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Chronic atrial fibrillation does not further decrease outward currents. It increases them.

Departments of Pharmacology and Pediatrics, Center For Molecular Therapeutics, Columbia University, New York, New York 10032

Submitted 13 February 2003 ; accepted in final form 4 June 2003

	ABSTRACT

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Rapid atrial pacing causes electrical remodeling that leads to atrial fibrillation (AF). AF can further remodel atrial electrophysiology to maintain AF. Our previous studies showed that there was a marked difference in the duration of AF in dogs that have been atrial paced at 400 beats/min for 6 wk. We hypothesized that this difference is based on the changes in the degree of electrical remodeling caused by rapid atrial pacing versus that by AF. Right atrial cells were isolated from control dogs (Con, N = 28), from dogs with chronic AF (cAF dogs, N = 13, episodes lasting at least 6 days), or from dogs with nonsustained or brief episodes of AF (nAF dogs, N = 10, episodes lasting minutes to hours). Both transient outward (I_to) and sustained outward K⁺ current (I_sus) densities/functions were determined using whole cell voltage-clamp techniques. In nAF cells, I_to density was reduced by 69% at +40 mV: from 7.1 ± 0.5 pA/pF (Con, n = 59) to 2.2 ± 0.2 pA/pF (nAF, n = 24) (P < 0.05). The voltage dependence of inactivation of I_to was shifted positively and decay kinetics were changed; however, recovery from inactivation was not altered in nAF cells. In contrast, I_to density in cAF cells was both significantly different from Con cells and larger than that in nAF cells [at +40 mV, 3.5 ± 0.3 pA/pF (cAF, n = 29), P < 0.05]. In cAF cells, recovery from inactivation and decay of I_to were both slow; yet, voltage dependence inactivation of I_to approached that of Con cells. Furthermore, "recovered" I_to of cAF cells was more sensitive to tetraethylammonium than currents of Con and nAF cells. I_sus densities of nAF and cAF cells did not differ. Both nAF and cAF cells have reduced I_to versus Con cells, but I_to remodeling of nAF cells differed from that of cAF cells. I_to in cAF dogs was likely remodeled by AF per se, whereas that in nAF dogs was likely the consequence of the rapid rate in the absence of sustained AF.

potassium currents; cellular electrophysiology; remodeling

We have shown that similar to the APs of dogs that are paced but have nonsustained AF (nAF), APs of right atrial (RA) fibers from dogs with chronic AF (cAF; >6 days) are also reduced in duration (9). Importantly, although the AP phenotype is reasonably similar in nAF versus cAF RA cells (9), there are significant differences in the remodeled I_Ca,L between cells from nAF and cAF dogs (17). This suggests to us that persistence of AF involves a remodeling process different from that resulting from rapid atrial pacing.

Therefore, the purpose of this study was to determine whether I_to and sustained outward K⁺ current (I_sus) of RA cells from nAF dogs are altered and whether any further changes occur in RA cells from cAF dogs.

	METHODS

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Animal preparation. This investigation conforms with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Pub. No. 85-23, Revised 1996).

Adult mongrel dogs weighing 20–25 kg were anesthetized with thiopental sodium (17 mg/kg iv) and ventilated with 1.5–2% isoflurane and 2 l/min O₂. Morphine sulfate (0.15 mg/kg) was injected into the epidural space to reduce the pain after dogs awaked from anesthesia. With the use of sterile techniques, Medtronic active fixation leads were attached to the RA appendage and right ventricular free wall, tunneled subcutaneously, and then connected to a Medtronic Thera 8962 pacemaker (Minneapolis, MN). A bipolar stimulating and recording electrode was also attached to the RA appendage for the induction of AF. Complete atrioventricular 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 beats/min. The ventricular pacemaker was programmed as follows: rate, 60 beats/min (and held at 60 beats/min throughout the pacing protocol); pulse amplitude, 3.3–5 V; pulse width, 0.35–0.5 ms; sensitivity, 2.5 V; and refractory period, 300 ms. The dogs were given cefazolin (25 mg/kg im) prophylactically once before surgery and for 2 days after surgery. After recovery for at least 2 wk, atrial pacing was instituted (rate, 400–900 beats/min; amplitude, 2.5–4 V; pulse width, 0.2–0.4 ms; Itrel 7424 or MINIX 8340) and maintained for 5–7 wk. At the beginning of pacing, there was no difference in RA ERP in dogs from the two different groups (RA ERP, S1-S1 = 400 ms; nAF 143 ± 12 ms vs. cAF 132 ± 8 ms, P > 0.05). Each dog was monitored intermittently in the laboratory every 3–5 days and for several hours each time.

