Background Atrial fibrillation is self-perpetuating, suggesting that the tachyarrhythmia causes electrophysiological changes that contribute to the progressive nature of the disease. In animal models, pacing-induced rapid atrial rates result in sustained atrial fibrillation. This is mediated by shortening of refractory periods termed electrical remodeling. The purpose of the present study was to characterize the time course of electrical remodeling and to define mechanisms of the phenomenon.
Methods and Results Closed-chest dogs were anesthetized, pretreated with atropine and propranolol, and subjected to 7 hours of atrial pacing at 800 bpm. The effective and absolute refractory periods (ARP and ERP) were measured during and after rapid pacing, and transvenous endocardial biopsy specimens were examined using electron microscopy. Despite autonomic blockade and the absence of change in right atrial pressure, persistent atrial tachycardia caused ARP and ERP to fall by >10%. Electrical remodeling developed quickly, with more than half of the phenomenon occurring during the first 30 minutes of high-rate pacing. Pretreatment with glibenclamide in doses sufficient to block the ATP-sensitive potassium current had no effect. Atrial electrical remodeling was blocked by verapamil and accentuated by hypercalcemia. Biopsy specimens from controls subjected to rapid pacing showed mitochondrial swelling consistent with calcium overload. Biopsies from verapamil-treated animals were normal.
Conclusions Atrial electrical remodeling develops quickly, is progressive, and may be persistent. Shifts in autonomic tone, atrial stretch, or depletion of high-energy phosphates do not contribute significantly to the phenomenon. Results of the study suggest that atrial electrical remodeling is mediated by rate-induced intracellular calcium overload.
Atrial fibrillation is a ubiquitous arrhythmia and is often incompletely controlled by antiarrhythmic drug therapy.1 2 3 Several epidemiological observations suggest that atrial fibrillation is self-perpetuating; that is, the tachyarrhythmia itself may produce electrophysiological changes that contribute to the problem.4 5 6 The frequency, duration, and drug resistance of paroxysmal atrial fibrillation tend to increase with time.7 8 Although this may simply reflect the natural history of the underlying myopathic process,9 10 direct effects of the fibrillation may also contribute. It is well known that both the probability of spontaneous conversion and the maintenance of sinus rhythm after electrical cardioversion are highly dependent on the duration of the antecedent atrial fibrillation episode.9 10 It is possible that sustained rapid rates progressively perturb atrial electrophysiology and contribute to the difficulty in achieving and maintaining an organized rhythm.
Two recent reports11 12 have described animal models that clearly show this phenomenon of atrial fibrillation begetting more atrial fibrillation. In both cases, chronic pacing was used to produce an ongoing atrial tachyarrhythmia. In contrast to the baseline state in which there was prompt spontaneous termination of induced atrial fibrillation, animals subjected to chronic, rapid atrial rates developed persistent atrial fibrillation.
The main mechanism underlying this increase in atrial fibrillation duration appears to be a progressive decrease in atrial refractoriness that has been termed electrical remodeling.5 Although this phenomenon is thought to be of importance in the self-perpetuation of atrial fibrillation, the mechanism of electrical remodeling is unknown.
A number of possible causes for rate-induced remodeling have been proposed; these include a shift in autonomic tone, mechanoelectrical feedback, or a direct effect of tachycardia on the number or function of potassium channels.12 13 14 Like ischemia, sustained rapid atrial rates might reduce refractory periods through depletion of high-energy phosphates and activation of ATP-sensitive potassium channels.12 Finally, a persistent atrial tachyarrhythmia might overwhelm exchange pumps as well as other homeostatic mechanisms, resulting in cytosolic calcium overload.15
The purpose of our present study was to characterize the time course of onset and resolution of electrical remodeling in an intact animal model and to define the possible mechanisms underlying this phenomenon.
