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(Circulation. 1997;96:1686-1695.)
© 1997 American Heart Association, Inc.

Articles

Effects of Atrial Dilatation on Refractory Period and Vulnerability to Atrial Fibrillation in the Isolated Langendorff-Perfused Rabbit Heart

Flavia Ravelli, PhD; ; Maurits Allessie, MD, PhD

From the Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Netherlands (M.A.), and Medical Biophysics, Centro Materiali e Biofisica Medica (CMBM), Trento, Italy (F.R.).

Correspondence to Prof Dr M.A. Allessie, Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands.

	Abstract

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Background Atrial fibrillation (AF) is frequently observed under conditions that are associated with atrial dilatation. The aim of this study was to investigate the effects of atrial dilatation on the substrate of AF.

Methods and Results In 15 Langendorff-perfused rabbit hearts, the interatrial septum was perforated, and after occlusion of the caval and pulmonary veins, biatrial pressure was increased by raising the level of an outflow cannula in the pulmonary artery. Right and left atrial effective refractory periods (AERPs), monophasic action potentials (MAPs), and inducibility of AF by single premature stimuli were measured as a function of atrial pressure. Increasing the atrial pressure from 0.5±0.7 to 16.2±2.2 cm H₂O resulted in a progressive shortening of the right AERP from 82.2±9.8 to 48.0±5.1 ms. In the left atrium, an increase in pressure up to 7.4±0.3 cm H₂O had no effect on the AERP. At higher pressures, however, the left AERP also shortened, from 67.5±7.5 to 49.3±2.0 ms. The duration of MAPs also decreased by an increase in atrial pressure, showing a high correlation with the shortening in AERP (r=.94, P<.01). All these changes were completely reversible within 3 minutes after release of the atrial stretch. Dilatation of the atria was a major determinant for the vulnerability to AF. The inducibility of AF increased from 0% at low pressures to 100% when the atrial pressure was >10 cm H₂O. Release of the atrial wall stress resulted in prompt cardioversion of AF. The increased vulnerability for AF was highly correlated with the shortening in AERP (logistic regression r=.97). No correlation was found with the spatial dispersion between right and left AERPs.

Conclusions Increased atrial pressure in the isolated rabbit heart resulted in a significant increase in vulnerability to AF that was closely correlated to shortening of the AERP. These changes were completely reversible within 3 minutes after release of the atrial stretch, resulting in prompt termination of AF.

Key Words: fibrillation • tachyarrhythmias • action potentials • pressure • atrium

	Introduction

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Atrial arrhythmias frequently occur under conditions associated with atrial dilatation.^{1 2 3} In patients with acute myocardial infarction, the onset of atrial arrhythmias is thought to be related to the elevated left ventricular end-diastolic pressure, resulting in stretch of the atrial wall.¹ AF is also often seen in heart failure or mitral valve disease with left atrial enlargement, and it is not uncommon that sinus rhythm is restored when, after surgical repair of the mitral valve, the size of the atria diminishes. Variations in atrial pressure have also been shown to modulate the cycle length of atrial flutter.^{4 5} Although the electrophysiological effects of volume and pressure overload are still incompletely understood, it is clear that mechanoelectrical feedback plays an important role in the development of cardiac arrhythmias.⁶

The potential importance of mechanoelectrical feedback in arrhythmogenesis has been quite extensively studied at the ventricular level. Initial studies in isolated cardiac tissue have shown that the membrane potential and duration of the action potential are affected by changes in the length of the ventricular cells.^{7 8 9} Thereafter, various kinds of myocardial stretch, in both isolated and in situ hearts, have been shown to induce ventricular arrhythmias because of the occurrence of transient depolarizations and shortening of the MAP and refractory period.^{10 11 12 13 14 15 16}

Few studies have been performed so far to assess the role of mechanoelectrical feedback in atrial tissue.¹⁷ In human atrium, the effect of atrial pressure on atrial refractoriness was evaluated by varying the AV interval during sequential AV pacing. Whereas the Zipes group reported a prolongation of the human atrial refractory period in response to a rise in intra-atrial pressure,^{18 19} Calkins et al^{20 21} observed either a shortening or no change of the refractory period, depending on the time course of the changes in atrial pressure. In dogs, dilatation of the left atrium by inflation of a balloon catheter produced shortening of the AERP and an increase of the vulnerability to arrhythmias.²² In goats, acute atrial dilatation by infusion of a plasma expander did not change the AERP.²³ However, in these in vivo measurements, the degree and duration of the rise in atrial pressure are limited, and the effects on the electrophysiological properties of the atria might be modulated by changes in neurohumoral balance or ventricular performance.

