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(Circulation. 2000;101:1861.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Role of the Na⁺/H⁺ Exchanger in Short-Term Atrial Electrophysiological Remodeling

J. Vijay Jayachandran, MD; Douglas P. Zipes, MD; Juan Weksler, MD; Jeffrey E. Olgin, MD

From the Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis.

Correspondence to Jeffrey Olgin, MD, Krannert Institute of Cardiology, Indiana University School of Medicine, 1111 W 10th St, Indianapolis, IN 46202. E-mail jolgin{at}iupui.edu

	Abstract

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Background—The pathophysiology underlying electrophysiological remodeling (ER) from rapid atrial rates is unknown. We tested the hypothesis that activation of the Na⁺/H⁺ exchanger (NHE) by ischemia contributes to ER.

Methods and Results—Twenty-eight dogs were studied under autonomic blockade. In 15 closed-chest dogs, atrial fibrillation was simulated by right atrial pacing at 600 bpm over 5 hours. Of these, 9 (pace/NHEI) received HOE642, a selective inhibitor of the NHE, and 6 (pace/control) received saline. In pace/controls, atrial effective refractory period (AERP) at a drive cycle length (DCL) of 400 ms shortened from 143±7 to 118±5 ms (1 hour) and to 122±17 ms (5 hours). Shortening of AERP was prevented in the pace/NHEI group (P=0.02 compared with pace/controls). At baseline in all 15 dogs, pacing at shorter DCL resulted in shortening of AERP (physiological rate adaptation), which was lost at 5 hours in pace/controls. In pace/NHEI animals, rate adaptation was maintained despite 5 hours of pacing (P=0.02). In 13 other open-chest dogs, right atrial ERP was determined before and after occlusion of the right coronary artery. Five received HOE642 (ischemia/NHEI), 5 saline (ischemia/control), and 3 intravenous glibenclamide. In ischemia/controls, AERP₄₀₀ decreased (156±30 to 130±32 ms). Shortening of AERP was not prevented by glibenclamide (180±20 to 153±33 ms) but was prevented in ischemia/NHEI dogs (169±12 to 184±19 ms, P=0.001 compared with ischemia/controls and ischemia/glibenclamide). Rate adaptation was lost in ischemia/controls and preserved in ischemia/NHEI dogs (P=0.02).

Conclusions—Activation of the NHE is one mechanism underlying short-term ER.

Key Words: fibrillation • electrophysiology • remodeling • sodium • calcium • arrhythmia • ischemia • glibenclamide

	Introduction

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The self-perpetuating nature of atrial fibrillation (AF) has been attributed to shortening of atrial refractoriness and a loss of rate adaptation of the atrial refractory period in response to shortening in drive cycle length (DCL),^{1 2} collectively called electrophysiological remodeling (ER).² The histopathology of atria in chronic fibrillation is similar to that of chronically ischemic ventricular myocardium.^{3 4} Recently, we also found that chronic AF is associated with a reduction in atrial myocardial blood flow.⁵ These findings suggest that atrial ischemia is a possible trigger in ER. Although the K_ATP channel is critical in mediating electrophysiological changes from ischemia in the ventricle,^{6 7} glibenclamide does not prevent pacing-induced atrial ER.^{8 9} Another important alteration in ventricular myocardium during ischemia is activation of the Na⁺/H⁺ exchanger (NHE) to regulate intracellular pH.^{10 11} Activation of the NHE is known to be arrhythmogenic,^{12 13} possibly by secondary changes in intracellular calcium.^{14 15} The purpose of the studies reported here was to use HOE642, a specific blocker of the cardiac NHE subtype 1,¹⁶ to test the hypothesis that electrophysiological changes produced by rapid atrial pacing are in part from activation of the NHE. We also hypothesized that atrial ischemia would mimic the electrophysiological changes produced by rapid pacing and that these changes would also be prevented by blockade of the NHE.

