Mechanisms for the initiation of human atrial fibrillation
Introduction
Human atrial fibrillation (AF) likely encompasses a heterogeneous group of diseases, each resulting from a complex interaction between triggers and functional and structural substrates.1 While great strides have been made in catheter ablation for AF in various populations,2 the pathophysiological targets for ablation are understood clearly only in patients with short-lived paroxysms of AF.3 The extensive lesions needed to treat longstanding AF4, 5 and the limited success of medications that target plausible and defined ionic mechanisms6 reaffirm our limited understanding of human AF. Notable studies in the basic science literature have revealed mechanisms to explain AF in animals,7, 8 and identifying those that contribute to human AF is an urgent clinical challenge.
Section snippets
Trigger versus substrate
Since the seminal observation that pulmonary veins (PVs) may act as sources of triggering ectopy for AF,3 PV isolation has become a cornerstone of invasive therapy for paroxysmal as well as persistent AF.2 Nevertheless, the mechanistic role of the PVs is not defined, particularly for persistent AF. The fact that the majority of potential triggers do not initiate AF2 suggests some role for an AF substrate in most patients. However, it is unclear whether AF substrates are fixed and related to
Current mechanistic hypotheses for human AF
At the present time, two hypotheses predominate to explain AF: the multiwavelet reentry and localized source hypotheses. Evidence exists to support both, and they may potentially coexist in certain types of AF.
Multiwavelet reentry
In this mechanism, leading circle reentry produces multiple atrial circuits that may each meander, interact, and extinguish. Evidence for multiwavelet reentry comes from multielectrode mapping in dogs,11 from intraoperative mapping of AF in humans,12 and from the success of atrial compartmentalization via the Cox-Maze surgical procedure.13 Nevertheless, clinical evidence remains indirect,8 since early surgical mapping was performed in patients without clinical AF and the Cox-Maze III-IV
Localized source
Alternatively, AF may be maintained by rapid localized sources that activate too rapidly for the surrounding atrium, thus leading to AF via fibrillatory conduction. Experimentally, stable and regular microreentrant sources have been shown to sustain AF in isolated sheep heart7 and in vivo in dogs.8
In humans, evidence for localized sources comes from the observation of intra-atrial gradients in AF rate. The seminal intraoperative mapping studies of Wu et al14 and Sahadevan et al (summarized in
AF begets AF
Electrical remodeling refers to alterations in atrial electrophysiology as a result of AF that actually promote AF.11 The primary and consistent effect of remodeling is to shorten action potential duration (APD), which shortens the wavelength for reentry and may exaggerate the spatial dispersion of repolarization and thus promote AF. Conduction slowing is part of electrical remodeling in some but not all animal models, and its role in humans is uncertain.11
It is uncertain whether electrical
The impact of atrial stretch on AF initiation
Stretch is an attractive mechanism for AF. Clinically, AF episodes are more frequent at times of worsened heart failure,2 while elevated left atrial pressure may explain the association between lone AF and left ventricular diastolic dysfunction31 and contribute to the link between AF and mitral valve disease.2 Stretch likely reduces APD and refractoriness (to facilitate AF) via stretch-activated channels, and, in rabbit hearts, this may be inhibited by gadolinium and by an extract from
Evidence for structural factors in the AF substrate
Elegant mathematical and experimental33 studies show that fixed spatial dispersion of refractoriness may facilitate wave break and initiate reentry. In humans, atrial scarring and fibrosis in older patients34 and those with heart failure35 may explain their propensity for AF, and they also occur in patients with AF.10 At a cellular level, APD and the effective refractory period are shorter in canine left than right atrium owing in part to larger IKr, thus allowing the left atrium to activate
Dynamic conduction slowing in patients with persistent AF
Conversely, the maximum APD restitution slope was relatively shallow in patients with persistent AF (0.7 ± 0.2), and no patient exhibited slope >1.37 We found that shallow APD restitution may have been caused by the fact that patients with persistent AF exhibited marked conduction slowing for early premature atrial contractions, thus prolonging their diastolic intervals and truncating the left portion of the curve (i.e., short diastolic intervals).37
Both experimental11 and human38, 39 studies
Repolarization alternans and human AF
Computer models of the human atria have shown that APD alternans may cause repolarization dispersion and lead to human AF,40 analogous to experimental and computational evidence linking APD alternans with fibrillation in the ventricle.33
APD alternans provides one potential mechanism by which dynamic slowing may cause AF. Because rapid beats may encounter varying conduction delay, those beats may arrive at a particular region of the heart with variable (oscillating) timing, and those beats will
Summary
Human AF likely represents a constellation of related diseases with varied mechanisms. Although each may depend on triggers and functional and structural substrates, the relative contribution of each may vary with the clinical context. Therefore, additional mechanistic studies in patients with AF are urgently needed to complement elegant descriptions of AF mechanisms revealed experimentally. This translational approach is likely the best strategy to address the heterogeneous milieu of human AF
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Supported by grants from the American College of Cardiology–Merck Foundation (to Dr. Krummen) and the National Institutes of Health (nos. HL70529, HL83359), Doris Duke Foundation, and American Heart Association (to Dr. Narayan).