© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Atrial fibrillation-induced electrical remodeling in humans
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Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
* Tel.: +043-388-1202-00; fax: +043-388-41-66
Received 2 August 1999; accepted 2 August 1999
See article by Bosch et al. [1] (pages 121–131) in this issue.
In the article elsewhere in this issue, "Ionic mechanisms of electrical remodeling in human atrial fibrillation", Ralph Bosch and co-workers [1] describe the changes in atrial action potential characteristics and ion-channel densities in 8 patients with chronic atrial fibrillation (AF). The action potentials of single atrial cells isolated from patients in AF, showed a normal resting membrane potential more negative than –75 mV and amplitudes higher than 115 mV. However, compared to patients in sinus rhythm the repolarization phase was markedly changed. Both, the early rapid repolarization (phase 1), carried by Ito and the plateau of the action potential mainly carried by ICa,L(phase 2), were clearly attenuated or even abolished. As a result, atrial cells in AF patients seemed to repolarize almost exclusively by phase 3 repolarization. The total duration of the action potential was markedly decreased. At a pacing rate of 60 beats/minute, the duration had shortened from a control value of 255±45 ms to 104±9 ms (a reduction of 60%). In addition, also the physiological rate adaptation was reduced and the atrial action potentials showed almost no shortening anymore when the stimulation frequency was increased (98±8 ms at 240 beats/minute). An important consequence of this loss of the physiological rate adaptation is that chronically fibrillating atria can no longer be expected to prolong their action potentials when sinus rhythm is restored. Since short action potentials (and short refractory periods) facilitate the induction of atrial re-entry, this maladaptation may be the pathophysiological basis for the frequently observed early recurrences after cardioversion of AF [2,3].
Long-term shortening of the atrial refractory period by rapid pacing or atrial fibrillation has first been demonstrated in chronically instrumented dogs and goats [4,5]. In the goat, artificial maintenance of AF by a fibrillation pacemaker led to a slowly progressive shortening of the atrial refractory period during the first 48 hours of AF from an average of 146 ms to 81 ms. At the same time AF became more stable and the duration of paroxysms of AF increased progressively (AF begets AF) [5]. Confirmation of this AF-induced electrical remodeling in humans has been provided by Franz et al. [6]. By recording atrial monophasic action potentials (MAP) in patients with longstanding atrial flutter or fibrillation, these authors showed that after cardioversion, the MAP duration was considerably shorter than in patients with normal sinus rhythm [6].
Immediately after the discovery of tachycardia-induced electrical remodeling, studies were undertaken to elucidate the underlying cellular and molecular mechanisms. Shortening of the action potential can be the result of either an increase in repolarizing (outward) current or a decrease in (inward) depolarizing current. Since the outward current is mainly carried by potassium ions and the inward current during the plateau by Ca2+ ions, it was hypothesized that the AF-induced shortening of the atrial action potential was due either by an upregulation of potassium channels or a downregulation of Ca channels. The group of Van Wagoner et al. choose for an upregulation of potassium channels as the most likely candidate [7]. However, much to their surprise they found that in patients with chronic AF, both the density of the channels carrying the transient outward current (Ito) as well as the sustained potassium current (IKsus), were reduced rather than elevated. In addition, Western blot analysis showed that the expression of Kv1.5 (the alpha subunit of the delayed rectifier K+ channel) was reduced by more than 50%. These unexpected findings certainly did not explain the observed shortening of the atrial action potential in patients with atrial fibrillation. The alternative possibility (a reduction of Ca2+ current) was studied by Yue et al. in a canine model of atrial fibrillation [8]. In this study, dogs of 27.3+2.4 kg were instrumented with an atrial pacemaker programmed at 400 beats per minute. Atrial myocytes were isolated 1, 7, or 42 days after continuous rapid atrial pacing. After 42 days the APD90 was shortened from 161±11 to 85±5 ms. Voltage clamp studies showed no change in IK1, IKr, IKs, IKur.d, ICaT, or IClCa. In contrast, the density of the transient outward current (Ito) and the L-type Ca2+ current were markedly reduced. The action potentials and ionic currents in remodeled myocytes actually were similar to those recorded in normal cells subjected to nifedipine (an L-type Ca2+ blocker). The hypothesis that the long-term shortening of the atrial action potential and its reduced rate adaptation was mainly due to a reduction of the L-type Ca2+ current was further supported by the observation that administration of Bay K 8644 (an agonist of the L-type Ca2+ current) largely restored the plateau phase in remodeled cells [8].