	Methods

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The experiments performed in this study were approved by the Institutional Animal Care and Use Committee of Indiana University and were in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication 86-23, revised 1985). Twenty-eight mongrel dogs with a mean weight of 28 kg were anesthetized with methohexital (70 mg/kg IV). After intubation and mechanical ventilation with a volume-cycled ventilator, anesthesia was maintained with isoflurane. Autonomic blockade was achieved in all animals with an initial bolus of atropine and propranolol (0.04 and 0.2 mg/kg), followed by maintenance infusion for the duration of the experiment (0.007 and 0.04 mg · kg^-1 · h^-1).¹⁷

Group 1
In 15 closed-chest dogs, AF was produced by rapid atrial pacing. An active fixation pacing lead was inserted via the right internal jugular vein and positioned in the right atrial appendage to achieve a bipolar pacing threshold of <2 mA. A steerable catheter (Bard Electrophysiology) was advanced to the lateral right atrium to record a sharp bipolar atrial electrogram and obtain a pacing threshold of <2 mA. This catheter was used for continuous rapid atrial pacing. The active fixation lead was used for all AERP measurements to ensure ERP determination at a fixed anatomic site throughout the experiment. Baseline AERP was determined in all animals at DCLs of 400, 300, and 200 ms at an output of twice diastolic threshold, using incremental extrastimuli in steps of 2 ms. The first extrastimulus to cause a propagated bipolar atrial electrogram was considered the AERP at that DCL. Once baseline AERP was determined, 10 dogs (pace/NHEI group) received an intravenous bolus of HOE642 (2 mg/kg), and 5 dogs received an equivalent volume of saline (pace/control group). AERP measurements were repeated in 20 minutes to determine the effect of HOE642 alone on ERP. Rapid atrial pacing was then immediately initiated at 600 bpm (time 0 in Figure 1). Rapid pacing was temporarily interrupted every 15 minutes for the first hour, then every hour for 5 hours, to determine AERP₄₀₀. Rapid pacing was continued throughout the duration of the experiment to assess changes in atrial electrophysiology over time and was interrupted for no more than 2 minutes during each AERP measurement time point.

View larger version (18K): [in this window] [in a new window]   Figure 1. Time course of AERP changes with rapid atrial pacing in pace/NHEI dogs () (that received HOE642) and pace/control (•) dogs. Y axis denotes mean±SD change in AERP (ms) from baseline AERP at DCL 400. PreDrug () is baseline before infusion of HOE642 or saline. Time 0 is 20 minutes after infusion of HOE642 or saline and also marks initiation of rapid pacing. AERP in pace/NHEI dogs did not vary significantly from baseline (P>0.05). Shortening of AERP occurred within first hour in pace/controls and persisted through 5 hours (P=0.002 vs pace/NHEI).

Group 2
Thirteen dogs underwent general anesthesia, mechanical ventilation, and autonomic blockade as described for group 1. A right lateral thoracotomy was performed in all, and the proximal right coronary artery was exposed. Two intramyocardial plunge electrodes were inserted into right atrial muscle close to the AV groove and were used for unipolar pacing to determine AERP. A closely spaced pair of intramyocardial plunge electrodes was inserted into the right atrial appendage and used to record a bipolar atrial electrogram (ie, to record atrial depolarization). The distal pole of a quadripolar catheter (Bard Electrophysiology) positioned in the inferior vena cava was used as the reference electrode for unipolar pacing. Of the 13 animals in group 2, 5 dogs received HOE642 at a dose of 2 mg/kg IV (ischemia/NHEI group), and 5 dogs received an equivalent volume of saline (ischemia/controls). Three animals received intravenous glibenclamide at a dose of 4.94 mg/kg (see Reference 9⁹ ), followed by a continuous infusion of glibenclamide at a dose of 0.032 mg · kg^-1 · h^-1 (see Reference 8⁸ ) (ischemia/glibenclamide group). Threshold of pacing was determined before each AERP measurement. Baseline AERP was then determined with the same protocol as described above for group 1. The proximal right coronary artery was then ligated. Fifteen minutes after RCA ligation, AERP measurements were repeated.