At the time of terminal study, dogs were anesthetized with pentobarbital (30 mg/kg) and the hearts were removed. Only sections of the RA free wall were excised for myocyte studies to eliminate the heterogeneity in ion channel function that has been reported for normal canine atria (5). RA trabeculae were removed from adjacent tissue for cellular electrophysiological studies (9).

Three groups of dogs were studied. Dogs in nAF (N = 10) had been paced, but when AF was induced, it was short lived. A nAF dog was defined as an animal having all episodes of AF <6 days duration (usually <24 h). nAF animals could have multiple episodes of AF. Pacemakers of nAF dogs were stopped on the day of death. The second group of dogs were those in cAF (N = 13). These dogs had been paced as above, but when AF occurred, it persisted for at least 6 days. cAF dogs were killed during AF. Age-matched animals (2–5 yr, N = 28) were used for control (Con) RA free wall cells.

Myocyte preparation. Single calcium-tolerant atrial cells were dispersed from the RA sections using our previously described method (17). Briefly, the tissue was rinsed twice in a Ca²⁺-free solution containing (in mM) 115 NaCl, 5 KCl, 35 sucrose, 10 dextrose, 10 HEPES, and 4 taurine (pH 6.95) to remove blood. It was then triturated in 20 ml of enzyme-containing solution (collagenase type II from Worthington Biochemical, 0.13 mg/ml, 36–37°C) for 30 min, after which the solution was decanted and discarded. The second trituration was discarded after 30 min. The next six to seven triturations were each done for 15 min. Each time, the solution was centrifuged at 500 rpm for 3 min to collect the supernatant and dispersed cells. Resuspension solution was changed every 30 min for solutions containing increasing concentrations of Ca²⁺ (from 0 to 0.5 mM). With this procedure, the living atrial cell yield was 30–40%. Only rod-shaped cells with staircase ends, clear cross-striations, and surface membranes free from blebs were used for study.

Whole cell voltage-clamp recording. I_to and I_sus were recorded using the whole cell configuration of voltage-clamp techniques. Borosilicate glass microelectrodes (outer diameter, 1.5 mm) had resistances from 1 to 2 M when filled with the internal solution [containing (in mM) 140 KCl, 1 MgCl₂, 10 EGTA, 5 MgATP, 5 creatine phosphate, 0.2 GTP, and 10 HEPES (pH 7.2) with KOH]. To measure I_to, atrial cells were externally superfused with a Na⁺-free solution containing (in mM) 144 N-methyl-D-glucamine-Cl, 5.4 KCl, 1 MgCl₂, 2.5 CaCl₂, 0.5 CdCl₂, and 10 HEPES (pH 7.4) at 30–31°C. Na⁺ currents were suppressed with the use of this Na⁺-free solution, and I_Ca,L was blocked with 0.5 mM Cd²⁺. Membrane currents associated with Na⁺/Ca²⁺ exchange were eliminated by the absence of external Na⁺. I_to was elicited by a 210-ms voltage step to test potentials of –50 and +60 mV from a holding potential of –60 mV at 0.1 Hz after a 10-ms prepulse to –90 mV. The amplitude of I_to was determined as the difference between the peak of I_to and the current level at the end of the pulse or as noted. I_sus was taken as the amplitude of the current at the end of the test pulse relative to the zero-current level (7, 12). I_to was fit with a double- and/or single-exponential function to estimate the time constants of decay. The steady-state inactivation relationship was determined using a double-pulse protocol: a 500-ms prepulse to various conditioning potentials (V_c) between –90 to +20 mV, followed by a 210-ms test pulse to +60 mV. Peak current elicited at each test pulse was expressed as a fraction of the current at V_c = –90 mV. A Boltzmann equation was used to fit normalized data to obtain the half-maximal voltage and slope factor for each cell. The time course of recovery from inactivation was evaluated using a paired-pulse protocol: two identical 210-ms pulses from a holding potential of –80 to +40 mV were delivered with increasing interpulse coupling intervals (IPI) from 5 to 5,000 ms. The degree of recovery at each IPI was determined by normalizing I_to at each IPI by the I_to at IPI = 5,000 ms. The time course of recovery was estimated by fitting data to a biexponential function using a simplex algorithm.