To avoid these limitations, we developed an experimental model in which the right and left atrial pressures could be varied over a wide range of values. The direct effects of acute and sustained biatrial dilatation on the duration of the MAP and refractory period were measured and related to the inducibility of atrial arrhythmias by programmed electrical stimulation.

	Methods

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Experimental Model of Biatrial Dilatation
Fifteen rabbits of either sex weighing 3.0 to 3.6 kg were used for this study. The animals were sedated with 0.5 mL/kg Hypnorm (0.2 mg/mL fentanyl+10 mg/mL fluanisone), and after injection of 1000 IU heparin IV, they were killed by cervical dislocation. The thorax was opened by a midsternal incision, and the heart was rapidly removed and placed in cold perfusion fluid (10°C). The aorta was cannulated, and the heart was perfused at a pressure of 65 mm Hg and a temperature of 37°C. The composition of the perfusion fluid was (in mmol/L) NaCl 130, NaHCO₃ 24.2, KCl 4.0, CaCl₂ 2.2, MgCl₂ 0.6, Na₂HPO₄ 1.2, and glucose 12. It was gassed with a mixture of 95% O₂/5% CO₂, resulting in a pH of 7.4. To vary the atrial pressure and to control the degree of dilatation, the caval and pulmonary veins were ligated and the perfusion fluid entering the right atrium from the coronary sinus was allowed to leave the heart exclusively through a cannula in the pulmonary artery (Fig 1). The hydrostatic pressure in the right and left atria was measured by a Y-shaped manometer inserted into both the superior caval vein and one of the pulmonary veins. Because this Y-shaped manometer connected the cavities of both atria, the right and left atrial pressures were controlled simultaneously. To further guarantee an equal pressure in both atria, the interatrial septum was perforated as well. We have no indication that perforation of the atrial septum affected the vulnerability of the atria for AF. In this way, the atrial pressure and degree of biatrial dilatation could be varied by simple adjustment of the height of the pulmonary outflow cannula. To avoid variation in atrial pressure by contraction of the ventricles, ventricular fibrillation was induced by rapid pacing through a pair of electrodes sutured to the right ventricle. Retrograde activation of the atria during ventricular fibrillation was prevented by radiofrequency ablation of the AV junction. In most hearts, the atrial pressure was varied between 0 and 15 cm H₂O. In one heart, the intra-atrial pressure could be raised up to 20 cm H₂O. The interindividual variation in maximal atrial pressure obtained was mainly due to some minor leakage of the Tyrode's solution. Fig 2 shows the dilatation of the right atrium as a result of increasing atrial pressure from 0 to 10 cm H₂O. The surface area of the free wall of the right atrium increased almost twofold.

View larger version (24K): [in this window] [in a new window]   Figure 1. Schematic of Langendorff-perfused rabbit heart and method to vary biatrial pressure. All caval and pulmonary veins were ligated, and perfusion fluid flowing out of coronary sinus could leave heart exclusively through a cannula in pulmonary artery (PA). Interatrial septum was perforated, and a Y-shaped manometer was inserted into both superior caval vein (SVC) and one pulmonary vein (PV). In this preparation, biatrial pressure could be varied simply by adjusting height of pulmonary outflow cannula. An MAP catheter was introduced into right atrial (RA) cavity through inferior caval vein (IVC) to record atrial MAPs from right atrial midwall. LA indicates left atrium.

View larger version (84K): [in this window] [in a new window]   Figure 2. Photographs of right atrium at atrial pressures of 0 (left) and 10 (right) cm H2O. Dilatation of right atrium was significant, and surface area was estimated to increase by 95%. In dilated atrium, complex structure of atrial wall can be clearly seen, crista terminalis and pectinate muscles forming an interlacing network with thin myocardium in between.

Electrophysiological Measurements
The electrical activity of the ventricles was recorded by a catheter electrode inserted into the right ventricle through the pulmonary artery cannula. Two bipolar hook electrodes were attached to the right and left atrial appendages to record right and left epicardial electrograms. The electrograms were filtered (bandwidth, 1 to 500 Hz) and amplified (gain, 1000). MAPs were recorded from the right atrial endocardial midwall with a Ag-AgCl contact MAP catheter (EP Technologies) by the technique described by Franz et al.²⁴ The catheter was introduced into the right atrial cavity through the orifice of the inferior caval vein. After insertion of the catheter, the caval vein was ligated around the catheter to prevent leakage of Tyrode's solution. MAPs were amplified by a differential DC-coupled amplifier with automatic offset control and internal 5-mV calibration (model 1009, EP Technologies). After amplification, all signals were displayed on a computer with custom-made data acquisition and analysis software. In addition, all signals were stored on a seven-channel magnetic-tape recorder (TEAC R-71) for off-line analysis.