Statistical Analysis
Values are presented as mean±SD. Two-way comparisons were made with t tests, paired when appropriate. ANOVA was used for multiple comparisons. For comparison of 3 groups, Tukey’s HSD multiple-comparison procedure was used to identify where the differences among the 3 groups occurred after the significant ANOVA. In the presence of a significant interaction term by ANOVA, the Newman-Keuls test was used within each group to identify changes from baseline. A value of P0.05 was considered significant.

	Results

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Group 1
Figure 1 shows the time course of effective refractory period (AERP) change with rapid pacing in pace/control and pace/NHE inhibited (NHEI) groups. In the pace/control group, after the initiation of rapid pacing, AERP at a DCL of 400 ms (AERP₄₀₀) shortened from 148±7 ms at baseline to 118±5 ms at 1 hour. This shortening persisted throughout the study, and the AERP₄₀₀ at all time points from 15 minutes to 5 hours of rapid pacing was less than that at baseline in the pace/control dogs (P=0.05).

In pace/NHEI dogs, baseline AERP₄₀₀ (158±24 ms) was not significantly different from baseline AERP in pace/controls (P=0.13). After infusion of HOE642 in the pace/NHEI group, before the initiation of rapid pacing, AERP (168±35 ms) was not significantly different from baseline (P=0.32). With the initiation of rapid pacing, contrary to the finding in controls, AERP did not shorten in pace/NHEI dogs, with AERP₄₀₀ of 168±26 ms at 1 hour and AERP₄₀₀ of 183±33 ms at 5 hours (P>0.05, NS, compared with baseline).

Furthermore, comparison between pace/control and pace/NHEI dogs found significantly shorter AERPs in pace/controls at all time points (15 minutes to 5 hours) compared with pace/NHEI dogs (P=0.002).

At baseline in pace/control dogs, pacing at shorter DCLs resulted in a shortening of AERP or physiological rate adaptation (Figure 2). However, whereas at baseline in pace/controls, AERP at DCL 300 ms shortened by 13±8 ms from that at DCL 400 ms, after 5 hours of rapid pacing, AERP at DCL 300 ms lengthened by 0.8±13 ms from that at DCL 400 ms (P=0.03). Similarly, whereas at baseline, AERP at DCL 200 ms shortened by 25±5 ms from that at DCL 400 ms, after 5 hours of rapid pacing, AERP at DCL 200 ms shortened by only 0.2±11 ms from that at DCL 400 ms (P=0.002) (Figure 2).

View larger version (19K): [in this window] [in a new window]   Figure 2. Rate adaptation of AERP in pace/control dogs at baseline () and after 5 hours of pacing (•). Y axis denotes difference (mean±SD) in AERP at DCL 300 and 200 from that at DCL 400. Shortening in AERP at DCL 300 from that at DCL 400 was significantly less after 5 hours of pacing vs baseline (+P<0.05). Shortening in AERP at DCL 200 from that at DCL 400 was also significantly less after 5 hours of pacing vs baseline (*P<0.05). Thus, rate adaptation of AERP to shortening DCL was lost after 5 hours of rapid pacing in pace/controls.

In pace/NHEI animals at baseline before the infusion of HOE642, AERP was shorter at the faster DCLs, similar to pace/controls at baseline. Thus, in pace/NHEI dogs at baseline, AERP at DCL 300 ms shortened by 9±12 ms from that at DCL 400 ms, and AERP at DCL 200 ms shortened by 19±14 ms from that at DCL 400 ms, which was not significantly different from pace/controls at baseline. This physiological rate adaptation was maintained after the infusion of HOE642, before rapid pacing (AERP at DCL 300 ms shortened by 12±12 ms and AERP at DCL 200 ms shortened by 25±17 ms from that at DCL 400 ms), which was not significantly different from baseline (P=0.85 and 0.83 for DCL 300 and 200 ms) (Figure 3). Contrary to the findings in pace/controls, however, after 5 hours of rapid pacing in pace/NHEI dogs, shortening of AERP at the faster DCLs was maintained. Thus, AERP at DCL 300 ms shortened by 8±5 ms from that at DCL 400 ms, and AERP at DCL 200 ms shortened by 19±13 ms from that at DCL 400 ms, neither of which was significantly different from baseline (P=0.37 and 0.94 for DCL 300 and 200 ms) (Figure 3).

