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Cardiovascular Research 1999 42(2):455-469; doi:10.1016/S0008-6363(99)00044-9
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Steady-state and nonsteady-state action potentials in fibrillating canine atrium: abnormal rate adaptation and its possible mechanisms

Motoki Hara, Alexei Shvilkin, Michael R Rosen, Peter Danilo, Jr. and Penelope A Boyden*

Departments of Pharmacology and Pediatrics College of Physicians and Surgeons of Columbia University New York, 630 West 168 Street, New York, NY 10032, USA

pab4{at}columbia.edu

* Corresponding author. Tel.: +1-212-305-7907; fax: +1-212-305-0529

Received 1 December 1998; accepted 22 January 1999


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 4. Discussion
 References
 
Objective: Our goal was to study rate adaptation of atrial action potentials in non-steady and steady states to further our understanding of mechanisms determining inducibility and stability of atrial fibrillation. Methods: We used standard microelectrode techniques to examine the characteristics of steady-state action potentials paced at regular cycle lengths (CL) and of nonsteady-state action potentials observed after an abrupt change of CL in atria from canine hearts that had been rapidly paced. Results: We compared action potential characteristics among normal atria, atria in which chronic atrial fibrillation (cAF, lasting more than 3 days) had been induced and atria in which only nonsustained atrial fibrillation (nAF, lasting less than 12 h) had been induced. In steady-state, the rate adaptation of maximum diastolic potential (MDP) and action potential duration (APD) was markedly reduced in both cAF and nAF. Action potential characteristics did not differ between cAF and nAF atria, suggesting that factors other than electrophysiological properties determine the chronicity of AF. The time course of change in APD after an abrupt change of CL was altered in nAF/cAF atria; i.e., when CL was prolonged, APD also prolonged at the first beat, and then shortened during several subsequent beats (initial phase). Thereafter, APD slowly prolonged to a new steady-state (slow phase). In nAF/cAF atria, the initial phase was enhanced (greater shortening of APD) and the slow phase was reduced (less prolongation of APD). This latter phase was modified by ryanodine. Conclusions: Thus the reduced rate adaptation of steady-state APD is explained mainly by the loss of a slow phase of APD adaptation in nAF/cAF which is reversed in the presence of ryanodine. Therefore, in both nAF and cAF atria, rate adaptation of MDP as well as APD are reduced, nonsteady state as well as steady state, AP characteristics are markedly altered and these changes are partially explicable by Cai-dependent processes.

KEYWORDS Pathophysiology; Electrophysiology; Arrhythmia; Remodeling


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 4. Discussion
 References
 
Rapid atrial pacing [1] and atrial fibrillation [2] both change the electrophysiological characteristics of the atria. This electrical remodeling and associated structural changes are thought to promote the inducibility and persistence (stability) of atrial fibrillation. Clinically, paroxysmal atrial fibrillation can become sustained in patients having lone atrial fibrillation [3] and pharmacological and electrical defibrillation and the maintenance of sinus rhythm after defibrillation are more successfully effected when the duration of atrial fibrillation is short [4–8]. Experimentally, in chronically instrumented goats in which atrial fibrillation is artificially maintained, the fibrillation, itself, markedly shortens the atrial refractory period (referred to as electrical remodeling) and increases the inducibility and stability of further atrial fibrillation [2]. In addition, rate adaptation of the atrial refractory period is markedly reduced or reversed [2]. These observations led Wijffels et al. to state that ‘atrial fibrillation begets atrial fibrillation’ [2].

In dogs whose atria are rapidly paced (400 bpm, 6 weeks), the rapid atrial rate, alone, can initiate electrical remodeling [1]. Atrial fibrillation lasting over 15 min is readily induced in such rapidly paced atria, and increased atrial size and/or shortening of the refractory period are highly predictive of the induction of sustained atrial fibrillation [1]. This is consistent with the previous demonstration of the relationship of atrial size and pressure to the occurrence of atrial fibrillation in human subjects [9]. In the goat, the shortening of the atrial refractory period during rapid atrial pacing is attenuated by verapamil, suggesting the reduction of refractory period duration in electrically remodeled atria may be triggered by persistent Ca2+ overload at rapid atrial rates [10].

While it has become clear that prolonged periods of rapid atrial rate influence the function of some sarcolemmal ion channels [11] such that steady-state atrial action potentials are altered, most discussions thus far have focused on the linkages between changes in these sarcolemmal channels and changes in the action potential. The possibility that changes in intracellular Ca2+ handling might also influence atrial action potentials has received less attention. The transitions that occur between steady-state rhythms and sudden accelerations and decelerations in rate, and the arrhythmogenic potential of these also have not been explored. Therefore, we used conventional microelectrode techniques to determine the changes in both steady-state and nonsteady-state atrial action potential characteristics in atria from dogs in which rapid atrial pacing was imposed for weeks to induce nonsustained or sustained atrial fibrillation.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
4. Discussion
 References
 