I_to and I_sus were normalized by the membrane capacitance of each cell (in pF) and expressed as current density (pA/pF). Average cell capacitance was 80 ± 1.9 pF in Con cells (n = 110), 105 ± 6.9 pF in nAF cells (n = 33, P < 0.05 vs. Con), and 123 ± 6.1 pF in cAF cells (n = 45, P < 0.05 vs. Con and nAF).

Statistics. Group data are presented as means ± SE; N is the number of dogs and n is the number of cells. Statistical comparisons between groups were made using ANOVA/Bonferroni's method or a Student's t-test. P < 0.05 was considered significant.

	RESULTS

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Effects of persistence of AF on I_to and I_sus. Representative original current tracings of I_to and I_sus from canine RA cells from Con, nAF, and cAF dogs are shown in Fig. 1, A–C. Data were obtained using the pulse protocol shown in Fig. 1D, inset. Figure 1, D and E, shows average I_to and I_sus density-voltage relations for Con cells (n = 59), nAF cells (n = 24), and cAF cells (n = 29). I_to density was significantly reduced in nAF and cAF cells. For example, at +40 mV, I_to averaged 7.1 ± 0.3 pA/pF in Con cells compared with 2.2 ± 0.2 pA/pF in nAF cells (P < 0.05 vs. Con) and 3.5 ± 0.3 pA/pF in cAF cells (P < 0.05 vs. Con). Interestingly, I_to density in cAF cells was significantly greater than that of nAF cells (P < 0.05). In contrast, I_sus densities were similar in all three groups. At +40 mV, mean current densities were 3.9 ± 0.2 pA/pF in Con cells, 4.3 ± 0.7 pA/pF in nAF cells, and 4.4 ± 0.4 pA/pF in cAF cells.

View larger version (31K): [in this window] [in a new window]   Fig. 1. A–C: representative current recordings in right atrial (RA) cells from control (Con; A), nonsustained atrial fibrillation (nAF; B), and chronic atrial fibrillation (cAF; C) dogs. Data were obtained using the protocol shown in the inset. D and E: current (I)-voltage (V) relations for average transient outward K+ current (Ito; D) and sustained outward K+ current (Isus; E) as a function of test potential (Vt), respectively. Con: n = 59 cells, N = 28 dogs; nAF: n = 24 cells, N = 10 dogs; cAF: n = 29 cells, N = 13 dogs. *P < 0.05 vs. Con; +P < 0.05 vs. cAF.

To evaluate possible mechanisms involved in the AF-related changes in I_to, voltage-dependent and kinetic properties were determined and compared. A double-pulse protocol was used to assess the voltage dependence of inactivation of I_to. The results are illustrated in Fig. 2. Figure 2, A–C, displays original current tracings from RA cells isolated from Con, nAF, and cAF dogs. Figure 2D shows the average "steady-state" inactivation relations of I_to in Con, nAF, and cAF cells. In both nAF and cAF cells, curves were shifted to more positive voltages versus Con. Mean values for half-maximum inactivation voltage were –34.9 ± 1.3, –21.6 ± 1.9, and –29.1 ± 1.9 mV in Con, nAF, and cAF cells, respectively (P < 0.05, nAF vs. cAF). The slope factor averaged –7.3 ± 0.3, –11.0 ± 1.2, and –11.7 ± 0.9 mV in Con, nAF, and cAF cells (P < 0.05).

View larger version (20K): [in this window] [in a new window]   Fig. 2. A–C: representative current recordings showing voltage-dependent inactivation of Ito in cells isolated from Con (A), nAF (B), and cAF (C) dogs using the protocol shown. D: dependence of current elicited by test pulse on conditioning pulse voltage (Vc). Curves are fit to data using the following Boltzmann equation: y = (A1 + A2)/[1 + e(x – V0.5)/k], where V0.5 is the half-maximal inactivation voltage and k is the slope factor. Ito max, maximum Ito. Con: n = 24 cells, N = 17 dogs; nAF: n = 15 cells, N = 6 dogs; cAF: n = 12 cells, N = 10 dogs. *P < 0.05 vs. Con.