View larger version (22K): [in this window] [in a new window]   Figure 3. Rate adaptation of AERP in pace/NHEI dogs at baseline after infusion of HOE642 before rapid pacing () and after 5 hours of pacing (). Y axis denotes difference (mean±SD) in AERP at DCL 300 and 200 from that at DCL 400. Shortening in AERP at DCL 300 and 200 from that at DCL 400 was not significantly different after 5 hours of pacing vs baseline. This was also significantly different from pace/control dogs (P=0.02). Thus, rate adaptation in pace/NHEI dogs was preserved despite 5 hours of rapid pacing.

Comparison of the effect of pacing on rate adaptation between pace/control and pace/NHEI groups found a significant difference (P=0.02) between the 2 groups, with rate adaptation being preserved in the pace/NHEI group despite 5 hours of rapid pacing.

Group 2
During extrastimulus testing of AERP, there was no significant difference in threshold of capture between baseline (mean, 2.0±0.2 V at 2.0-ms pulse width) and during ischemia from RCA occlusion (mean, 2.2±0.3 V at 2.0-ms pulse width).

Figure 4 shows the change in AERP after RCA occlusion in the ischemia/control, ischemia/NHEI, and ischemia/glibenclamide groups. In the ischemia/control group, after RCA occlusion, AERP₄₀₀ decreased from 156±30 ms at baseline to 130±32 ms. In ischemia/glibenclamide dogs, as in ischemia/controls, after RCA occlusion AERP₄₀₀ shortened from baseline (180±20 to 162±10 ms). In the ischemia/NHEI group, baseline AERP₄₀₀ (169±12 ms) was similar to that at baseline in ischemia/controls (P>0.05, NS). After RCA occlusion in the ischemia/NHEI group, however, no significant change in AERP was observed (184±19 ms). This response was significantly different from that in the ischemia/control or ischemia/glibenclamide groups, in which AERP₄₀₀ shortened (P=0.001).

View larger version (13K): [in this window] [in a new window]   Figure 4. Change in AERP after RCA occlusion. Y axis denotes mean±SD change in AERP (ms) from baseline AERP at DCL 400 after RCA occlusion. After RCA occlusion, AERP shortened significantly in ischemia/control (•) and in ischemia/glibenclamide () groups vs ischemia/NHEI dogs () (P=0.001).

At baseline in ischemia/control dogs, as in pace/control animals, pacing at shorter DCLs resulted in a shortening of AERP or physiological rate adaptation (Figure 5). At baseline in ischemia/controls, AERP at DCL 300 ms shortened by 6±2 ms; after RCA occlusion, AERP at DCL 300 ms shortened by only 1±7 ms from that at DCL 400 ms. Whereas at baseline, AERP at DCL 200 ms shortened by 35±9 ms from that at DCL 400 ms, after RCA occlusion, AERP at DCL 200 ms shortened by 6±22 ms from that at DCL 400 ms (P<0.05) (Figure 5).

View larger version (20K): [in this window] [in a new window]   Figure 5. Rate adaptation of AERP in ischemia/control dogs at baseline () and after occlusion of RCA (•). Y axis denotes difference (mean±SD) in AERP at DCL 300 and 200 from that at DCL 400. Shortening in AERP at DCL 200 from that at DCL 400 was significantly less after RCA occlusion vs baseline (*P<0.05). Rate adaptation of AERP to shortening DCL (at DCL 200) was lost after RCA occlusion in ischemia/controls.

In ischemia/NHEI animals at baseline, as in ischemia/controls at baseline, AERP was shorter at the faster DCLs (Figure 6). AERP at DCL 300 ms shortened by 3±11 ms from that at DCL 400 ms, and AERP at DCL 200 ms shortened by 19±10 ms from that at DCL 400 ms, which was not significantly different from ischemia/controls at baseline. However, after RCA occlusion in ischemia/NHEI dogs, AERP at DCL 300 ms shortened by 10±12 ms from that at DCL 400 ms, and AERP at DCL 200 ms shortened by 28±9 ms from that at DCL 400 ms. These values were not significantly different from those before RCA occlusion (Figure 6).