2.1 Animal preparation
This investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US NIH Pub. No. 85-23, 1996.

Mongrel dogs weighing 20–25 kg were anesthetized with thiopental sodium (17 mg/kg, i.v.) and ventilated with isoflurane, 1.5–2%, and O2, 2 l/min. Morphine sulfate, 0.15 mg/kg, was injected into the epidural space to reduce the pain after awaking from anesthesia. Using sterile techniques, a right intercostal thoracotomy was performed, the pericardium was opened and the heart was suspended in a pericardial cradle. Medtronic permanent pacing leads were attached to the epicardium of the right atrial appendage and the right ventricular free wall. The leads were tunneled subcutaneously and connected to Medtronic MINIX 8340 pulse generators (Medtronic, Minneapolis, MN, USA) which were placed in subcutaneous pockets. A bipolar stimulating electrode was attached to the right atrial free wall for the induction of atrial fibrillation, and subcutaneously tunneled to the intrascapular region. Complete AV conduction block was produced by injection of 0.1–0.3 ml of 40% formaldehyde into the His bundle, usually resulting in an idioventricular escape rhythm of 30–50 bpm. Ventricular pacing was programmed as: rate 60 bpm; pulse amplitude 3.3–5 V; pulse width 0.35–0.5 ms; sensitivity 2.5 V; refractory period 300 ms. After the incisions were closed and the dogs awoke from anesthesia, they were maintained for 2 days in the recovery room before moving to routine care. The dogs were given cefazolin, 25 mg/kg i.m. prophylactically once before surgery and for 2 days after surgery. They were then allowed to recover for at least 2 weeks at which time recovery was complete, the ECG was stable and they had been laboratory trained. After recovery, atrial pacing was instituted (rate 400 bpm; amplitude 2.5–4 V; pulse width 0.2–0.4 ms) and maintained for about 5 weeks. At the time of terminal study, dogs were anesthetized with pentobarbital, 30 mg/kg, the hearts removed via a thoracotomy, the atria were excised and studied as described below.

2.2 Experimental protocols
The hearts were immersed in cold Tyrode’s solution equilibrated with O2–CO2 (95:5) and containing (in mM): NaCl 131, NaHCO3 18, KCl 4, CaCl2 2.7, MgCl2 0.5, NaH2PO4 1.8, and dextrose 5.5. Bachmann’s bundle (1.0x1.0x0.1 cm) and right atrial trabeculae were then excised. The preparations were placed in a tissue bath (for Bachmann’s bundle, epicardial side-up; for trabeculae endocardial side up) and superfused with Tyrode’s solution equilibrated with O2–CO2 (95:5) and warmed to 36°C (pH 7.35±0.05, ±S.E.). Solutions were pumped through the tissue bath at a flow-rate of 12 ml/min, with chamber content changed three times/min. The bath was connected to ground with a 3M KCl/Ag/AgCl junction. Preparations were impaled with 3M KCl-filled glass capillary microelectrodes with tip resistances of 10–20 M{Omega}. The electrodes were coupled by an Ag/AgCl junction to an amplifier with high-input impedance and input capacity neutralization (model Duo 773, World Precision Instruments, CT, USA). The maximum rate of rise of phase 0 of the action potential (Vmax) was obtained by electronic differentiation with an operational amplifier. Transmembrane action potentials and Vmax were displayed on a digital storage oscilloscope (model 4074, Gould, OH, USA) and stored in digitized form in a personal computer for subsequent analysis. The system was calibrated as previously described [12,13]. For stimulation of preparations, a programmed, computer-controlled stimulator was used to deliver 3.0-ms square-wave pulses 2.5 times threshold through bipolar PTFE-coated silver electrodes [12,13].

We used standard microelectrode techniques to study atrial action potentials from eight non-instrumented control dogs, six chronic atrial fibrillation (cAF) dogs, and six nonsustained atrial fibrillation (nAF) dogs. The transmembrane potential characteristics determined were the maximum diastolic potential (MDP), action potential amplitude, Vmax and duration to 50% (APD50) and 90% (APD90) repolarization. Action potentials of both Bachmann’s bundle and atrial trabeculae were examined. Only those preparations for which stable impalements were maintained throughout an experimental protocol were used for data analyses.

(1) Steady-state action potential characteristics: steady-state action potential characteristics were examined during drive at CL=4000 ms, decrementally decreased at 3–5 min intervals to 250 ms.