The experiments performed in this study were approved by the Institutional Animal Care and Use Committee of Emory University and were done in accordance with the “Guide for Care and Use of Laboratory Animals” published by the National Institutes of Health (NIH publication No. 86-23, revised 1985). A total of 20 mongrel dogs (weight, 26±3 kg) were used in the study. The animals were anesthetized with morphine (4 mg/kg SC) followed by methohexital (70 mg/kg IV). After intubation and mechanical ventilation, anesthesia was maintained with isoflurane. Tidal volume was adjusted to maintain arterial pH between 7.35 and 7.45. The surface ECG, right atrial pressure, and blood pressure were continuously monitored. Hemostatic sheaths were inserted into the femoral vein, and two quadripolar electrode catheters (5-mm interelectrode spacing, Bard Electrophysiology) were advanced into the right atrial appendage and the lateral right atrium. Next, a bipolar active-fixation permanent pacing lead (model 4269, CPI) was introduced into the right internal jugular vein and placed in the right atrial appendage. Autonomic blockade was induced 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 per hour). These doses have been shown to produce complete blockade.16
Thirty minutes after infusion of atropine and propranolol, high-frequency atrial pacing was initiated and maintained for the following 7 hours. Bipolar pacing of the electrode catheter positioned in the right atrial appendage was performed at a rate of 800 bpm and an output of 4 mA with a 2-ms pulse duration. Atrial effective and absolute refractory periods (ERP and ARP) were determined just before the initiation of high-frequency pacing. Rapid pacing was briefly interrupted every 30 minutes for the following 2 hours and thereafter once an hour for the duration of rapid pacing to allow repeated assessment of ARP and ERP. Finally, measurements were made at 10-minute intervals for 30 minutes after cessation of pacing. To minimize confounding effects due to electrode movement or electrode polarization, all refractory period measurements were made using the permanent pacing lead, which was not used for high-frequency pacing and which was positively affixed to the right atrial appendage. A drive train of eight stimuli (S1, 350-ms cycle length, 2-ms pulse duration) was delivered via the permanent pacing lead. An extra stimulus (S2) was added early in atrial diastole, and the interval between S1 and S2 was incremented in 2-ms steps until a propagated atrial response was produced. A pulse amplitude of 12 mA was used for estimation of ARP, and twice the late diastolic threshold was used to determine the ERP.
Just before termination of high-frequency atrial pacing, a transvenous endocardial biopsy of the anterolateral right atrium was performed using a 7F flexible bioptome catheter (Mansfield Scientific). Biopsy specimens were fixed in Trump's fixative (4% formaldehyde and 1% glutaraldehyde in phosphate buffer) overnight at 4°C. The specimens were then osmicated, dehydrated through graded alcohols, and imbedded in epoxy resin. Sections of 0.5 μm thickness were stained with toluidine blue and examined by light microscopy. Areas of longitudinal sections were chosen for electron micrographic examination. Ultrathin sections ≈600 Å thick were stained with uranyl acetate and lead citrate and examined with a Phillips EM201 electron microscope.
The magnitude and time course of rate-induced electrical remodeling were assessed in five control animals subjected to the high-frequency pacing protocol described above. To assess the effects of calcium entry blockade on electrical remodeling, the protocol was repeated in six animals pretreated with verapamil. An initial dose of 0.15 mg/kg was administered as an intravenous bolus 30 minutes before the initiation of high-frequency pacing. An infusion of 0.1 mg/kg per hour was maintained throughout the duration of the study. The effects of hypercalcemia on electrical remodeling were assessed in an additional five animals. A bolus of 25 mL of 10% calcium-gluconate solution was infused at the beginning of the study, followed by a maintenance infusion (8±2 mL/h) so as to maintain serum ionized calcium concentrations between 1.8 and 2.0 mmol/L. In four additional dogs, glibenclamide was infused before and during rapid pacing. An initial bolus of 0.2 mg/kg followed by a maintenance infusion of 0.032 mg/kg per hour was used because previous studies have suggested this dose is sufficient to block the ATP-sensitive potassium current (IKATP).16 Blood glucose levels were maintained in these four animals through repetitive injections of 50% dextrose solution (mean total dose, 11.3±4.9 g) to maintain blood glucose in a range of 3.5 to 5.5 mmol/L.
All values are expressed as mean±1 SD. ANOVA for repeated measures was used to compare the effects of high-frequency pacing in the control animals to the response in the three experimental groups. The time course of electrical remodeling was estimated using linear regression. A value of P<.05 was considered statistically significant.
