Q J Med 2000; 93: 563-565
© 2000 Association of Physicians
Editorial |
Atrial electrical remodelling and atrial fibrillation
Manchester Heart Centre, Manchester Royal Infirmary, Manchester
Atrial fibrillation (AF) is the most common tachyarrhythmia in humans. It causes palpitations, decreased cardiac output, heart failure and systemic thromboembolism, and is associated with significant morbidity, mortality1 and healthcare costs. Current treatment strategies for AF are far from satisfactory.
Atrial fibrillation has a tendency to become more persistent with time, a large percentage of patients with paroxysmal AF eventually developing chronic AF.2 Although progression of an underlying disease has previously been considered as the most likely explanation for this phenomenon, in a proportion of cases, no underlying disease is evident. Recently Wijffels and coworkers have demonstrated, in a chronically instrumented conscious goat model, that episodes of AF may be self-perpetuating (‘AF begets AF’) and have suggested that there may be a purely electrophysiological explanation (termed atrial electrical remodelling) for the increased persistence of AF with time.3 This hypothesis has considerable clinical importance in that it would, if proven, support a more aggressive approach to the overall management of AF. If AF leads to more AF, then it is reasonable to expect that earlier termination and preventative therapy for the arrhythmia would improve the long-term outcome of patients with the condition.
In the original model of Wijffels and Allessie,3 goats initially had electrodes sutured to the epicardium of both atria. After this initial surgery, the goats were connected to an external automatic fibrillator. The device was programmed to deliver a 1 s burst of electrical stimuli whenever sinus rhythm was sensed. In the normal animal, the first burst of atrial pacing resulted in an episode of AF which almost invariably terminated spontaneously within a few seconds. However, when AF was repetitively reinduced, the duration of AF episodes gradually increased until, after a period that varied from a few days to 2 weeks, it no longer self-terminated, i.e. it became persistent. Since this initial demonstration of the self-perpetuation of AF in the goat, this phenomenon has been confirmed in different models by a number of different groups.4–6 In the experiment described above, the Maastricht group also demonstrated a marked shortening of atrial refractoriness after only a few hours of repetitive AF induction. These authors suggested that this change provided the mechanism (atrial electrical remodelling) for the increased stability of AF as predicted by Moe's multiple wavelet hypothesis.7,8 Reduction of refractoriness is a consistent finding in a number of different animal models of AF,4–6 and it has proven difficult to separate the refractoriness change from the self-perpetuating process.9
In a series of further experiments with the goat model, the Maastricht group investigated a number of possible mechanisms of the AF-induced decrease in atrial refractoriness.10 The process was not influenced by acute atrial stretch, autonomic blockade or the ATP-dependent potassium channel blocker glibenclamide, and could be reproduced by rapid atrial pacing as well as repetitive reinduction of AF. They concluded that the changes in atrial refractoriness were the result of the high rate of activation of the atrial myocytes that is common to both rapid atrial pacing and AF.
Yue and coworkers11 examined the development of ionic and cellular changes associated with atrial remodelling in an equivalent model of AF in dogs. Atrial cells were examined from control dogs in addition to those who had been rapidly atrial paced for 1, 7 or 42 days. Action potential duration shortening was evident within 1 day of rapid pacing and was virtually complete by 7 days. This shortening was accompanied by a progressive decline in L-type Ca2+ current and ITO amplitude with no change in Ik1, Ikr, Iks, ICaT or ICl.Ca. Similar reductions in action potential duration to those seen in chronically paced dogs were reproduced by exposure to nifedipine in control cells, suggesting that depression of ICa was responsible for much of the action potential abbreviation in paced dogs. Blockade of ITO caused little change in action potential duration additional to that seen with blockade of ICa. Other biophysical properties of the currents, including voltage and time dependence, were unaltered, suggesting that there is a decrease in the number and/or conductance of ICa channels without a change in their fundamental nature. There is experimental evidence to indicate that the refractoriness shortening associated with brief episodes (<1 h) of AF is likely to be due to functional changes such as Ca2+-induced inactivation of ICa, and that the longer term changes associated with several days of rapid atrial rates are mediated via downregulation of Ca2+channel proteins (in particular 
lc subunits of the L-type calcium channel).12 Although such downregulation of Ca2+ channels would account for the action potential changes and refractoriness shortening associated with atrial electrical remodelling, it is still unclear as to how the process is initiated and controlled. Several authors have suggested that the initiating factor may be intracellular calcium overload due to an abnormality of intracellular calcium handling associated with repetitive activation of atrial myocyte during AF.6,12–14 This hypothesis is based on a number of lines of evidence, including histological changes compatible with Ca2+ overload-induced injury that have been seen in rapidly-paced atria.6
What is the evidence for atrial electrical remodelling in humans? It has been known for some time that patients with chronic AF have shorter atrial refractoriness than those with acute AF, but until recently it has not been possible to exclude the alternative view that these changes represent the primary abnormality causing AF rather than being an AF-induced phenomenon. Indeed, before the experimental demonstration of atrial remodelling this was the preferred explanation of these changes. Recent studies of patients following cardioversion of persistent AF have shown that these changes are reversible following a period of sinus rhythm, however, effectively confirming their AF-induced nature.15–17
The crucial question that needs to be answered relates to the possibilities available for inhibiting the remodelling and self-perpetuating processes. Stimulated by the evidence suggesting intracellular calcium overload is the trigger for atrial remodelling, a number of experimental studies have shown that AF-induced reduction in atrial refractoriness can be suppressed by the L-type calcium antagonist verapamil.6,18 Clinical data are conflicting, however, and the latest experimental evidence indicates that the anti-remodelling effects of this agent are outweighed by a different, profibrillatory effect19 such that the net result is to accentuate rather than inhibit the self-perpetuation of AF.20 The T-type calcium current is smaller than the L-type current in normal atrial tissue but, unlike the L-type current, is not downregulated by rapid atrial rates and so provides a relatively greater contribution in remodelled cells. T-type calcium antagonism with mibefradil has particular promise, in that it has been shown in experimental models to be devoid of the direct profibrillatory effect of verapamil, and effectively inhibits both atrial remodelling and the self-perpetuation of AF.21 The fly in the ointment in the case of mibefradil, however, is its propensity to cause serious adverse drug interactions via potent cytochrome P450 inhibition which has led to its recent withdrawal from clinical use as an antihypertensive agent. The direct clinical application of these findings will therefore have to await the development of T-type calcium channel blockers devoid of effect on cytochromes. In the meantime the race is on to understand the molecular mechanisms of calcium handling and remodelling in atrial cells in order to define other potential targets for drug action.
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