(2) Nonsteady-state action potential characteristics

1. Restitution of APD and Vmax: Restitution of APD90 and of Vmax was determined using single test pulses (S2) delivered after every 35th basic pulse (S1) at a basic CL (BCL) of 800 ms. The S1S2 coupling interval was progressively decreased from 15 s to 200 ms.
2. Time course of APD and MDP changes after an abrupt change of CL: the time course of APD50 and APD90 or MDP changes was studied after abruptly changing CL from 500 to 1500 ms and from 1500 to 500 ms. Preparations were stimulated for at least 5 min at a given CL before changing to a new one, and action potentials were recorded for at least 5 min after the change of CL. This provided enough time to attain a new steady-state.
In the experiments in which CL was abruptly prolonged, action potentials were recorded for the first six consecutive beats and thereafter every 10 s. In the experiments in which CL was abruptly shortened, action potentials were recorded for the first 13 consecutive beats and thereafter every 10 s. In general, when CL was abruptly prolonged the duration of the first action potential prolonged (referred to as ‘abrupt APD prolongation’), then gradually shortened during 5–6 beats (‘early shortening phase’). Subsequently, APD prolonged slowly to a new steady-state (‘slow prolongation phase’). When CL was shortened abruptly, the duration of the first action potential shortened (‘abrupt APD shortening’), then became longer during the subsequent 10–13 beats (‘early prolongation phase’). Subsequently APD shortened slowly to a new steady state (‘slow shortening phase’).
3. CL dependence of the early shortening phase: to study the characteristics of the abrupt APD prolongation and early shortening phases, APD90 of the first beat and sixth beat after abrupt prolongation of CL were compared at various CL. First, CL was abruptly prolonged from 500 to 1000 ms, then to 1200 ms, 1500 ms, 2000 ms, 3000 ms and 4000 ms. Then CL was abruptly prolonged from a steady-state 800 ms CL to the longer CLs, and then from 2000 ms to the longer CLs.

2.3 Effects of ryanodine on the time course of APD
In the last series of experiments, effects of ryanodine on the time course of changes of APD50 and APD90 were examined. The time course of APD change after an abrupt change of CL from 500 to 1500 ms and from 1500 to 500 ms was examined in the presence of 10–8 M ryanodine (40–50 min were allowed for equilibration).

2.4 Statistical analysis
Data were analyzed using ANOVA for repeated measures and Bonferroni’s test [14]. P<0.05 was considered significant. Data are reported as x±S.E.M.

3. Results
Atrial fibrillation was repeatedly induced by burst atrial stimuli (cycle length 80–100 ms; pulse width 5 ms; five times diastolic-threshold current) 3–4 days a week. cAF occurred in six dogs, and lasted 4–10 days in five dogs and 9 months in one. In six other dogs, only nAF (lasting 30 min to 10 h) occurred. Tissues obtained from these animals were used for microelectrode studies. In addition, eight age-matched animals were used for control tissues.

3.1 Action potential configuration
Fig. 1 shows representative action potential recordings from Bachmann’s bundle and right atrial trabecular muscle of normal, nAF and cAF atria paced at CL of 500 and 2000 ms. In normal atria, trabecular action potentials were more triangular in shape (especially at short CL) and had shorter APD than those of Bachmann’s bundle. A marked acceleration of repolarization and attenuation of the response to a change in CL (i.e., electrical remodeling) occurred in both nAF and cAF atria (see Fig. 1 for representative experiments and Fig. 2 for a summary of data). Moreover, the heterogeneity of action potential configuration that characterizes normal atria persisted in both the nAF and cAF preparations. For example, in cAF atria, APD of Bachmann’s bundle remained shorter than normal (Figs. 1A and 2Go) but longer than that of the cAF right atrial trabeculae (Figs. 1B and 2Go).


Figure 1
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  		Fig. 1 Representative steady-state action potential recordings from (A) Bachmann’s bundle and (B) trabecular muscle of normal, nAF and cAF atria at CL of 500 ms and 2000 ms. Note the shortening of APD at both CL and the reduced difference between the two CL in both types of AF preparations as compared to the normal.

 

Figure 2
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  		Fig. 2 Steady-state action potential characteristics from normal (Cont), nAF and cAF Bachmann’s bundle (left) and right atrial trabeculae (right) at CL from 250 to 4000 ms. Abscissa of left panel: CL (ms). Ordinate of left panel: MDP (–mV), Amp (mV), Vmax (V/s), APD50 (ms) and APD90 (ms). * Indicates P<.05 cf the values at CL=500 ms; **indicates P<.05 cf the values at shortest CL; +indicates P<.05 cf cAF and nAF atria at each CL. Note that the steady-state rate adaptation of each action potential parameter was reduced in both nAF and cAF atria.

 
3.2 Rate dependent changes of steady-state action potential characteristics
Fig. 2 shows the CL dependence of the steady-state action potential characteristics (MDP, amplitude, Vmax APD50, APD90) from normal (Cont, n=6), nAF and cAF Bachmann’s bundle fibers (n=6, each group) (left panels) and from right atrial trabeculae from normal (Cont, n=3) and nAF or cAF animals (nAF/cAF, n=5) (right panel). In normal atrium, MDP was maximal at CL=500 ms (Bachmann’s bundle) or 1000 ms (trabeculae) and depolarized as CL became longer or shorter. At short CL, depolarization was at least in part due to incomplete repolarization since when pacing was stopped, the last paced beat revealed nearly complete repolarization (data not shown). Depolarization of MDP due to incomplete repolarization at short CL was minimal in nAF and cAF, which had intrinsically shorter APD90 (Fig. 2). In both nAF and cAF, depolarization of MDP at longer CL was reduced. Thus, the rate adaptation of MDP of normal atria was significantly altered in nAF and cAF atria. Finally, average MDP values in nAF and cAF Bachmann’s bundle were significantly greater than those of normal atria at CL=250 and 4000 ms.