The importance of the paper of Bosch et al. [1] is that it completes the picture of the AF-induced changes in ion channels in humans. In their study they established that the shortening of the human atrial action potential by AF was due to a 70% reduction in ICa,L and Ito together with an increase in IK1 and IKACh. This concerted action of the atrial potassium and calcium channels in response to prolonged atrial fibrillation offers a good explanation for the observed shortening of the action potential and the perpetuation of the arrhythmia.
At this point one may wonder why the atrial myocytes are responding in this way. There must be a good reason for the atria to give up their protection against reentrant arrhythmias and to ‘choose’ to shorten their action potentials rather than to maintain (or even prolong) the plateau. A likely reason is to prevent calcium overload of the cell. During atrial fibrillation the rate of the atrial action potentials is very high and the cell membrane is depolarized most of the time. As a consequence, the L-type calcium channels are almost always in the open state, causing a constant flux of calcium ions into the cell. Downregulation of the expression of the L-type Ca2+ current counteracts this chronically increased calcium influx and thus may be regarded as part of the calcium-handling system of the cell. Little is yet known about the regulating mechanisms determining the palette of ion-channels involved in repolarization of the cardiac action potential. There exists a wide variation in action potential duration in hearts of different size. In general, there seems to be a direct correlation between the length of the plateau and the cardiac tissue mass, with the atria having a shorter action potential than the ventricles, and the action potentials of the atria as well as the ventricles becoming longer with increasing body weight. It is not clear at this point whether these marked differences in repolarization are solely due to differences in genotype, or whether they are also partly the result of changes in phenotype. The frequency of the normal heart beat amongst different species (from mouse to elephant) varies more than the difference in atrial rate during sinus rhythm and atrial fibrillation. It is tempting to speculate that the different duration of the cardiac action potentials in small and large animals is the result of similar intracellular signalling processes as the ones leading to changes in expression of membrane ion-channels during atrial fibrillation.
Although it now has been firmly established that AF-induced electrical remodeling also takes place in humans, still a number of questions have to be answered before one can tell how important this process is for the natural history of atrial fibrillation. The first thing to determine is the time course of tachycardia-induced electrical remodeling in humans. This knowledge is important to determine the optimal moment for pharmacological or electrical cardioversion of AF. How long can one wait for spontaneous termination without jeopardizing the effectiveness of pharmacological defibrillation or increasing the risk of early recurrences after cardioversion? The second question that should be answered is how long AF-induced electrical remodeling is still completely reversible and whether reverse remodeling follows the same time course as AF-induced remodeling. A third important point is whether electrical remodeling alters the action of class I and class III drugs. Since atrial fibrillation changes the expression of ion-channels involved in atrial repolarization, it is quite likely that the effects of class III drugs are changed (become less effective). Last but not least, knowledge of the intracellular signal-transduction pathways involved in tachycardia-induced remodeling may provide new targets to interrupt the chain of cause and effect leading to ‘domestication’ of atrial fibrillation. Only if we find answers to these questions the role of electrophysiological remodeling in the development of a substrate for sustained atrial fibrillation can be estimated. Although it should not be forgotten that other factors like ageing, atrial dilatation, atrial ischemia and neurohumoral changes may be of greater clinical importance, the work of Bosch et al. [1] has set the stage for basic clinical studies to further elucidate the role of electrical remodeling. The present availability of the implantable atrial cardioverter provides an opportunity for systematic studies in humans which otherwise would have only been possible in animals.
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[Abstract/Free Full Text] - Timmermans C., Rodriguez L.M., Smeets J.L.R.M., Wellens H.J.J. Immediate reinitiation of atrial fibrillation following internal atrial defibrillation. J Cardiovasc Electrophysiol (1998) 9:122–128.[Web of Science][Medline]
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[Abstract/Free Full Text]
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