Programmed electrical stimulation was performed at the right and left midatrial walls by an epicardial unipolar electrode (0.3-mm diameter) embedded in a soft plastic tube (2.0-mm diameter). This permitted stable contact with the epicardium without application of high local pressure at the site of measurement. The aortic cannula was used as indifferent electrode. A custom-made computer-controlled stimulator was used to deliver cathodal constant-current pulses of 1-ms duration. The AERP was determined during atrial pacing (stimulus strength, 2xthreshold) at a cycle length of 250 ms. Single premature stimuli of 4xthreshold were interpolated at every 10th basic interval. At a stimulus strength of 4xthreshold, the strength-interval curve is quite steep, and slight variations in effective stimulus strength or threshold have no significant effect on the value of the measured AERP. Starting well within the refractory period, the premature coupling interval was incremented in steps of 1 ms. The shortest coupling interval that resulted in a propagated atrial response was taken as the AERP. This method of measuring the refractory period is fast and reproducible and has the advantage that the coupling interval of the test stimulus can be incremented rapidly without disturbing the regular heart rhythm.²⁵

Experimental Protocol
To measure the time course of the changes in atrial refractoriness in response to an acute change in atrial pressure, in six hearts the right AERP was monitored after a stepwise change in pressure from 0 to 10 cm H₂O. After the AERP had reached a new steady-state value, the atrial pressure was decreased again and the time course of recovery of the AERP was measured.

The effects of sustained high atrial pressure on the AERP were evaluated in 15 hearts. During continuous pacing at a cycle length of 250 ms, the refractory period of the right atrium was measured in all hearts. In 9 hearts, the refractory period of the left atrium was also determined. Initially, the atrial pressure was set at zero (with the midatrium used as a reference point). Then the pressure was increased progressively in steps of 2 to 3 cm H₂O up to 15 cm H₂O. After a pressure step, the heart was allowed to adapt to the new pressure for at least 3 minutes. Then the diastolic pacing threshold and the AERP were determined. In the 9 hearts in which the refractory period was measured in both atria, the right and left AERPs were determined sequentially at each pressure step. After measurement of the AERP at the highest pressure, the atrial pressure was lowered again and the refractory period was redetermined to verify that the pressure-induced changes in AERP were completely reversible.

The effects of intra-atrial pressure on the right MAP were studied in five hearts. During a stepwise increase in pressure from 0 to 15 cm H₂O, the right atrial MAP was recorded from a single site during continuous pacing at 250-ms intervals. MAPs were analyzed by custom-made software for automatic measurement of the amplitude and MAPD₅₀, MAPD₇₀, and MAPD₉₀. The MAP durations of 10 consecutive beats were averaged.

The vulnerability of the atria to fibrillation was quantified by measurement of the induction of AF by single early premature stimuli. AF was defined as a rapid irregular rhythm lasting for >1 second. AF intervals were measured automatically on a beat-to-beat basis from a right or left atrial electrogram.²⁶

Statistical Analysis
All data are presented as mean±SD. The time course of changes in AERP in response to a stepwise change in atrial pressure was fitted by the exponential function y=A+Be^{-C ·x}, where the parameter 1/C is the time constant. Linear regression analysis was used to compare changes in MAP duration with changes in AERP as a result of changes in atrial pressure. Logistic regression analysis was performed to calculate the inducibility of fibrillation by single atrial premature stimuli at different atrial pressures and refractory periods by the following function: y=e^B0+B1x/(1+e^B0+B1x), where B0 and B1 are fitting parameters determined by an iterative procedure with a convergence criterion of a change of <0.1% for the two parameters. Statistical analysis was performed by the paired Student's t test corrected for multiple comparisons. A value of P<.05 was considered to be statistically significant.

	Results

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Effects of Atrial Pressure on Atrial Refractoriness
Fig 3 shows an example of the time course of the changes in refractory period of the right atrium in response to an acute change in atrial pressure from 0 to 10 cm of H₂O. Within <3 minutes, the AERP shortened, in this case from 85 to 45 ms. In six hearts, after a stepwise increase in atrial pressure from 0 to 10 cm H₂O, during the first minute the refractory period shortened from 86.7±4.7 to 69.2±6.6 ms. A new steady-state value of 55.8±6.7 ms was reached after 2.4±0.8 minutes. The average time constant was 1.3±0.4 minutes. This marked shortening of the AERP was completely reversible, with a similar time course when the atrial pressure was lowered again. After restoration of the atrial pressure to zero, the AERP gradually lengthened again to an average value of 84.1±14.2 ms (not statistically different from control).

