The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: a critical analysis

Abstract

Atrial fibrillation (AF) is an extremely common clinical problem associated with increased morbidity and mortality. Current antiarrhythmic options include pharmacological, ablation, and surgical therapies, and have significantly improved clinical outcomes. However, their efficacy remains suboptimal, and their use is limited by a variety of potentially serious adverse effects. There is a clear need for improved therapeutic options. Several decades of research have substantially expanded our understanding of the basic mechanisms of AF. Ectopic firing and re-entrant activity have been identified as the predominant mechanisms for arrhythmia initiation and maintenance. However, it has become clear that the clinical factors predisposing to AF and the cellular and molecular mechanisms involved are extremely complex. Moreover, all AF-promoting and maintaining mechanisms are dynamically regulated and subject to remodelling caused by both AF and cardiovascular disease. Accordingly, the initial presentation and clinical progression of AF patients are enormously heterogeneous. An understanding of arrhythmia mechanisms is widely assumed to be the basis of therapeutic innovation, but while this assumption seems self-evident, we are not aware of any papers that have critically examined the practical contributions of basic research into AF mechanisms to arrhythmia management. Here, we review recent insights into the basic mechanisms of AF, critically analyse the role of basic research insights in the development of presently used anti-AF therapeutic options and assess the potential value of contemporary experimental discoveries for future therapeutic innovation. Finally, we highlight some of the important challenges to the translation of basic science findings to clinical application.

Keywords: Ablation; Antiarrhythmic drugs; Atrial fibrillation; Cellular electrophysiology; Ectopic activity; Imaging; Re-entry.

Figure 1

Conceptual overview of the major components of AF pathophysiology. AF is a progressive disease (black box) with important clinical consequences (red box). AF is initiated and maintained by two major arrhythmogenic mechanisms (green box) that are modulated by numerous mediators (teal box). Several risk factors and co-morbidities (orange box) as well as AF itself promote AF development and progression by acting upon these mediators. A number of therapeutic strategies (purple boxes) have been developed to treat AF and/or its clinical consequences. HF, heart failure; LAA, left-atrial appendage; NSTEMI, non-ST segment elevation myocardial infarction; PV, pulmonary vein.

Figure 2

Atrial electrophysiology and basic arrhythmogenic mechanisms. (A) Representative atrial action potentials (APs) and Ca²⁺ transients from sinus rhythm (Ctl), paroxysmal AF (pAF) and long-standing persistent (chronic) AF (cAF) patients (left), and schematic overview of the major atrial ion channels and Ca²⁺-handling proteins (right). (B) Electrophysiological mechanisms of AF-promoting triggered activity (left part) and re-entry (right part). Blue and red symbols in boxes indicate changes in AF-promoting factors observed in pAF (blue, left side) and cAF (red, right side) patients. APD, action-potential duration; DAD, delayed after-depolarization; ERP, effective refractory period; SR, sarcoplasmic reticulum. See text for further abbreviations.

Figure 3

Leading-circle (A) and spiral-wave (B) models of re-entry. (A) Maintenance of the leading circle depends on there being a zone of tissue large enough to accommodate a re-entry circuit of the dimension (wavelength) travelled by the cardiac impulse in one effective refractory period (ERP), given by the product of conduction velocity (CV) and ERP. Importantly, drugs (like Class I antiarrhythmics) that reduce CV should favour leading-circle re-entry by reducing the wavelength. (B) Maintenance of spiral-wave re-entry depends on current source/tissue excitability (favouring propagation) and current sink (impairing propagation). In this paradigm, Class I agents destabilize spiral-wave sources by reducing current source/excitability.

Figure 4

Development of non-pharmacological AF therapies based on basic clinical research interaction. (A) Development of surgical maze procedure based on basic theory and observation. (B) Clinical recognition of role of pulmonary veins (PVs) led to experimental definition of mechanisms. (C) Experimental studies of role of cardiac ganglionated plexuses in AF led to clinical approaches. (D) Experimental and theoretical work on rotors and mapping led to improved methods for persistent AF ablation.

Figure 5

Schematic overview of pharmacological anti-AF therapies and their targets. (A) Antiarrhythmic drugs targeting ion channels/transporters involved in atrial repolarization and Ca²⁺ handling. (B) Compounds targeting Ca²⁺-dependent signalling pathways involved in electrical remodelling, including Ca²⁺/calmodulin-dependent protein kinase-II (CaMKII) and calcineurin-A (CnA)-mediated signalling cascades, as well as calpain-dependent protein degradation. Clinically approved antiarrhythmic drugs are shown in green, compounds evaluated in clinical trials are shown in orange, with abandoned compounds indicated with †. Experimental compounds with anti-AF properties in animal studies in vivo or human atrial samples in vitro are shown in blue and purple, respectively, whereas compounds with anti-arrhythmic properties in animal samples are shown in grey.

Figure 6

Elements involved in the translation from novel potential antiarrhythmic targets to clinical application. Several types of basic research studies (in vitro, ex vivo, in vivo) play critical roles in target identification and optimization, but each individually have several limitations/challenges (purple boxes), resulting in a significant translational gap before clinical application. Both clinical trials and patient therapy present additional challenges and are complicated by regulatory requirements. New/improved methodologies including in silico research, genetic/biomarker-based patient stratification and improved imaging may help to overcome some of these challenges, but also require further development. RAA, right atrial appendage.