Significant changes of amplitude and Vmax occurring in nAF and cAF appeared to follow the changes in MDP, consistent with their dependence on MDP. Similar to findings of others [11], rate adaptation of steady state APD50 and APD90 was markedly reduced in nAF and cAF; that is, at long CL, normal atrial potentials became prolonged while those of both cAF and nAF prolonged less, remaining significantly shorter than those of normal atria. At short CL, the differences among APDs of the different study groups were small. APD90 of normal atria were significantly longer than those of nAF and cAF atria at all CL; however the differences among average APD50 values did not reach statistical significance at CL <300 ms in both Bachmann’s bundle and right atrial trabecular preparations. Finally, there were no differences in steady-state action potential characteristics between cAF and nAF.

Thus, the steady-state rate adaptation of MDP and of APD was reduced in both Bachmann’s bundle and trabecular preparations of nAF and cAF atria. Because of the qualitative similarity of results in Bachmann’s bundle and trabecular muscle and the greater ease of maintaining impalements in Bachmann’s bundle preparations, the remainder of the data reported will be from experiments completed using Bachmann’s bundle.

3.3 Restitution curves of APD and Vmax
Fig. 3A and B show the restitution curves for APD90 (S1S1=800 ms) and representative action potential tracings of Bachmann’s bundle preparations from normal, nAF and cAF atria. The APD restitution curve of normal atria attained a plateau at S1S2 intervals >2000 ms, while those of the nAF and cAF atria failed to reach a plateau even at S1S2=15 s. Similar results were seen in the restitution curves for APD50 (data not shown). Restitution data for APD90 of each normal atrial preparation were fit using the following monoexponential equation: APD90=K[1–A1exp(–DI/{tau}1)], where DI is the test diastolic interval which was measured from the point corresponding to APD90 of the preceding action potential to the upstroke of the action potential. In contrast to normals, restitution data for APD90 of both nAF and cAF atria were better fit using a biexponential equation: APD90=K[1–A1exp(–DI/{tau}1)–A2exp(–Dl/{tau}2)]. Data are shown in Table 1. Clearly, the time course of APD restitution was markedly slowed in nAF and cAF atria. Furthermore, a second slow component ({approx}10 s) became prominent. Again, there were no significant differences in APD restitution between cAF and nAF.


Figure 3
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  		Fig. 3 Restitution curves of APD90 at BCL=800 ms (A) and representative studies (B) from normal (n=6), nAF (n=6) and cAF (n=6) atria. Abscissa of left panel: log plots of S1S2 intervals (ms). Ordinate of left panel: APD90 (ms) of S2. Note that while restitution curve of normal atria attained a plateau in roughly 2000 ms, those of nAF and cAF did not, even at 15 s. (C) Relationship of slope of APD restitution curves of (A) for control and cAF atria to S1S2 intervals. Note slope <1 for most S1S2 intervals in cAF atria.

 

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  		Table 1 Restitution of APD90 of S2a

 
The steepness of APD restitution curves is an important determinant of stability of reentrant circuits [15–17]. Accordingly, we assessed the slope of the APD restitution curves of normal and cAF atria for several S1S2 intervals (Fig. 3C). In normal atria, the APD/DI relationship varied from <1 for short S1S2 intervals, to >1 at intervals between 300 and 800 ms intervals. In contrast, the slope of the restitution curve in the cAF preparations was <1 at most S1S2 intervals.

The time course of recovery of Vmax did not differ among normal, cAF and nAF preparations (P>0.05, Table 2). The relationship between APD restitution and Vmax restitution markedly differed between the normal and the nAF and cAF atria. Representative restitution curves of APD90 and Vmax for a typical normal (control) atrium (upper panel) and for a cAF atrial preparation (lower panel) are plotted on the same log scale to emphasize these differences in Fig. 4. The recoveries of APD90 and Vmax in the normal atrium (upper panel) follow similar time courses. In contrast, in this cAF preparation (lower panel), the very short APD remained very short over a wide range of S1S2 intervals indicating the slowed APD restitution (see above). Nevertheless, these very short APD were accompanied by a very rapidly recovering Vmax . Thus, while most premature stimuli may have short APD, upstroke velocities are normal or nearly normal in cAF.


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  		Table 2 Restitution of Vmax of S2a

 

Figure 4
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  		Fig. 4 Representative examples of recovery of Vmax (squares) and APD90 (circles) for S2 in normal (upper panel) and in cAF atria (lower panel). Ordinate of each panel: APD90 (ms) of S2 or Vmax of S2. Abscissa of each panel: log plot of S1S2 interval (ms). See text for further information.

 
3.4 Relationship between steady-state and restitution of APD90
In nine experiments, impalements were maintained throughout both the steady-state and restitution protocols and thus both relations could be compared within the same preparations (Fig. 5). In normal atria (n=4), steady-state and restitution curves were nearly identical except at the short CL, while, in the nAF/cAF atria (n=5), steady-state APD90 was significantly shorter than restitution values at CL>800 ms and longer at CL<800 ms. Data in Fig. 5 roughly predict the time course of the change in APD90 following an abrupt change of CL from 800 ms to a new CL. Furthermore, they suggest that the time course of change in APD after an abrupt change in CL may differ between normal and nAF/cAF atria.