View larger version (10K): [in this window] [in a new window]   Figure 3. Time course of right atrial refractory period (top) after abrupt change in atrial pressure (bottom). In response to a sudden increase in atrial pressure from zero to 10 cm H2O, AERP shortened markedly, reaching a new steady state within 3 minutes. Changes in refractory period were fully reversible as atrial pressure was restored to its initial value.

The effects of sustained changes in atrial pressure on the right and left AERPs are given in Figs 4 and 5 and Table 1. In Fig 4, top, the individual measurements of the duration of the right atrial refractory period are plotted for 15 hearts. In all hearts, the right AERP shortened with an increase in atrial pressure. On average, the AERP shortened from 82.2±9.8 to 48.0±5.1 ms with an increase in atrial pressure from 0.5±0.7 to 16.2±2.2 cm H₂O (Fig 4, bottom, and Table 1). The largest shortening of the AERP occurred when the right atrial pressure increased from 0 to 10 cm H₂O. Above 10 cm H₂O, the right AERP no longer changed significantly. Fig 5 shows the effects of changes in atrial pressure in the left atrium. In Fig 5, top, the individual data of 9 hearts are plotted, the bottom panel showing the average values. Compared with the right atrium, the left atrium seemed to be more resistant to moderate variations in atrial pressure, and the pressure had to rise to 7 to 8 cm H₂O before the AERP started to shorten. In total, the left atrial refractory period shortened from 69.7±5.8 to 49.3±2.0 ms as a result of a rise in atrial pressure from 0.6±0.6 to 15.0 cm H₂O (Table 1). Changes in left atrial pressure between 0.6±0.6 and 7.4±0.3 cm H₂O had no effect on the AERP. From 7.4±0.3 to 12.6±0.2 cm H₂O, the left AERP shortened progressively from 67.5±7.5 to 48.0±8.9 ms (P<.01). A further increase of the atrial pressure to 15 cm H₂O did not further shorten left atrial refractoriness. The shortening of the AERP by a sustained increase in atrial pressure was fully reversible. On restoration of a low atrial pressure, both right and left AERPs lengthened again to 83.3±17.4 and 71.2±16.5 ms, respectively. These values were not significantly different from the control refractory period at zero pressure. The pacing thresholds were not affected by changes in atrial pressure (Table 1).

View larger version (20K): [in this window] [in a new window]   Figure 4. Right atrial refractory period as a function of atrial pressure. Top, Individual measurements of duration of right AERP are superimposed for 15 hearts. Bottom, Average values. Right AERP decreased progressively when atrial pressure was elevated. Bars indicate SD. *P<.05 vs previous (lower) pressure.

View larger version (17K): [in this window] [in a new window]   Figure 5. Left atrial refractory period as a function of atrial pressure. Top, Individual measurements of duration of left AERP are plotted for 9 hearts. Bottom, Average values. Changes in left atrial pressure between 0 and 7 cm H2O had no effect on AERP. At higher left atrial pressures, AERP decreased progressively. Bars indicate 1 SD. *P<.05 vs previous (lower) pressure.

View this table: [in this window] [in a new window]   Table 1. Effects of Intra-Atrial Pressure on Atrial Refractoriness

To evaluate whether atrial dilatation affected the spatial dispersion in atrial refractory periods, Table 1 also gives the differences between right and left AERPs at the different pressure steps. Biatrial dilatation did not result in an increase in the spatial dispersion of atrial refractoriness. On the contrary, the difference between the right and left atrial refractoriness of 15.7±8.9 ms during low pressure decreased to 4.7±1.7 ms at a biatrial pressure of 15 cm H₂O (P=NS).

Effects of Atrial Pressure on the MAP
To investigate to what extent the changes in atrial refractoriness were a result of stretch-induced changes in the action potential, in five hearts MAPs were recorded from the right atrium while the atrial pressure was raised. Fig 6 shows an example of the differences in MAP configuration at right atrial pressures of 0, 5, 7.5, and 10 cm H₂O. On the right, the MAPs at different pressures are superimposed, both in absolute voltage (top) and after normalization for the decrease in amplitude of the MAPs at higher pressures (bottom). As can be seen, a rise in atrial pressure greatly altered the MAP morphology, both by shortening its duration and by lowering its amplitude. The shortening of the action potential was mostly due to an increase in the rate of early repolarization, and the plateau phase of the action potential disappeared when the atria were dilated. The observed decrease in amplitude of the MAP probably does not represent a true decrease in amplitude of the atrial action potential, but rather most likely results from a decrease in the number of atrial cells under the tip of the electrode when the atrium is stretched. However, other explanations, including temporary local injury to the atrium, cannot be completely excluded.