View larger version (20K): [in this window] [in a new window]   Figure 6. Rate adaptation of AERP in ischemia/NHEI dogs at baseline () and after occlusion of RCA (). Y axis denotes difference (mean±SD) in AERP at DCL 300 and 200 from that at DCL 400. Shortening in AERP at DCL 300 and 200 from that at DCL 400 was not significantly different after RCA occlusion vs baseline. Thus, in ischemia/NHEI dogs, rate adaptation after RCA occlusion was similar to that at baseline. This was significantly different from ischemia/control group (P=0.02).

Comparison of the effect of RCA occlusion on rate adaptation between ischemia/control and ischemia/NHEI groups found a significant difference (P=0.02) between the 2 groups, with rate adaptation being preserved in the ischemia/NHEI group despite ischemia.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The new observations in this study are that shortening of atrial ERP and loss of normal rate adaptation of AERP, produced by rapid atrial pacing in dogs, are prevented by blockade of the cardiac Na⁺/H⁺ exchanger. In addition, acute atrial ischemia produced by right coronary artery occlusion produces shortening of right atrial ERP and loss of rate adaptation of the atrial ERP, similar to that produced by rapid atrial pacing. These changes produced by ischemia from coronary occlusion are also prevented by blockade of the NHE. Furthermore, glibenclamide does not prevent shortening of AERP produced by right coronary artery (RCA) occlusion.

Electrophysiological Remodeling
In this study, we found evidence of shortening of atrial ERP produced by rapid pacing that parallels previous reports in animal models of AF^{1 2 18 19} as well as human experiments.^{20 21} Maladaptation of the atrial refractory period, first described by Attuel et al,²² has also been observed after rapid atrial rates in animals² and in humans suffering prolonged atrial tachyarrhythmias.²¹ Although the electrophysiological significance of this phenomenon in promoting multiple wavelet reentry in AF is not completely understood, it appears to be a consistent finding (as we also found in this study) in atria subject to rapid rates and may be considered a feature of the process of ER of the atria.

Pathophysiology of ER
In addition to electrophysiological perturbation, sustained AF is associated with myocardial ion channel,^{23 24} ultrastructural,^{4 25} and gross mechanical²⁶ atrial abnormalities. The stimuli that provoke such changes and the mechanisms by which these changes affect atrial electrophysiological properties have not been elucidated. Blockade of L-type calcium channels with verapamil has been demonstrated to blunt but not prevent the electrophysiological disturbances observed with rapid atrial rates.^{18 27} Indeed, verapamil also reduces the extent of mechanical dysfunction that is produced by AF.²⁸ This suggests that calcium transients may be one important factor in atrial arrhythmogenesis, as has been suggested in the pathophysiology of ventricular arrhythmias.^{29 30} However, because verapamil has other cardiac pharmacological actions, such as sodium channel blockade,³¹ it remains unclear whether the blunting effect of verapamil in ER is solely due to L-type Ca²⁺ channel blockade. In the ventricle, increases in intracellular Ca²⁺ are due to a variety of mechanisms. One mechanism of Ca²⁺ influx is that which is secondary to activation of the NHE during ventricular ischemia.^{14 32 33} Activation of the cardiac NHE by a decrease in intracellular pH leads to an exchange of intracellular hydrogen ions for extracellular Na⁺ ions. Such an increase in intracellular Na⁺ results in a lower, or more negative, equilibrium potential for the Na⁺/Ca²⁺ exchanger, thereby leading to a greater magnitude of "reverse-mode" functioning of the Na⁺/Ca²⁺ exchanger and therefore an influx of Ca²⁺ ions.³⁴ Calcium influx, in turn, promotes arrhythmogenesis by a variety of mechanisms.^{35 36}