Figure 5
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  		Fig. 5 Relation between steady-state and restitution of APD90 in normal (n=4) (A) and nAF/cAF atria (n=5) (B). Abscissa: CL or S1S2 intervals (ms). Ordinate: APD90 (ms) of steady-state and restitution. *indicates P<.05 cf restitution. Note that the relation between steady-state and restitution of APD90 was changed in atrial fibrillation. See text for further details.

 
3.5 Time course of change in APD after an abrupt change of CL
Fig. 6 shows the time course of APD50 (A) and APD90 (B) after an abrupt change of CL from 500 to 1500 ms and from 1500 to 500 ms. (Representative action potential recordings obtained during this type of protocol are shown in Fig. 8). In Fig. 6, note that the shapes of the transition curves of APD in normal (n=6) and nAF/cAF (n=6) atria were somewhat similar when CL was abruptly prolonged (left panels). In both experimental groups, APD of the first beat at the new CL was prolonged compared with that of the steady-state APD (500 ms CL) (abrupt APD prolongation) and then shortened during the next six beats (early shortening phase). Thereafter, APD prolonged slowly to a new steady-state (slow adaptation phase). However, while the shapes of transition curves appeared similar, the initial changes in APD (abrupt prolongation and early shortening phases) were significantly augmented and the slow prolongation phase was significantly reduced in nAF/cAF atria compared to normal. Thus, it appears that the altered rate adaptation of steady-state APD in nAF and cAF atria (Fig. 2) can be explained mainly by the loss in the slow adaptation phase of the APD seen during these transition stimulation protocols.


Figure 6
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  		Fig. 6 Time course of (A) APD50 and (B) APD90 after an abrupt change of CL from 500 to 1500 ms (left panel) and from 1500 to 500 ms (right panel) in normal (n=6) and nAF/cAF atria (n=6). To facilitate the visualization of changes in APD during the first several beats at the new CL, the x axis is a log plot of time after the change of CL. Ordinate: (A) APD50 (ms) and (B) APD90 (ms). Numbers indicate percentage change in APD value at various points. *P<.05 cf control.

 

Figure 8
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  		Fig. 8 Action potential recordings during abrupt change in CL from 500 to 1500 ms in absence and presence of ryanodine. Tracings from both a normal (upper two panels) and nAF/cAF atrial preparation (lower two panels) are shown. Representative action potential recordings are from protocol after an abrupt change of CL from 500 to 1500 ms. Action potentials during the first six beats are superimposed on the left and those from 10 to 300 s after the change of CL are superimposed on the right. First action potential in each protocol is depicted by filled symbol. Sixth beat is unfilled symbol. See text for details.

 
On transition from a long pacing CL to a short CL (1500 to 500 ms) similar differences were observed between the two experimental groups (see Fig. 6 right panels). The degree of the abrupt APD prolongation of the first beat and the consequent early shortening phase following a change in CL (left panels) depended both on the basic drive CL and the new CL. In Fig. 7, we compare APD (only the data for APD90 are shown) of the first beat and the sixth beat after abrupt prolongation of CL, from either CL=500 ms, 800 ms or 2000 ms to multiple new CL. As a reference point, the early shortening phase observed in Fig. 6 is indicated in Fig. 7 by dotted vertical lines. At CL=500 ms, in normal atrium, APD90 of the first beat and the sixth beat diverged if the new CL was short, but converged if the new CL was long (early shortening phase eliminated). In nAF/cAF atria, the difference of APD90 between the first beat and sixth beat was much larger than in normal atrium, and APD90 of the first beat always remained longer than APD90 of the sixth beat even if the new CL was long, suggesting persistence of the early shortening phase. In both normal and nAF/cAF atria, the difference between the first beat and sixth beats became smaller as CL became long. At CL=2000 ms, the early shortening phase was not observed in either experimental group. In sum, in nAF/cAF atria, the nonsteady-state changes in APD observed with an abrupt change in CL differ from normal such that the slow adaptation phase of APD to the new CL is lost or the early shortening phase persists.


Figure 7
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  		Fig. 7 Comparison of APD90 of the first and sixth beats after abrupt prolongation of CL from either BCL=500 ms (left panel), 800 ms (center panel) or 2000 ms (right panel) to various new CL in normal (n=5) and nAF/cAF atria (n=5). Abscissa: new CL (ms) prolonged to. Ordinate: APD90 (ms). See text for details.