View larger version (13K): [in this window] [in a new window]   Figure 6. MAPs recorded from right atrium during increase in atrial pressure. Right, MAPs at different pressures are superimposed, both in absolute voltages (top) and after their amplitude was normalized (bottom). Rise in atrial pressure greatly altered MAP morphology by shortening its duration and lowering its amplitude. P indicates intra-atrial pressure.

The quantitative changes in MAPD₇₀ are shown in Fig 7, in which the individual data points of five experiments are plotted. As the atrial pressure was increased from 0 to 15 cm H₂O, the MAPD₇₀ progressively shortened in all five hearts. The average values of MAPD₅₀, MAPD₇₀, and MAPD₉₀ are given in Table 2. As the atrial pressure increased from 0.6±0.5 to 13.5±1.2 cm H₂O, the MAPD₅₀, MAPD₇₀, and MAPD₉₀ shortened from 57.9±18.1 to 24.5±6.5 ms, from 80.7±18.5 to 41.2±7.9 ms (P<.05), and from 114.6±20.8 to 71.7±11.9 ms, respectively (P<.05). To evaluate which phase of repolarization was most greatly affected by atrial pressure changes, the durations of the various segments of repolarization are also given (MAPD_20-50, MAPD_50-70, MAPD_70-90). It is clear that the largest shortening of the MAP occurred during the early phase of repolarization. An increase in atrial pressure from 0.6 to 13.5 cm H₂O shortened MAPD_20-50 by 55% (from 28.6 to 12.8 ms), compared with 26% of MAPD_50-70 (from 22.7 to 16.8 ms). No significant shortening was observed in MAPD_70-90 (from 34.0 to 30.4 ms).

View larger version (18K): [in this window] [in a new window]   Figure 7. Right atrial MAPD70 as a function of atrial pressure. Individual data points of five experiments are plotted. In all hearts, MAPD70 progressively shortened as atrial pressure gradually increased from 0 to 15 cm H2O.

View this table: [in this window] [in a new window]   Table 2. Effects of Intra-Atrial Pressure on MAP Durations

The shortening in MAP duration at higher atrial pressures was strongly correlated with the observed shortening in atrial refractoriness. In Fig 8, the changes in right AERP are plotted against the changes in MAPD₇₀ measured at the same sites in five hearts. Linear regression analysis showed a significant correlation between the changes in AERP and MAP duration due to variations in atrial pressure (r=.94, P<.01).

View larger version (13K): [in this window] [in a new window]   Figure 8. Correlation between changes in atrial refractory period and MAPD70 due to increase in atrial pressure. Both AERP and MAPD70 are expressed as percentage of value at atrial pressure of 0 cm H2O. Shortening of MAP duration was strongly correlated with observed shortening in atrial refractoriness (r=.94; P<.01).

Effects of Acute Atrial Dilatation on Vulnerability to AF
In undilated atria, AF was never induced by a single premature stimulus. However, as the atrial pressure was raised, the atria started to become progressively more vulnerable to AF. This is illustrated in Fig 9. During a pressure of 0 cm H₂O, the earliest premature stimulus that elicited a propagated premature beat was 86 ms, and this premature beat did not induce an arrhythmia. After the atrial pressure was increased to 5 cm H₂O, the shortest possible coupling interval had decreased to 63 ms, and now the premature stimulus elicited two extra beats instead of one. As the atrial pressure was further raised to 7.5 cm H₂O, the earliest premature stimulus with a coupling interval of 49 ms produced an episode of AF.

View larger version (17K): [in this window] [in a new window]   Figure 9. Earliest possible atrial premature beat at different atrial pressures. Unipolar electrogram was recorded from right atrium during regular pacing with an interval of 250 ms. At atrial pressure of 0 cm H2O, shortest S1-S2 interval that resulted in premature atrial response was 86 ms. At 5 cm H2O, shortest possible S1-S2 interval of 63 ms evoked two premature atrial beats. When atrial pressure was further elevated to 7.5 cm H2O, a single stimulus with a coupling interval as short as 49 ms produced AF. P indicates intra-atrial pressure; S1, basic stimulus; and S2, premature stimulus.

