]. Moreover, atrial fibrosis disturbs the continuity between cardiomyocytes reducing wave front homogeneity and conduction velocity, creating the ideal substrate for FA maintenance.

Extensive evidence suggests that these modifications of the atrial substrate are related with changes in the complexity of the fibrillatory activity. Epicardial atrial recordings from patients suffering persistent AF are characterized by a faster activation rate and a larger number of simultaneous wave fronts [10]. The specific mechanisms that produce these changes remain controversial. Modifications of the calcium homeostasis during AF have demonstrated an increased probability of the appearance of delayed after depolarizations [11,12]. These sarcoplasmic reticulum Ca2+ leaks may serve as trigger events and could promote the perpetuation and increase of complexity of persistent AF. On the other hand, Allessie et al. relate the increase in the complexity of persistent AF with an electrical dissociation that promotes the generation of a higher number of multiple independent fibrillation waves originated over the entire atrial tissue [10]. A third hypothesis is based on the existence of relatively stable functional reentries that hierarchically govern the fibrillation [13]. The stability of these functional reentries, so-called rotors during human AF remains unclear: while some authors have failed to find them [10], their localization and ablation is becoming a novel target for therapeutic strategy [3].

Rotors are characterized by spiraling wavefronts that surround a tip point and have been described both in animals and humans [14]. The characteristics of rotors (e.g., reentrant rate, tip meandering, curvature, etc.) are governed by the electrophysiological properties of the atrial tissue [13]. It has been shown that a shortening of the action potential duration allows a reduction in the tip meandering and this allows for a faster and a smaller circumscription of the core of the rotor. In addition, an increase of the rotor curvature further reduces the area needed by a spiral wave to maintain a rotor. This reduction in the rotor core area may allow the existence of multiple small rotors in the atrial tissue and may also explain the observed increase in the number of simultaneous wavefronts by Allessie et al. [10].

Experimental models with persistent AF

A potential explanation for the absence of effective treatments for persistent AF is the lack of appropriate research models to elucidate the mechanisms that produce the modifications on the AF process due to remodeling. The main limitation for the development of experimental models of chronic AF is the inherent need for remodeled tissues or whole hearts suffering AF for at least several weeks or months.

Most of our knowledge about the tissue remodeling has been gained by using rapid atrial pacing models both in single cells [8] or the atria of large mammalians [15]. Unfortunately, the mechanisms of AF maintenance in these tachypacing models may differ significantly from clinical persistent AF. Recently, a novel sheep model of long-term persistent AF, in which the tachypacing was stopped once AF was self-maintained [16], was used to indirectly corroborate the essential role of rotors in AF maintenance. This model reproduced the shortening in the dominant atrial cycle length (or an increase in the atrial dominant frequency) observed in persistent AF patients during the remodeling process [16]. Unfortunately, current mapping technology does not allow the simultaneous evaluation of the global atrial activity and the tracking of each individual rotor which precludes the identification of the specific mechanisms responsible for AF maintenance. Besides, the generation of these animal research models requires huge economic and time efforts.

Another potential approach to clarify the electrophysiological mechanism that governs persistent AF is the generation of in vitro models in which the fibrillatory process is self-maintained during several days or weeks. By co-culturing neonatal cardiomyocytes and fibroblasts at different fibroblast infiltration ratios, Zlochiver et al. reported that the electrical interaction between myocytes and fibroblasts determines fibrillation dynamics by altering the conduction velocity and wavefront complexity [17]. In vitro models also allowed the evaluation of the effects of mechanical stretch on the calcium dynamics and the mechanisms of initiation of AF in a model of HL-1 cells (i.e., atrial murine immortalize adult cardiomyocytes) [18]. Interestingly, HL-1 cells have demonstrated their ability to undergo in vitro myocyte remodeling similar to that found in patients with AF (i.e., reduction of the expression of L-type calcium current proteins, myolisis, nuclear condensation and an increase in calpain activity) [18]. However, murine cardiomyocytes present significant differences with human atrial cells and thus extrapolation of these results to the clinical setting is limited. Today, novel advanced cell technologies allow the development of in vitro human cardiac structures from embryonic stem cells or from adult human cells dedifferentiated into induced pluripotent stem cells [19]. In the near future, the investigators will have the possibility to use in vitro models of human atrial cells obtained from specific patients and with different stages of remodeling. Those in vitro models, together with the novel optical mapping techniques that enable the simultaneous recording of transmembrane voltage and calcium transients [20] will allow the identification of treatment targets to prevent or even reverse the effects of tissue remodeling.

Five-year view

Until now, pharmacological treatments trying to counteract specific ionic or molecular modifications produced by the remodeling have shown a limited effect. Potentially, a different therapeutic strategy could aim at modifying of the reentrant process in such a way that prevents the perpetuation of the arrhythmia, even if the structural remodeling cannot be reversed. Specifically, a reduction in the excitability of the core of the rotors may increase their meandering and promote the termination of the arrhythmia by collisions, either between rotors or with anatomical obstacles. Novel cell and mapping technologies will be useful for elucidating the mechanisms that govern re-entry during persistent AF and may help in defining new therapeutic approaches to terminate AF.

Financial & competing interests disclosure

The authors were supported by grants from the Spanish Ministry of Science and Innovation (PLE2009-0152), the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain: PI13-01882 and PI13-00903) the Red de Investigación Cardiovacular (RIC) from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain). F Atienza served on the advisory board of Medtronic and has received research funding from St. Jude Medical Spain. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.