 
3.6 Effects of ryanodine on the time course of change in APD after an abrupt change of CL
Since intracellular Ca2+ may affect the changes in APD differently in normal and nAF/cAF atria during transitions from one CL to another, we determined the effects of a low concentration of ryanodine on the time course of recovery of APD after an abrupt CL change. Ryanodine augmented plateau amplitude, reduced phase 1 magnitude, and shortened steady-state APD in both normal (n=5) and nAF/cAF (n=4) atria (Fig. 8) and markedly attenuated the abrupt APD prolongation phase and the early APD shortening phase in both groups (Fig. 9, note: compare these data to drug-free experiments in Fig. 6). Further, in the presence of ryanodine, APD50 of nAF/cAF atria now showed a prominent slow adaptation phase similar to that of normal atria (Fig. 9A, upper left). As a result, unlike the drug-free state (Fig. 6), APD50 of nAF/cAF atria, although still significantly shorter than normal, could rate adapt to either the short–long or long–short CL change (Fig. 9). In the presence of ryanodine, both normal and nAF/cAF APD50 prolonged with an increase in CL (Fig. 9A left) and shortened with a decrease in pacing CL (Fig. 9A right). In sum, in the presence of ryanodine, APD of nAF/cAF atria approach normal atria qualitatively, but not quantitatively, in their rate adaptation of APD.


Figure 9
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  		Fig. 9 Time course of change of (A) APD50 and (B) APD90 after an abrupt change of CL from 500 to 1500 ms (left panel) and from 1500 to 500 ms (right panel) in the presence of 10–8 M ryanodine (40 min) in normal (n=5) and nAF/cAF (n=4) atria. Abscissa: log plots of time (s) after the change of CL. Ordinate: (A) APD50 (ms) and (B) APD90 (ms). Scales are the same as in Fig. 6. Numbers indicate percentage change in APD value at various points. *P<.05 cf control.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 4. Discussion
References
 
We have found that in nAF and cAF atria, (1) rate adaptation of MDP as well as APD was reduced; (2) nonsteady-state as well as steady-state action potential characteristics were remarkably changed and; (3) these changes were explicable, in part, by changes in intracellular Ca2+ handling. Further, we found no differences in action potential characteristics between cAF atria in which fibrillation lasting 4 days – nine months was induced and nAF atria in which fibrillation lasting less than 12 h was induced, suggesting that remodeling of electrophysiologic properties measured here is not the only factor to determine the stability of atrial fibrillation.

The action potentials of nAF and cAF both differ from normal and are similar to the brief action potentials described by Yue et al. [11]. In the latter study, myocytes were dispersed from dog atria subjected to chronic pacing where the longest episode of fibrillation studied was {approx}3700 s in duration (comparable to the shorter episodes in our nAF dogs). Our study has addressed the issue of whether longer, more chronic episodes of atrial fibrillation (>4 days, and in one animal as long as 265 days) are associated with any further/additional electrical changes in myocyte cellular electrophysiology. Clearly there are no differences in steady-state or nonsteady-state changes in APD between nAF and cAF (Figs. 1 and 2Go). Hence, our data suggest that chronicity of atrial fibrillation is not related to further increments in ion channel dysfunction beyond those associated with nAF or chronic rapid pacing.

By comparing atrial potentials from two regions of the same atria (Bachmann’s bundle and right atrial trabecular muscle) we have shown that the electrophysiologic changes characterizing nAF/cAF atria occur in both regions. Thus electrical heterogeneity of normal canine atrial potentials persists in nAF/cAF, yet all action potentials of nAF/cAF atria are intrinsically shorter than their normal counterparts (except at very short CL).

Similar to the findings of others using atrial pacing-induced animal models [11,18] we report here that rate adaptation of steady-state APDs is abnormal in both nAF and cAF atria (Fig. 2). Wijffels et al. [2] found that while normal goats in sinus rhythm showed a clear shortening of the atrial refractory period at shorter CL, goats which had been artificially maintained in atrial fibrillation lost this physiological adaptation and showed either a constant duration of the refractory period at different CL or an inverse adaptation curve of atrial refractory period. Maladaptation of the atrial refractory period or APD to rate such as that seen in the present study has been reported in humans vulnerable to atrial tachyarrhythmias or atrial fibrillation [19–21]. Yue et al. [11] have suggested that a reduction of ICa density is responsible for APD abbreviation and for the lack of rate adaptation of steady state APD in remodeled atria, based on their finding that rate adaptation of APD of normal atria is reduced by administration of a Ca2+ channel blocker.

4.1 Rate adaptation of MDP
We report here that rate adaptation of steady-state MDP is reduced in nAF/cAF atria (Fig. 2). In normal atria, at CL>500 ms, MDP markedly depolarized as pacing CL increased. In contrast, depolarization of MDP did not occur in nAF/cAF atria and cells remained polarized. The mechanisms of rate dependent changes of MDP have been examined by many (e.g., [22–26]). When CL is abruptly shortened, MDP initially depolarizes due to an accumulation of K+ into confined extracellular spaces, and subsequently, the electrogenic Na–K pump is activated and hyperpolarization dominates, as extracellular [K] returns to the control level [23,25,26]. When CL is abruptly prolonged, further hyperpolarization occurs due to extracellular K+ depletion, and then MDP depolarizes slowly to its control value as the Na–K pump rate reequilibrates [23,25,26].