The inducibility of AF by a single early premature stimulus at different atrial pressures is given in Table 3. The inducibility of AF was tested in all 15 hearts at a total of 24 pacing sites. All together, 112 attempts were made to induce AF at atrial pressures ranging between 0.5 and 16.2 cm H₂O. AF was induced in 30 instances. At low pressures, not a single case of AF was observed. At a pressure of 7.5 cm in 8 of 14 hearts (8 of 23 sites), AF was induced (57% of hearts; 35% of pacing sites). At 10 cm H₂O in 11 of 14 hearts (11 of 21 sites), AF was induced (78% of hearts; 52% of sites). At a biatrial pressure 12.6±0.2 cm, AF occurred in 100% of the atria and 71% of the pacing sites. In Fig 10, the inducibility of AF is correlated with the atrial pressure (top), the atrial refractory period (middle), and the dispersion in AERP between right and left atria (bottom). AF inducibility increased as a function of atrial pressure according to a logistic regression curve (r=.98). No AF episodes were induced at pressures <6 cm H₂O. Above this pressure, AF inducibility increased sharply to approach 100% at pressures >10 cm H₂O. Logistic regression analysis calculated a 50% inducibility of AF at an atrial pressure of 7.6 cm H₂O.

View this table: [in this window] [in a new window]   Table 3. Effects of Intra-Atrial Pressure on AF Inducibility

View larger version (15K): [in this window] [in a new window]   Figure 10. Inducibility of AF by single premature stimuli plotted as a function of atrial pressure (top), atrial refractory period (middle), and spatial dispersion of refractory period between right and left atria (bottom). Data points represent success rate of induction of AF in all hearts (n=15). Curve drawn was fitted by a logistic model. Increase in atrial vulnerability by an increase in atrial pressure and a shortening of AERP followed a sigmoidal curve. A 50% chance of induction of AF corresponded with an average pressure of 7.6 cm H2O and an atrial refractory period of 53 ms. No correlation could be found between inducibility of AF and spatial difference in AERP between right and left atria.

In Fig 10, middle, the logistic regression curve between the AERP and the vulnerability for fibrillation is plotted. A high correlation between these two parameters was also found (r=.97). AF was not induced at refractory periods >70 ms. An inducibility of 20% correlated with a refractory period of 57.8±1.5 ms, whereas at an AERP of 53.2±1.1 ms, the inducibility of AF was 50%. When the refractory period further shortened to 48.2±0.9 ms, the inducibility of AF became >80%. The high vulnerability to AF due to atrial dilatation was not associated with an increase in spatial dispersion in AERP between the right and left atria.

Conversion of AF by Lowering of Intra-Atrial Pressure
Of the 30 episodes of induced AF, 12 episodes cardioverted spontaneously within 3 minutes (40%). The other 18 episodes of AF were sustained (60%). When in these cases atrial stretch was released by lowering of the atrial pressure to 0, sinus rhythm was restored again. In 8 of 18 cases, AF terminated almost immediately after the atrial pressure was lowered, whereas in the other 10 cases, cardioversion occurred 30 seconds to 2 minutes after "dedilatation" of the atria. Fig 11, top, shows a unipolar right atrial electrogram recorded during AF at an atrial pressure of 10 cm H₂O. In this case, AF terminated 40 seconds after the atrial pressure was lowered to 0 (middle). The release of the atrial stretch was associated with a clear slowing of the rate of AF (bottom). In the 10 cases of AF that were cardioverted by removal of atrial dilatation, the average fibrillation interval increased from 46.0±4.7 ms during sustained AF to 63.4±11.2 ms before termination (P<.05).

View larger version (35K): [in this window] [in a new window]   Figure 11. Cardioversion of AF by lowering atrial pressure. Top, A unipolar atrial electrogram is shown during sustained AF at an atrial pressure of 10 cm H2O. Middle, Same electrogram 40 seconds after release of atrial stretch (pressure 0 cm H2O). Termination of AF by removal of atrial dilatation was associated with slowing of rate of fibrillation. Bottom, Beat-to-beat cycle lengths during sustained AF (left) and before termination (right). In this example, mean fibrillation interval (dashed line) increased from 40 to 52 ms. AF terminated with a last long AF cycle length of 78 ms. P indicates intra-atrial pressure.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In this study, the isolated Langendorff-perfused rabbit heart was used to investigate the electrophysiological consequences of atrial dilatation. The major findings of this study are that (1) the durations of the atrial refractory period and MAP are shortened by an increase in atrial pressure, (2) a rise in atrial pressure greatly increases the vulnerability to AF, and (3) lowering of the atrial pressure is able to promptly cardiovert AF.