Throughout the 8 hours after autonomic blockade, sinus rate varied by only 4±2 bpm in the control group, by 4±2 bpm in the animals treated with calcium gluconate, and by 4±2 bpm in the glibenclamide group. Four of six animals treated with verapamil developed at least one episode of sinus arrest. The ventricular response during rapid atrial pacing was comparable in the control group and in the calcium and glibenclamide groups (161±12 versus 166±20 and 165±21 bpm). As expected, the ventricular response was slower in the verapamil group. To prevent bradycardia during the study, the verapamil-treated animals had ventricular pacing at a rate equal to the baseline sinus rate (92±6 bpm). Despite the difference in ventricular rate between groups, right atrial pressures were comparable. Right atrial pressure in the control group was 5.5±1.3 mm Hg compared with 4.6±0.8, 7.4±2.7, and 5.0±1.0 mm Hg in animals treated with glibenclamide, verapamil, and calcium gluconate, respectively (P=NS). The right atrial pressure did not change significantly during the course of the experiment (5.5±1.6 mm Hg at the onset of rapid pacing versus 6.1±2.9 mm Hg at the offset of pacing 7 hours later).
As with the right atrial pressure, mean arterial pressure was comparable between control and experimental groups and did not change significantly over the course of the experiment.
Time Course and Magnitude of Electrical Remodeling
The baseline (after autonomic blockade and before the onset of high-frequency pacing) ERP and ARP were 169±10 and 156±5 ms in the control animals. There was a prompt and persistent decrease in refractory periods as the result of rapid pacing (Fig 1⇓). The mean ERP after 7 hours of pacing was 21±2 ms (12±1%) less than the baseline (P<.001). Similarly, the ARP fell by 18±9 ms (12±6%; P<.001).
The onset of electrical remodeling was rapid, with the ERP decreasing by 24±2 ms/h and ARP decreasing by 24±4 ms/h during the first 30 minutes of high-frequency pacing. Electrical remodeling was more gradual but nevertheless progressive during hours 1 through 7 of high-frequency pacing; the ERP shortened by an average of 1±2 ms/h, and the ARP fell by 2±1 ms/h.
The time course of resolution of electrical remodeling after cessation of rapid pacing was comparable to the onset kinetics. The ERP and ARP increased by 34±5 and 39±13 ms/h over the first 30 minutes after the offset of high-frequency pacing. Thus, at the conclusion of the experiment, ERP and ARP had recovered to within 97±4% and 97±1% of baseline values, respectively.
Effects of Verapamil, Calcium, and Glibenclamide on Electrical Remodeling
Mean systolic blood pressure during the 7 hours of rapid pacing was comparable in the control animals and the three experimental groups (control, 111±40 mm Hg; verapamil, 114±26 mm Hg; calcium gluconate, 121±21 mm Hg; and glibenclamide, 117±11 mm Hg; P=NS). Similarly, there were no differences in mean right atrial pressure between the groups during the 7-hour pacing study (control, 6±1 mm Hg; verapamil, 8±3 mm Hg; calcium gluconate, 5±1 mm Hg; glibenclamide, 5±1 mm Hg; P=NS). In addition, there were no differences in baseline ERP and ARP between the three experimental groups and the control group.
Verapamil infusion completely abolished electrical remodeling (Fig 2B⇓). During rapid pacing, there was a nonsignificant rise in ERP and ARP by 4±8 and 3±7 ms. The verapamil effect did not appear to be the result of exit block from the pacing site because the mean atrial rate during the first 2 hours of high-frequency pacing was comparable in the verapamil and control groups. There were no differences in the average duration of induced atrial fibrillation recorded at the time of refractory period measurements between the verapamil and control groups. However, the mean fibrillatory cycle length was longer in the verapamil group than in the controls (163±22 versus 125±5 ms, P<.05). To determine whether the verapamil effect could be overcome by hypercalcemia, two dogs in the verapamil group were treated with calcium gluconate at the conclusion of the 7-hour high-frequency pacing period. This produced an increase in the ionized calcium concentration from 1.41±0.1 to 2.16±0.3 mmol/L. Despite continuation of the verapamil infusion, reinitiation of rapid pacing in these two animals caused a fall in ERP and ARP by 24±26 and 16±25 ms, respectively, which is comparable to the initial shortening of refractory periods seen in the control group (Fig 3⇓). Although the sample size is small, the dramatic reversal of the verapamil effect by hypercalcemia suggests that it is mediated by L-type calcium channel blockade, rather than a nonspecific effect of the drug.