I_to decay was analyzed by curve-fitting data obtained at the +40-mV test pulse (protocol in Fig. 1D, inset). Figure 3, A–C, shows the current tracings from Con, nAF, and cAF RA cells. Seventy-six percent of Con cell data was fit using a biexponential function. In contrast, 88% of nAF cells were best fit using a monoexponential function. However, 54% of cAF cell data was fit using biexponential functions, suggesting that the additional remodeling of the I_to channel is heterogeneous in cAF cells. Compared with Con cells, cAF cells showed a significant increase in the slow time constant (_s) of decay of I_to (P < 0.05), with no change in the fast time constant (_f) (Fig. 3D). Compared with the I_to decay of nAF cells, the decay in cAF cells was faster than that in nAF cells (P < 0.05). Thus, while nAF and cAF RA cells have a decrease of overall I_to, the kinetics of I_to decay differ in the two cell groups. Recovery from inactivation was studied using a double-pulse protocol (Fig. 4). A biexponential function provided best fit of data describing the recovery kinetics of I_to. _f of recovery were similar in all cell groups, but _s differed (Table 1). Thus a slow, second component of recovery from inactivation may contribute to the "recovered" I_to of cAF cells.

View larger version (15K): [in this window] [in a new window]   Fig. 3. Current recordings elicited by a step depolarization to +40 mV for one cell from each group (A–C). In 76% Con cells (A; n = 59 cells, N = 28 dogs), Ito decay was best fit with a biexponential function. In the nAF group (B; n = 24 cells, N = 10 dogs), most cells (88%) were best fit using a monoexponential function. In the cAF group (C; n = 29 cells, N = 13 dogs), 54% of cells was fit best using a biexponential function. D: fast and slow decay time constants (f and s, respectively) for Ito from Con, cAF, and nAF cells. Af %, amplitude of the fast-component time constant normalized to total amplitude. *P < 0.05 vs. Con.

View larger version (14K): [in this window] [in a new window]   Fig. 4. Time course of recovery of Ito from inactivation in Con (n = 10 cells, N = 8 dogs), nAF (n = 6 cells, N = 5 dogs), and cAF (n = 8 cells, N = 6 dogs). Ito recovery was determined using the protocol shown (inset). Normalized Ito [I/maximum current (Imax)] is plotted against the value of the interpulse interval time (IPI; in ms). Time course of recovery was best described by a biexponential function. P1 and P2, pulse 1 and pulse 2. See Table 1.

Effects of TEA on outward currents in Con, nAF, and cAF cells. The effects of TEA were determined in a subset of cells from each group using two protocols. In the initial constant pacing protocol (holding potential = –60 to +40 mV, every 15 s; see Fig. 5, A and B, inset), 5 mM TEA (3–4 min) inhibited 11.3 ± 2.4%, 19.3 ± 6.4%, and 42.5 ± 7.8% of drug-free I_to at +40 mV in Con, nAF, and cAF cells, respectively (P < 0.05, Con vs. cAF and nAF vs. cAF). Furthermore, when the magnitudes of the TEA-sensitive currents were compared, cAF cells had I_to and I_sus components larger than those in nAF and Con cells (Fig. 5, A and B). Second, from cells where current-voltage protocols (see Fig. 1) were completed in both the absence and presence of TEA (Fig. 5, C–E), TEA-insensitive currents were measured and compared. Figure 6 shows that I_to remaining in the presence of TEA (TEA-insensitive currents) did not differ between nAF and cAF cells, but nAF I_sus remained significantly reduced versus Con cells. Thus TEA-sensitive transient/sustained currents contribute greatly to the increase in outward currents of RA cells from cAF animals.

View larger version (34K): [in this window] [in a new window]   Fig. 5. Effects of tetraethylammonium (TEA; 5 mM) on Ito and Isus. A and B: TEA-sensitive currents at +40 mV determined from a constant paced protocol (inset) in a subset of Con (n = 14; N = 10), nAF (n = 8; N = 4), and cAF (n = 8; N = 4) cells. *P < 0.05 vs. Con; +P < 0.05 vs. nAF. C–E: original current recordings of a Con (C), nAF (D), and cAF (E) cell in the absence (before TEA; top) and presence of TEA (+TEA; middle) and TEA-sensitive currents (bottom).

View larger version (14K): [in this window] [in a new window]   Fig. 6. Ito-V (A) and Isus-V (B) in the presence of TEA for a subset of Con, nAF, and cAF cells. The voltage-clamp protocol used was similar to that shown in Fig. 1. *P < 0.05 vs. Con.