The magnitude of the rate dependent change of MDP has been used by some to indirectly assess the function of Na–K pump activity [27–29]. A reduction of the slow adaptation phase of MDP to a change in rate has been reported to occur when a Na–K pump inhibitor is added to cardiac muscle [30,31]. While there have been no reports on the function of the Na–K pump in atria fibrillating secondary to chronic atrial pacing Kim and Fan [32] and Spinale et al. [33] have reported a reduction of Na–K ATPase activity in ventricles subjected to rapid pacing. Therefore our results might suggest that Na–K pump function is reduced in nAF/cAF atria. However our data also show the membrane potential of nAF/cAF atria is reasonably polarized compared to that in normal atria (Fig. 2). This observation is inconsistent with a loss in function of the Na–K pump. Rather, it suggests that a potassium conductance(s) important for setting the resting potential in atrial myocytes (e.g., IK1, IKATP or IKACh) may be enhanced in nAF/cAF atria. While Yue et al. [11] found no changes in IK1 or IKACh in myocytes of their canine model of atrial fibrillation, van Wagoner et al. [34] have shown enhanced IK1 currents in the left atrial myocytes of fibrillating human atria. Recent data have confirmed enhanced IK1 currents and also show larger IKACh currents in cells of human atria [35]. Finally, rate dependent changes of action potential amplitude and Vmax in nAF/cAF atria showed a similar trend as MDP, suggesting a dependence on MDP (Fig. 2).

4.2 Mechanism of loss of steady-state rate adaptation of APD in nAF/cAF atria
The slow phase of adaptation of APD is absent in nAF/cAF atria during transitions from short to long or long to short CL (Fig. 6). When pacing CL is increased, APD in various preparations slowly prolongs taking several minutes to reach a new steady-state (Fig. 6). Because incomplete recovery of ionic currents would be expected to produce changes within the first several beats, it cannot explain such slow changes of APD [36]. Gradual changes of intra- or extracellular ion concentrations due to the change of CL are thought to be responsible for this slow adaptation phase in normal muscle. The effects of extracellular K accumulation and depletion on this slow adaptation phase, which are important mechanisms in frog heart [27,36,37], are thought to be minimal in normal mammalian heart [36–38]. Electrogenic Na–K pump current along with the gradual change of Nai may contribute to the slow adaptation phase of APD. We think that this is unlikely for the following reasons: Attwell et al. [38] showed that an increase in stimulation rate still shortened the action potential in the presence of strophanthidin. Second, the time courses of MDP and APD changes were not in parallel in our studies; that is, when CL was abruptly shortened from 1500 to 500 ms (Fig. 6B) a slow hyperpolarization of MDP attained a plateau in roughly 100 s (data not shown), whereas it required roughly 300 s for the slow shortening of APD to reach a plateau (Fig. 6). These results suggest that electrogenic Na–K pump current is not a major contributor to the slow adaptation phase of APD to rate in normal atrial preparations.

It is likely that a slow change of Cai is involved in the slow APD adaptation phase for the following reasons: first there is a close inverse relationship between the slow adaptation phase of APD and peak tension in normal muscle [39]. High frequency stimulation increases Cai and increases tension. In addition, electrical restitution and mechanical restitution follow similar time courses in normal muscle of many species [40]. Furthermore, restitution curves of BAPTA-sensitive inward currents and contraction are similar [40] and both depend on the Cai transient . Finally restitution of an inward BAPTA-sensitive current is temporally similar to APD restitution in normal ferret muscle. Therefore, slowed APD restitution in nAF/cAF (Fig. 3) is consistent with loss of the repriming of BAPTA sensitive (Cai sensitive) inward currents [41] and/or with lack of accumulation of Cai due to an overall reduced Cai transient in nAF/cAF.

Alternatively, a persistent increase of Cai in nAF/cAF atria may shorten APD by decreasing the Ca2+ concentration gradient, by persistent activation of Cai-dependent L type Ca2+ current inactivation, and/or by persistent activation of IK. In this scenario, the altered slow adaptation phase of APD in nAF/cAF could be due to loss of recovery of ICa and IK that accompanies the slow change of Cai after a CL change.

In experiments reported here (Fig. 9), ryanodine, while suppressing the early APD prolongation phase in all preparations, restores the slow adaptation phase of APD in the nAF/cAF preparations while little affecting the slow adaptation phase of normal muscle. We selected ryanodine for study since it is known to specifically bind to the Ca2+ release channel [42,43] and at the low concentration used in this study, it locks SR release channels in an open state, causing Ca2+ leakage from SR into cytosol and subsequently out of cell [44–48]. This suggests that the blunted slow adaptation of APD in nAF/cAF is due to the presence of abnormal Cai-dependent processes.

Cai handling in cells from fibrillating human atria is not yet described but recent data [49] suggest that in atrial fibrillation in the paced canine model, impaired Cai handling of the myocyte can account for contractile dysfunction. The impact of the reported depressed, globally and spatially averaged Ca2+ transients on atrial myocyte electrophysiology is less clear. First, this same laboratory reported prominent Ca2+ activated chloride currents in cells from fibrillating atria [11] similar to their findings in control myocytes. These data suggest then that Ca2+ induced Ca2+ release in fibrillating atrial cells can produce significant electrical effects. Consistent with this latter idea are our data showing that ryanodine restores the plateau phases of action potentials in nAF and cAF fibers, similar to its effects on normal atrial cells (Fig. 8). Thus, we might suggest that Cai handling of subsarcolemmel SR in cells from fibrillating atria is still efficient while that of the corbular SR is impaired. Such differential regulation of Ca2+ stores has been described for human atrial myocytes [50].