In the experimental group treated with calcium gluconate, there was a significant rise in serum ionized calcium concentration from 1.37±0.1 to 1.9±0.1 mmol/L. There was no difference in the magnitude of electrical remodeling between the hypercalcemic dogs and control animals (Fig 2A⇑). The mean decrease in ERP and ARP was 16±13 and 16±14 ms, respectively (P=NS versus control). Interestingly, calcium infusion produced a distinct delay in the recovery from electrical remodeling after cessation of rapid pacing (Fig 4⇓). The ERP and ARP prolonged by only 2±4 and 13±20 ms, respectively, during the first 30 minutes of recovery compared with 19±5 and 22±9 ms in the control group (P<.05 for the ERP).
Glibenclamide infusion did not appear to affect the magnitude or time course of electrical remodeling (Fig 2C⇑). The ERP and ARP decreased by 24±8 and 32±10 ms, respectively, during rapid pacing (P=NS versus control). The onset of remodeling was brisk (ERP, −35±9 ms/h; ARP, −58±19 ms/h), as were the offset kinetics (ERP, +30±13 ms/h; ARP, +50±23 ms/h; P=NS versus control).
Histological Effects of Rapid Pacing
Light microscopic examination of all atrial biopsy specimens was normal. There were no contraction bands, interstitial edema, cellular infiltration, or nuclear pyknosis.
Electron microscopic studies of the atrial biopsy specimens in the control group were normal in two of five cases. In the remaining three specimens, there was distinct mitochondrial swelling (Fig 5A⇓). This swelling was associated with a decrease in the density of the cristae and a loss of definition, suggesting possible lysis of the cristae. Abnormalities were confined to the mitochondria, without intracellular edema, swelling of the transverse tubular system or of the sarcoplasmic reticulum. In contrast to the control specimens, all of the samples obtained from the verapamil-treated group, in which electrical remodeling was blocked, were normal (Fig 5B⇓).
In this study of closed-chest dogs subjected to rapid pacing, persistent tachycardia resulted in a decrease in atrial refractory periods by >10%. The phenomenon was consistently observed despite autonomic blockade and the absence of change in right atrial pressure. This electrical remodeling developed quickly, with more than half of the effect occurring during the first 30 minutes of high-rate pacing. The time course of remodeling had a bimodal pattern. After the initial rapid shortening, ERP and ARP decreased much more gradually, at a rate of only 1 or 2 ms/h, for the subsequent 7 hours of high-rate pacing. The time course of resolution of electrical remodeling was similar to the onset with ERP and ARP, returning to 97% of baseline within 30 minutes after cessation of rapid pacing.
Verapamil infusion prevented electrical remodeling. Conversely, hypercalcemia accentuated the phenomenon, as manifested by a markedly delayed recovery of refractory periods after pacing was stopped. Glibenclamide, which selectively blocks IKATP, had no effect.
Finally, electron microscopic examination of atrial tissue subjected to rate-induced remodeling revealed mitochondrial swelling as well as disorganization and possible lysis of the cristae.
Comparison With Previous Studies
Morillo et al11 subjected 22 dogs to continuous atrial pacing at 400 bpm for 6 weeks. The ERP decreased by an average of 23 to 25 ms, which is quite similar to the 21-ms mean shortening seen in the present study. These investigators also described histological changes of an atrial myopathy, with early hypertrophy evident on light microscopic examination. As with our study, electron microscopy revealed mitochondrial swelling and degenerated cristae. They noted an increase in the number of mitochondria, disruption of sarcoplasmic reticulum, enlarged nuclei, and dilation of the rough endoplasmic reticulum. The more dramatic nature of these derangements is presumably the result of the much longer duration of induced atrial tachyarrhythmia compared with that of the present study.