Shortening of the Atrial Refractory Period and MAP
Previous studies on the effects of pressure and volume overload on atrial refractoriness have provided different results. In dogs and humans, when the atrial pressure is raised by reduction of the AV delay during sequential pacing, either a prolongation,^{18 19} a shortening,²¹ or no change of the atrial refractory period was reported.²⁰ In the goat, volume loading by 0.5 to 1.0 L of a plasma expander also yielded no changes in atrial refractoriness.²³ Our data are in agreement with the study by Solti et al,²² who found that left atrial dilatation in dogs by inflation of a balloon catheter caused shortening of the AERP and an increase in atrial irritability. The magnitude of the stretch-induced changes in AERP in our study was larger than observed in intact animals. Whereas in isolated rabbit atria, an increase in atrial pressure of 15 cm H₂O caused the refractory period to shorten by 20 ms in the left and 35 ms in the right atrium, in vivo studies showed a maximal shortening in AERP between 7 and 20 ms.^{21 22} In the studies by the Zipes group,^{18 19} a maximal lengthening of the AERP between 3 and 57 ms was found. This may be explained either by less pronounced changes in atrial pressure that can be produced in vivo or by the possibility that in intact animals the stretch-induced changes in atrial refractory period are partially counteracted by changes in neurohumoral balance.

Shortening of action potential duration and/or refractory period has also been demonstrated in the ventricles.^{10 11 15 16} However, as in our study, the stretch-induced shortening of the action potential was not immediate but rather required some time to develop.²⁷ Together with our present observation that in the left atrium the pressure had to rise to a certain critical level before the refractory period started to shorten, this may help to explain the conflicting results of the different studies. Apart from possible species differences and changes in neurohumoral balance, both the duration and degree of the changes in atrial pressure may determine their electrophysiological effects. The compliance of the atrial wall also plays an important role in the amount of local wall stress because of a certain increase in atrial pressure.

In our study, the stretch-induced shortening in the atrial refractory period could be completely explained by a shortening in the duration of the action potential. This is in agreement with the study of Nazir and Lab,²⁸ who found a clear stretch-induced shortening of the MAPD₅₀ in guinea pig atria. However, they also found that because of the development of early afterdepolarizations, at 90% of repolarization the action potential could also become prolonged. Afterdepolarizations and ectopic beats can be induced by acute stretch and are not seen during more gradual or sustained dilatation.^{9 11 12 14} In our study, changes in atrial pressure were produced by adjustment of the level of the pulmonary outflow tract. The resulting changes in pressure were not instantaneous but rather developed more gradually within 10 to 30 seconds. This may explain why no early afterdepolarizations were seen in our experiments.

The lowering in amplitude of the MAP as a result of dilatation has also been observed by others.^{11 14 28} Although myocardial stretch does induce a slight decrease in the amplitude of the action potential recorded with a microelectrode,²⁹ the considerable decrease in the MAP amplitude is probably due to other factors. The amplitude of a MAP differs greatly from the true action potential and depends on the contact pressure, the angle between the catheter and the myocardial surface, and the thickness of the tissue under the electrode.³⁰ Thus, the decrease in MAP amplitude may simply reflect the decrease in number of atrial cells beneath the electrode when the atrial wall is stretched and not true changes in action potential amplitude.

The ionic mechanisms responsible for the shortening of the action potential by atrial dilatation remain unknown. Patch-clamp studies of ventricular myocardium have identified sarcolemmal stretch-activated channels that transport nonspecific monovalent cations (primarily Na⁺ and K⁺) and to a lesser extent, divalent cations like Ca²⁺ and Mg²⁺.^{31 32} A volume-sensitive outward rectifying Cl^- current has recently been found in rabbit and canine atrial myocytes that might also contribute to the observed shortening of the action potential by dilatation.^{33 34 35} In guinea pig atria, shortening of the action potential was inhibited by streptomycin, which blocks mechanosensitive channels.^{36 37}

Our observation that the plateau of the MAP disappeared by atrial dilatation is in agreement with a study comparing action potential and ionic currents in trabeculae and myocytes isolated from dilated and nondilated human atria.³⁸ In dilated atria, the action potential was shorter than in preparations obtained from nondilated human atria because of depression of the plateau phase of the action potential, which was explained by a more severe depression of the inward calcium current compared with the total outward current.³⁸

Increase in Atrial Vulnerability
In the normal rabbit heart, AF, if elicited at all, self-terminates almost immediately after it has been induced.^{39 40} It was shown a long time ago that a critical tissue mass is required for perpetuation of fibrillation.⁴¹ Only after shortening of the atrial refractory period by vagal stimulation or administration of acetylcholine may intra-atrial reentry and AF become sustained.^{42 43} This is explained by the multiple-wavelet mechanism,^{43 44 45} in which the stability of fibrillation depends on the average number of wavelets simultaneously present in the atria. The number of wavelets that can coexist is determined by both the atrial tissue mass and the wavelength of the atrial impulse.⁴⁶ Because the rabbit atria are so small, under normal conditions the number of wavelets is too small for AF to be sustained. Not only does atrial dilatation increase the atrial surface area available for the wandering wavelets, but also, as with acetylcholine, the stretch-induced shortening of the action potential and refractory period markedly shortens the wavelength of the atrial impulse. In addition, it has been shown that stretch slows the conduction velocity of the cardiac impulse, which would shorten the wavelength even more.^{47 48} Finally, it is likely that an increase in atrial pressure will lead to increased heterogeneities in electrical properties, because the greatly inhomogeneous structure of the atrial wall will result in major local differences in wall stress.⁴⁹ It was recently shown that in dogs, unequal atrial stretch increases the spatial dispersion of refractoriness, which contributes to development of AF.⁵⁰