4.3 Nonsteady-state changes in APD of nAF/cAF atria – arrhythmogenic implications
By defining the nonsteady state potential changes in nAF/cAF atria we understand further the cellular abnormalities that underlie the susceptibility to atrial fibrillation of chronically paced canine atria. For example, our restitution results (Fig. 3) show that regardless of what the coupling intervals of an atrial premature depolarization in nAF/cAF atria, APD is short. Results of studies using agents that shorten atrial APD (adenosine, vagal stimulation) have clearly demonstrated the arrhythmogenicity of accelerated repolarization in atrial muscle (e.g. see [51]). Furthermore, our data illustrate that the slope of APD restitution is nearly always <1 in nAF/cAF atria. Restitution of APD is an important determinant of stability of several types of reentrant circuits [15–17]. In Frame and Simson’s experimental ring model of atrial reentry [17] the slope of APD restitution influenced the magnitude of CL oscillations and thus the stability of the rhythm. In their fixed path reentrant model, a steep slope (>1) favored large CL oscillations and termination of reentry. A corollary would be that intervals where slopes are less than 1 would decrease the likelihood of CL oscillations and improve the stability of reentrant excitation. Similar findings have been reported for stability of spiral wave reentry [15]. Finally, recent data describing a high incidence of immediate reinitiation of atrial fibrillation following internal cardioversion [52] are consistent with slowed restitution of APD in nAF/cAF atria.

There are therapeutic implications of our studies, as well. For example, Fig. 6A depicts changes in APD occurring in nAF/cAF on transition from short to long CL. These changes are similar to those that might be expected at the time of spontaneous termination of atrial fibrillation (short CL) to normal sinus rhythm (long CL). Clearly in nAF/cAF atria, reinitiation of atrial fibrillation is likely due to the persistence of the early shortening phase or loss of the slow adaptation phase of the APD. Our data suggest that agents that modify Ca2+ stores either by reducing ICaL (and Ca2+ influx) or blocking SR Ca2+ release may eliminate this cellular abnormality. While our studies have not addressed whether elimination of the cellular abnormality will be antiarrhythmic, we note that the effect of ryanodine to normalize the slow portion of the nAF/cAF curves still leaves the atrial action potentials far shorter than those of normal atria. Thus, nAF/cAF atria remain somewhat electrophysiologically remodeled.

4.4 Limitations of the study
It is clear that electrical remodeling occurs in this as it does in other canine and goat models (e.g. [1,2,11,18,33,34]). It is clear, as well that the chronic rapid pacing used to induce atrial fibrillation in animal models induces not only electrophysiologic change, but structural change, as well [1,53]. These structural changes include mural thrombi, focal, early hypertrophy, increased number and size of mitochondria, disruption of SR and enlarged nuclei, all of which are seen in chronically fibrillating human atria [9]. However, there are important differences between fibrillating canine and human atria. Perhaps the most telling difference electrophysiologically is that the MDP in our and other animal studies is not significantly depolarized; whereas in human subjects it is significantly reduced and is associated with markedly reduced action potential amplitudes and upstroke velocities not seen in canine studies.

Other limitations of these studies include the following: (1) our nAF and cAF data were compared to data obtained from normal atria of dogs that had not been sham operated. It is unlikely that the changes we report in nAF and cAF are due to the experimental preparation because our data for normal controls are similar to those of other laboratories that have used this model and have shown no differences between normal controls and sham-operated controls [1,11]; (2) we studied two sections of atria obtained from the same fibrillating hearts and concluded that electrical remodeling had occurred in both. However, with these data we can in no way suggest that regional electrical heterogeneity is not an important determinant of the stability of atrial fibrillation [54]. Rather we suggest that restitution characteristics of the remodeled atria are consistent with stability of reentrant circuits and thus the perpetuation of fibrillation; (3) like all single cell and isolated tissue experiments, our myocyte data may not be representative of the in vivo situation where electrical restitution properties are governed not only by intrinsic myocyte activity but also by characteristics of the propagating and stimulating impulses.

In conclusion, in the pacing model of atrial fibrillation, long term atrial fibrillation is not due to significant increments in altered cellular electrophysiology that have not occurred with pacing alone. Further, the reduced rate adaptation of steady state APD in remodeled atria is explained mainly by a loss of a slow phase of APD adaptation which in this model can be reversed by ryanodine. Finally both altered steady state and non steady state changes in APD in remodeled atria are arrhythmogenic.

Time for primary review 27 days.


   Acknowledgements
 
The authors express their gratitude to Dr. Natalia Egorova and to Francis Ruffy and Andrew Boyden for their assistance with a portion of the experiments and to Ms. Eileen Franey for her careful attention to the preparation of the manuscript. These studies were supported by USPHS-NHLBI grant HL-53956


   References
Top
 Abstract
 1. Introduction
 2. Methods
 4. Discussion
 References
 

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