In a comprehensive study of electrical remodeling, Wijffels et al12 used repetitive burst stimulation to artificially maintain atrial fibrillation in 12 chronically instrumented goats. After 6 hours of sustained high rates, the mean ERP (measured at a drive cycle length of 400 ms) had decreased by 23 ms, which is in remarkably close agreement with the results of the present study. The ERP continued to shorten by an additional 42 ms over the next 2 to 4 days. This is similar to the time course of electrical remodeling seen during hours 1 through 7 in our study, in which ERP decreased by ≈1 ms/h. Wijffels et al described a time course of recovery of refractory periods that was dramatically slower than that of the present study. One day after cessation of atrial fibrillation, mean ERP was still 30 ms shorter than baseline, but it returned to normal by 1 week after conversion. It is likely that the briefer exposure to tachycardia in our study produced changes that were more rapidly reversible.
Mechanisms of Electrical Remodeling
The negative results from our study help to exclude several proposed mechanisms of electrical remodeling. The doses of atropine and propranolol used in this study prevented significant change in sinus rate throughout the experiment. This total autonomic blockade did not prevent tachycardia-induced shortening of refractory periods, suggesting that shifts in vagal or sympathetic tone do not contribute significantly to electrical remodeling. Also, mechanoelectrical feedback does not seem likely to be important because there was no difference in mean right atrial pressure before and during high-rate pacing or between the control group and the verapamil-treated group, where remodeling was not observed.
It is well known that ischemia produces a rapid and progressive decrease in action potential duration and refractory periods.17 18 Most of this effect appears to be mediated by depletion by high-energy phosphates and resultant activation of the IKATP. Pretreatment with glibenclamide, a selective blocker of IKATP, dramatically attenuates ischemia-induced shortening of action potential duration.19 It is interesting to note that glibenclamide had no effect on rate-induced shortening of refractory periods, suggesting that activation of IKATP induced by metabolic “rundown” did not contribute significantly to electrical remodeling.
Blockade of electrical remodeling by verapamil and its enhancement by hypercalcemia suggest that cytosolic calcium overload is an important mediator of this phenomenon. Preliminary reports by Tieleman et al20 describe similar findings, with significant attenuation of atrial electrical remodeling as the result of verapamil infusion.
It is interesting to note that several studies of ventricular fibrillation in vitro have shown intracellular calcium overload resulting from rapid ventricular rates.21 22 23 24 Koretsuni and Marban21 used the calcium indicator 5F-BAPTA to study intracellular calcium kinetics in isolated, perfused ferret hearts. By maintaining coronary perfusion and lowering left ventricular volume during induced ventricular fibrillation, intracellular pH and high-energy phosphate levels remained constant. However, intracellular calcium concentration rose fivefold over a period of 15 to 20 minutes. The severity of the calcium overload appeared to correlate with the probability of postfibrillatory dysfunction. In a similar study, Zaugg et al22 used surface fluorometry to assess intracellular calcium concentration in isolated, perfused rat hearts. They noted a sevenfold rise in intracellular calcium concentration during ventricular fibrillation as well as a relationship between the mean ventricular rate and the severity of cytosolic hypercalcemia. In a preliminary report, Leistad et al15 used fluorometry to assess atrial calcium, lactate, and ATP concentrations during induced atrial fibrillation. After 25 minutes of atrial fibrillation, there was a doubling of intracellular calcium concentration without a significant change in ATP or lactate levels.
Although nonspecific, histological changes observed in this study are consistent with calcium overload as the cause for electrical remodeling. The mitochondria are not effective buffers of calcium ion under physiological conditions. However, the low-affinity Ca2+-uptake apparatus has a great capacity to accumulate calcium under noxious conditions when the cytosol becomes flooded with excessive calcium.25 The mitochondrial swelling and derangement of the cristae seen in the control animals are consistent with this “sponge” behavior of the organelle in the setting of early calcium overload myopathy.26
The calcium ion is a ubiquitous intracellular signal mediator, and its elevation during atrial fibrillation may shorten action potential duration in a number of ways. Increases in intracellular calcium concentration have been shown to produce a negative feedback effect on L-type calcium channel activity with a decrease in the plateau phase of the action potential.27 Patch-clamp studies have shown that the delayed rectifier current, IK, is enhanced by increases in intracellular calcium concentration via a calmodulin-dependent pathway.28 Calcium overload has also been shown to augment a subset of the transient outward potassium current, Ito2.29 30 Additional studies of the effects of potassium channel–blocking drugs on atrial electrical remodeling will be useful to better define the role of these membrane currents.
