Atrial Fibrillation
The prevalence of atrial fibrillation (AF), already the most common sustained cardiac arrhythmia, is constantly rising, even after adjusting for age and presence of structural heart disease. AF increases the risk of stroke sixfold and is associated with a twofold increase in mortality, which remains above 1.5-fold after adjusting for co-morbidity, predominantly caused by cerebrovascular events, progressive ventricular dysfunction, and increased coronary mortality. The adverse haemodynamic effects of AF are well described and relate not only to loss of atrial contraction, but also to the accompanying rapidity and irregularity of ventricular contraction. Although AF may be asymptomatic, up to two thirds of patients report that the arrhythmia is disruptive to their lives. Finally, the treatment of AF and its associated complications creates a significant and increasing economic burden. This article focuses predominantly on the pathophysiology of the arrhythmia and its pharmacological treatment. Anticoagulation for prevention of thromboembolism, a fundamental principle in the management of this arrhythmia, electrical cardioversion, percutaneous ablation techniques, and surgery for AF are not discussed in any detail.
PATHOPHYSIOLOGY AND MECHANISMS
Hypertensive, valvar, ischaemic, and other types of structural heart disease underlie most cases of persistent and permanent AF, whereas lone AF accounts for approximately 15% of AF cases. Familial AF is well described, although at present considered rare. A region on chromosome 10 (10q22-q24) was originally identified as containing the gene responsible for AF in families in which the arrhythmia segregated as an autosomal dominant trait. However, familial AF appears to be a heterogeneous disease. A family with a mutation in the gene encoding the pore forming α subunit of the cardiac IKs channel on chromosome 11 that results in increased function of this channel, with affected members developing persistent AF probably caused by a reduction in refractoriness, has more recently been described.
The pathogenesis of AF is now thought to involve an interaction between initiating triggers, often in the form of rapidly firing ectopic foci located inside one or more pulmonary veins, and an abnormal atrial tissue substrate capable of maintaining the arrhythmia. Although structural heart disease underlies many cases of AF, the pathogenesis of AF in apparently normal hearts is less well understood. Although there is considerable overlap, pulmonary vein triggers may play a dominant role in younger patients with relatively normal hearts and short paroxysms of AF, whereas an abnormal atrial tissue substrate may play a more important role in patients with structural heart disease and persistent or permanent AF.
Focal initiators of AF
It is now known that foci of rapid ectopic activity, often located in muscular sleeves that extend from the left atrium into the proximal parts of pulmonary veins, play a pivotal role in the initiation of AF in humans. Less frequently, focal initiation of AF may be result from ectopic activity that arises from muscular sleeves in the proximal superior vena cava, from the ligament of Marshall, or other parts of the right and left atria. Initiation of AF by rapid focal activity has been demonstrated not only in patients with structurally normal hearts and paroxysmal AF, but also during the process of reinitiation of persistent AF after electrical cardioversion, both in the presence and absence of associated structural heart disease.
Muscular sleeves that extend into the proximal pulmonary veins are present in the normal heart. The mechanisms involved in the production of ectopic activity by these sleeves in patients with AF, as well as the exact mechanism of initiation of AF by the rapid activity, remain to be elucidated. Proposed mechanisms for generation of abnormal focus activity include increased automaticity, triggered activity, and micro-reentry. Changes in autonomic tone around the time of initiation of AF paroxysms, with an increase in sympathetic activity followed by an abrupt change to parasympathetic predominance, have also recently been demonstrated.
Tissue substrate capable of maintaining AF
Both experimental and human mapping studies have demonstrated that persistent AF is generally characterised by the presence of multiple wavelets of excitation that propagate around the atrial myocardium. However, there is considerable variability in the observed patterns of activation, both between patients and between the two atria of individual patients. Perpetuation of AF is facilitated by the existence or development of an abnormal atrial tissue substrate capable of maintaining the arrhythmia, with the number of meandering wavelets that can be accommodated by the substrate determining the stability of AF. Re-entry within the atrial myocardium is facilitated by conduction slowing and shortening of the refractory period. Both have been demonstrated in animal models and patients with AF, with increased dispersion of refractoriness further contributing to arrhythmogenesis. Shortening of the atrial action potential, reduced expression of L type calcium channels, and microfibrosis of the atrial myocardium have also been demonstrated.
Electrophysiological remodelling
AF in itself can cause progressive changes in atrial electrophysiology such as substantial refractory period shortening, which further facilitate perpetuation of the arrhythmia. In animal studies, changes in ion channel function and shortening of refractory periods start within minutes of AF onset and, by 24 hours, sufficient atrial remodelling has occurred to increase the likelihood of AF persisting. However, restoration of sinus rhythm in this animal model, even after two weeks of persistent AF, results in a rapid reversal of the electrophysiological remodelling.
The science of atrial fibrillation
Contemporary theories of the mechanism of atrial fibrillation require an understanding of re-entry as a mechanism of arrhythmogenesis. Re-entry, which is not a disorder of impulse formation but rather a disorder of impulse propagation, occurs when an impulse travels around an abnormal circuit repetitively. Consider 2 distinct areas of tissue (Fig. 1), where area A is excited by a depolarizing wavefront. Once excited, cells in area A cannot be excited again until their cell membranes have repolarized and the cells have recovered; the depolarizing wavefront has left the cells in its wake refractory to further stimulus. A premature stimulus activating area B cannot excite area A if it occurs when the intervening tissue is still refractory. However, if that depolarizing wavefront travels to area A by an alternate route, allowing sufficient time for tissue in area A to recover, then area A may be re-excited. Under the right circumstances, areas A and B can then re-excite each other, which leads to sustained “re-entry.” Thus, re-entry requires an appropriately timed stimulus (trigger) that is able to find its way into a circuit (substrate) where its depolarizing wavefront never encounters refractory tissue.
(Fig 1)
Anatomic versus functional re-entry. In anatomical re-entry, circuit size is determined by fixed anatomic obstacles (left). In functional re-entry (middle), circuit size = conduction velocity х refractory period (length of the refractory tail). If the wavefront travels too quickly, or its refractory period is too long, its leading end would “bite its tail” and extinguish itself (right). Thus, these properties determine the smallest possible circuit size. Photo: Christine Kenney
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