	DISCUSSION

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We have shown that the degree of remodeling of I_to is related to AF duration in dogs. Similar to others (18), we show that after a period of rapid atrial pacing, brief episodes of AF (defined here as nAF) are accompanied by a marked decrease in I_to density. Furthermore, we show that this is accompanied by changes in the voltage-dependent and kinetic properties of I_to. However, in animals with long-term episodes of AF (cAF animals), I_to density did not further decrease; rather, it increased. Moreover, the voltage-dependent and kinetic properties of this "recovered I_to" in cAF cells differed from that of nAF and Con cells. Our results of I_to changes in cAF cells are consistent with human AF-induced remodeling of K⁺ currents (2) and smaller than those of Refs. 3 and 12. In contrast, I_sus density did not differ among the three groups, similar to the findings of Yue et al. (18). In human AF, some groups reported no changes in I_sus in AF (3, 15), whereas others have shown a reduction in I_sus (12, 2).

The mechanisms by which I_to changes with rapid atrial pacing or sustained AF are presently unknown. Interestingly, cell capacitance increased by 54% with the duration of AF, suggesting that modest RA hypertrophy occurred in cAF animals. In ventricular cells, a decrease in I_to is associated with hypertrophy (but see Refs. 11 and 13). However, cAF cells with large capacitances did not show a further decrease in I_to, but, unexpectedly, an increase over that in nAF cells. In cAF cells, it is likely that both a significantly long time course of I_to recovery from inactivation and slow decay of peak I_to contributed to the observed reduced I_to versus Con cells. Thus not only might the number of channels that comprise the composite I_to decrease, but the fundamental nature of channels contributing to I_to changes in the RA cells of the cAF dog. Yue et al. (18) found a downregulation of Kv4.3 mRNA and protein levels in their canine rapid paced model, which is similar to the nAF model in this study. Because no voltage-dependent or kinetic properties of remaining I_to were reported, they concluded that a decrease in the number of I_to channels contributed to the reduction in I_to density in nAF dogs. In the presence of TEA, we found there to be no difference between I_to in nAF and cAF animals (Fig. 6). Yet we report here that in cAF RA cells, composite I_to is increased in density over nAF cells. This is most likely due to an increase in TEA-sensitive outward currents in cAF cells (Fig. 5). Note that I_sus is small in our Con RA cells. This is dissimilar to the findings of others (5, 18, 19), where a prominent current, I_kurd (8 pA/pF at +40mV), was defined. Notably, Yue et al. (18) reported that I_kurd did not vary in their rapid paced AF model. We show in this report that, whereas I_sus did not differ between Con, nAF, and cAF cells, TEA-insensitive currents did.

The nature of the augmented TEA-sensitive current in cAF cells was not the focus of this study. However, because of its TEA sensitivity and the time course of these currents, it may be that in cAF cells where TEA-insensitive I_to is reduced, there is an adaptive augmentation of currents through Kv2 or Kv3 K⁺ channel proteins. In recent studies using mice genetically modified such that certain K⁺ channels are functionally knocked out or suppressed [e.g., Kv1DN mice (20) and Kv.DN2 mice (1)], the TEA-sensitive current component encoded by Kv2.1, I_Kslow2 (16), is upregulated (8, 20).

This is the first report of the effects of long-term AF on I_to and I_sus in the rapid atrial pacing dog model. The process of I_to remodeling during persistent AF as seen in this study suggests that the chronic electrical remodeling changes may facilitate the persistence of AF. Combined with our previous study (17) showing differences in inward currents in RA cells from nAF and cAF dogs, we suggest that pharmacological agents effective in terminating nAF may differ from those effective in sustained cAF.

Limitations. Not all currents were evaluated in this report. In particular, the relative contribution of other time-dependent and -independent currents to I_sus were not studied. Whereas I_sus does not differ among cells from different groups, individual components of I_sus may. Furthermore, we have not included changes in ion channel function in cells from other regions of the remodeled atria. Finally, within the cAF group, animals had AF of variable durations, but all were >6 days. At this time, we did not subgroup the cAF group by duration but rather focused this study on differences between nAF and cAF animals.

	DISCLOSURES

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This study was supported by National Heart, Lung, and Blood Institute Grant HL-67449.

	FOOTNOTES

 

Address for reprint requests and other correspondence: P. A. Boyden, Dept. of Pharmacology, Columbia College of Physicians and Surgeons, 630 W. 168th St., New York, NY 10032.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION DISCLOSURES REFERENCES

 

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