The use of an acute, closed-chest model of an atrial tachyarrhythmia is associated with several important limitations. The evidence suggesting that cytosolic calcium overload produces electrical remodeling is indirect because it is based on pharmacological interventions and ultrastructural changes. Additional studies with direct measurement of intracellular calcium concentration will be needed to confirm this hypothesis. In an intact animal preparation, it is not possible to confirm that the dose of glibenclamide used was sufficient to block cardiac IKATP. However, all animals required supplemental glucose infusions for hypoglycemia, which is consistent with blockade of IKATP in pancreatic β cells.
The use of an acute model prevented the study of long-term electrical remodeling. It is clear that additional mechanisms come into play during chronic atrial tachyarrhythmias. However, it seems likely that calcium overload is the primary process that triggers these longer-lasting changes.
The possibility that drugs used for general anesthesia or that “aging” of the preparation contributed to changes in atrial refractoriness cannot be definitively excluded because there was no control group that was subjected to the same protocol without rapid atrial pacing. However, observations from the study argue against nonspecific effects of anesthesia or time on atrial electrophysiology. There was no change in atrial refractoriness during the 30-minute period between administration of atropine and propranolol and initiation of rapid pacing. Furthermore, the ERP returned to baseline after cessation of pacing in the control group. It seems unlikely that changes in refractoriness produced by anesthesia or aging of the preparation would coincidentally resolve after 7 hours at the same time pacing was stopped.
The ventricular response in the control group treated with verapamil was slower than that of controls or the other experimental groups. Despite this difference, mean arterial pressure and right atrial pressure were comparable in all groups. Thus, it is unlikely that slower ventricular rates could have affected the right atrial ERP. However, the possibility of a subtle effect of the ventricular response that was not reflected by pressure measurements cannot be definitively excluded.
The results of the study suggest that even brief exposure to rapid rates may significantly influence atrial electrophysiology. This is supported by the preliminary report of Daoud et al,31 who induced atrial fibrillation in 21 patients undergoing electrophysiology study. Despite a duration of atrial fibrillation of only 7.6±1.1 minutes, the ERP decreased by an average of 30 ms. Thus, electrical remodeling develops quickly, is progressive, and may be persistent. It is intriguing to speculate that prompt termination of spells in patients with paroxysmal atrial fibrillation (as might occur with an implanted atrial defibrillator) might slow the natural history of progression in this disease. In addition, an appreciation of the dynamic nature of atrial electrophysiology may be an important factor in the assessment of antiarrhythmic drug efficacy. Results of this study suggest that a patient's rhythm history in the days or weeks preceding exposure to a drug may profoundly influence the response to the medication.
Calcium entry blockers are not effective for cardioversion of atrial fibrillation or for prevention of induction of atrial fibrillation during rapid stimulation in the electrophysiology laboratory.32 33 34 35 However, results of the present study suggest that calcium entry blockers might be useful adjuncts to antiarrhythmic drugs for the treatment of paroxysmal atrial fibrillation. By attenuating tachycardia-induced shortening of refractory periods, these agents might act synergistically with drugs that prolong action potential duration, further reducing the frequency and duration of paroxysms.
This research was supported in part by a gift from the Carlyle Fraser Heart Center. The authors gratefully acknowledge the assistance of Cynthia J. Addison in preparation of the manuscript.
Reprint requests to Jonathan J. Langberg, MD, Emory University Hospital, 1364 Clifton Rd NE, Suite F-414, Atlanta, GA 30322.
- Received December 27, 1995.
- Revision received August 20, 1996.
- Accepted August 22, 1996.
- Copyright © 1996 by American Heart Association
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