Recent evidence suggests that a similar substrate, ie, ischemia, may occur in the atrium during sustained rapid rates or atrial fibrillation.^{4 5} Because the NHE is activated primarily during intracellular acidosis, such as occurs during ischemia,^{14 37} the present study demonstrating prevention of ER from rapid pacing by NHE blockade suggests that atrial intracellular acidosis, perhaps secondary to ischemia, may play a role in ER. In the present study, we also found that acute ischemia produced by RCA occlusion produced electrophysiological changes that are very similar to those that occur with rapid atrial rates and are currently considered markers of ER, ie, shortening and maladaptation of the AERP. As expected, blockade of the NHE prevented these changes as well. Previous investigations into the role of ischemia in atrial ER addressed the role of the K_ATP channel in this process.^{8 9} Activation of the K_ATP channel produces shortening of the ventricular refractory period during ventricular ischemia.³⁸ However, as was demonstrated in animals by Wijffells et al⁹ and Goette et al,⁸ blockade of the K_ATP channel does not prevent shortening of the atrial ERP during ER from rapid rates. This does not exclude a possible role of ischemia in triggering the electrophysiological changes of ER, because the contribution of the K_ATP channel to shortening of refractoriness in AF is unknown. In the present study, glibenclamide (in doses used in previous studies) had no effect on the electrophysiological changes produced by ischemia from coronary occlusion. This suggests that either K_ATP channels contribute little to ERP changes in the atrium during ischemia or significantly higher doses of glibenclamide are required to block atrial K_ATP channels (ie, atrial K_ATP channels are less sensitive to glibenclamide).

Thus, the present findings are strongly suggestive that a common mechanism underlies the electrophysiological changes produced by either rapid atrial rates or ischemia from coronary occlusion. Blockade of the NHE prevents these electrophysiological changes in both situations, which further suggests that atrial ischemia is a common underlying pathophysiological process in provoking the electrophysiological changes described.

Limitations
Although HOE642 is a specific blocking agent of the cardiac NHE,¹⁶ other pharmacological actions cannot be excluded. Previous studies have shown a lack of effect of this drug on the Na⁺ current as well as the Na⁺/Ca²⁺ exchanger.¹⁶ In the present study, HOE642 had no effect on atrial electrophysiology at baseline, suggesting a lack of direct actions on membrane currents at baseline. In group 2, although collateral flow may have prevented maximal effects of ischemia of right atrial tissue, electrophysiological changes were observed after occlusion of the RCA, suggesting appropriate positioning of these electrodes. Autonomic nerve fibers transit this region,³⁹ and it is possible that some fibers were interrupted during exposure of the proximal RCA. However, all studies were performed with pharmacological autonomic blockade. Furthermore, if changes in refractoriness in ischemia/control or ischemia/glibenclamide dogs were secondary to changes in autonomic innervation from the methods followed, we would have expected similar changes in the ischemia/NHEI group as well.

Conclusions
Short-term ER is prevented by blockade of the cardiac NHE. Electrophysiological changes from atrial ischemia during RCA occlusion closely parallel the changes observed during rapid pacing and are also prevented by blockade of the NHE. Although we did not establish in this experiment that ischemia or anaerobic metabolism occurs during AF, it is apparent that the NHE is activated during atrial ischemia as well as during AF. These preliminary observations strongly suggest that atrial ischemia may be one trigger in the pathophysiology of ER during AF.

	Acknowledgments

 
This work was supported in part by the Herman C. Krannert Fund, a fund from the Indiana Heart Association, and grants HL-52323 and HL-03703 from the National Heart, Lung, and Blood Institute, National Institutes of Health. Dr Olgin is supported by grant HL-03703 from the National Heart, Lung, and Blood Institute, National Institutes of Health, and by a grant from the Indiana Heart Association. Dr Zipes is supported in part by grant HL-52323 from the National Heart, Lung, and Blood Institute, National Institutes of Health. The authors thank Kerry Antonuccio and C.J. Arnett for technical assistance.

Received August 10, 1999; revision received November 11, 1999; accepted November 29, 1999.

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