In the present study, the increase in vulnerability of the atria to fibrillation at higher atrial pressures followed a sigmoidal curve. At 0 pressure, the probability of inducing AF was 0. Above a threshold value of 5 cm H₂O, the inducibility of AF by a single premature stimulus increased sharply to become 100% at pressures >10 cm H₂O. Recently, Sideris et al⁴⁸ showed that the probability of AF was significantly increased by a rise in atrial pressure. Although the atrial conduction time was prolonged, no association could be established between this parameter and the increased tendency toward AF. In the present study, a close relationship was found between the vulnerability of the atria to fibrillation and shortening of atrial refractoriness. AF was not induced at refractory periods >70 ms, whereas inducibility of AF became as high as 50% when refractoriness had shortened to 53 ms. At even shorter AERPs, the inducibility of AF increased to 80%. This is in agreement with the study of Solti et al,²² who showed both a shortening in refractory period and an increased irritability of the atria when the atrial volume was increased.

Whereas an increase in intra-atrial pressure favored the induction of AF by a premature beat, conversely, lowering of the atrial pressure invariably terminated AF. Two different modes of termination were observed, either almost instantaneous or after a delay of some minutes. In the latter case, termination of AF was preceded by a slowing of the rate of AF. In case of immediate interruption of AF, the direct diminishment of the atrial surface area might explain AF termination. In the other cases, a gradual prolongation of the refractory period during the first minutes after lowering of the atrial pressure would prolong not only the average cycle length of AF but also the average wavelength of the multiple wandering wavelets. The concomitant progressive decrease in the average number of wavelets would increase the chance that at a certain moment, all wavelets extinguish at the same time and AF is interrupted.

Possible Clinical Relevance
Our study emphasizes that alteration in the intra-atrial pressure has important effects on atrial refractoriness and vulnerability to AF. In the ventricles^{11 14 15} and more recently also in the atria,²⁸ mechanoelectrical feedback has been proposed as an important arrhythmogenic mechanism because stretch is able to induce afterdepolarizations and triggered arrhythmias. Our study provides evidence for mechanoelectrical feedback as a potential mechanism for reentrant atrial arrhythmias by critical shortening of atrial refractoriness. In patients as well, modulation of the atrial refractory period by changes in atrial pressure may play a role in the genesis of AF. In case of a compromised ventricular function or in the presence of mitral or tricuspid stenosis or insufficiency, the atrial myocardium may be stretched and the atrial refractory period may be changed. However, it is still unclear to what extent this mechanism contributes to the creation of a substrate for clinical AF. It is quite likely that in patients, apart from mechanoelectrical feedback, other factors are operative in the genesis of AF.

Limitations
Our study found no clear relationship between the inducibility of AF and the spatial dispersion in refractory periods. However, only the differences in refractory period between two pacing sites, one in the right and one in the left atrium, were measured. This provides only a rough estimate of the true spatial dispersion in atrial refractory periods. Also, we did not measure the effects of increasing atrial pressure on intra-atrial conduction. Thus, we cannot exclude the possibility that other factors, such as heterogeneities in refractoriness or conduction or stretch-induced arcs of intra-atrial conduction block, may contribute to the creation of a substrate for sustained AF.

Caution should be taken in extrapolating our findings to clinical AF. First, the degree of atrial stretch as produced in our animal model might be larger than during human AF. Second, the degree of stretch of the atrial wall at a certain rise in pressure depends on the compliance of the atria, which differs greatly in rabbit and human atria. And finally, the effects of acute stretch of the myocardium as studied in our animal model may be completely different from the chronic stretch that occurs in patients.

	Selected Abbreviations and Acronyms

 

AERP = atrial effective refractory period AF = atrial fibrillation MAP = monophasic action potential MAPD50 = MAP duration at 50% repolarization MAPD70 = MAP duration at 70% repolarization MAPD90 = MAP duration at 90% repolarization

Received October 10, 1996; revision received March 7, 1997; accepted March 13, 1997.

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