Pathophysiology of Atrial Fibrillation
The pathophysiological basis of AF is multifactorial and complex.8,9 Electrophysiological hallmarks of AF are ectopic activity and reentry as the functional surrogates for trigger and susceptible substrate. Underlying molecular mechanisms include changes in expression and function of ion channels, altered calcium homeostasis, enhanced atrial automaticity, alterations in gap junction distribution, and adverse effects on atrial integrity such as dilatation, fibrosis or inflammation. These mechanisms are summarised as electrical and structural remodelling, and will be described here briefly.
Three main mechanisms causing focal ectopic activity are: enhanced atrial automaticity, early afterdepolarisations and delayed afterdepolarisations. Under normal physiological conditions, generation and conduction of electrical impulses in the heart is implemented by a characteristic sequence of voltage changes driven by depolarising and repolarising ion currents. Cardiomyocytes display a resting membrane potential of around -80 mV. An electrical impulse causes a swift depolarisation by rapidly activated sodium channels with subsequent influx of sodium ions. Following this, potassium ions exit the cell through potassium channels, initiating the repolarisation of the cell (re-establishing the resting membrane potential). Simultaneously, calcium ions enter the cell leading to cell contraction (excitation– contraction coupling) and slowing of the repolarisation.
In healthy hearts the sinus node dominates the generation of electrical signals. However, it is possible that a cell outside the sinus node reaches the threshold potential earlier resulting in ectopic firing at a more rapid rate, potentially leading to atrial tachycardia. In this regard alterations of the cellular calcium homeostasis may play an important role as has been demonstrated in animal models and patients with AF.9 Delayed afterdepolarisations result from an abnormal calcium leak from the sarcoplasmatic reticulum (SR). Physiologically, cellular calcium is removed by the SR Ca2+ATPase (SERCA) and the Na+–Ca2+ exchanger (NCX) during diastole to re-establish ionic homeostasis at the end of the cardiac cycle. During atrial tachycardia, however, calcium is progressively accumulated in the cell because of repetitive activation of the L-type Ca2+ channel. This Ca2+ overload leads to multiple maladaptive alteration, for example, a Ca2+ overload of the SR with concomitant dysfunction of the ryanodine receptor (SR calciumrelease channel). This distribution of the SR regulation can cause spontaneous diastolic Ca2+ release from the SR during diastole, which then can activate the electrogenic NCX (Ca2+ versus 3 Na+) causing a depolarising inward current (delayed afterdepolarisation). This leads to a progressive depolarisation of the cell and ectopic firing (when the threshold potential is reached; so-called triggered activity).10–12 Early afterdepolarisations occur when the action potential duration (APD) is excessively prolonged, for example, in the context of arrhythmia syndromes such as long-QT syndrome.9,11,12 In this setting, another phenomenon called dispersion of repolarisation has been described. In healthy myocardia, a more or less homogeneous-organised repolarisation prevents onset of arrhythmia; in diseased myocardium, however, a vulnerable substrate can be created by heterogeneous electrophysiological properties due to remodelling processes. This may be caused by transmural APD variations within the 3D myocardial structure. These changes causing electrophysiological heterogeneity can result in proarrhythmic repolarisation differences predisposing to the initiation of arrhythmias. Pacemaker cells express specific ion channels (funny channels) that are responsible for the so-called automaticity (i.e. the progressive diastolic depolarisation). Therefore, an upregulation of these ion channels, as seen in heart failure, could be a possible mechanism leading to enhanced automaticity.13
Another hallmark of AF is reentry that can occur when at least two (functionally or anatomically) distinct pathways, a unidirectional block in one of the pathways and a slowed conduction, are present. In this case the conduction time along the unblocked pathway must exceed the refractory period of the blocked pathway (conduction time x reentry circle length > refractory period). In healthy myocardia, the electrical properties are relatively homogeneous without slow conduction areas preventing the occurrence of reentry. In diseased myocardia, however, two mechanisms are important: altered electrical properties that cause a shortening of the refractory period or conduction slowing, and structural changes (e.g. atrial fibrosis) that disturb the uniform and homogeneous excitation and thereby provide an anatomical substrate for reentry. In a healthy heart, reentry cannot occur because cardiomyocytes display a certain refractory period that prevents premature stimuli to conduct. When the refractory period is shortened, however, the cell is excitable earlier, ectopic activity can be conducted and reentry can be initiated. Additionally, slowed conduction velocity can also allow reentry because cells are excitable again when the impulse arrives. Structural changes in the atrium such as dilatation and fibrosis extend conduction pathways, slow conduction and create conduction barriers favouring initiation and maintenance of reentry circuits. Interestingly, some of the electroanatomical changes implicated in AF pathophysiology initially act as a protective mechanism of the cell, but finally result in a fixed substrate for AF maintenance. Atrial tachycardia (as seen in AF) causes a cellular calcium overload. To reduce the calcium influx and to antagonise the calcium overload, the calcium current is reduced (by inactivation of calcium channels (short-term effect) and reduced gene expression of the calcium channels (long-term effects), leading to a shortening of the action potential. This favours reentry and therefore contributes to AF maintenance (‘AF begets AF’).14