(Circulation. 1996;94:1456-1464.)
© 1996 American Heart Association, Inc.
Articles |
Zones of Atrial Vulnerability
Relationships to Basic Cycle Length
the Departments of Medicine, Long Island College Hospital and SUNY Health Science Center, Brooklyn, NY.
Correspondence to Howard S. Friedman, MD, Chairman, Department of Medicine, Long Island College Hospital, 340 Henry St, Brooklyn, NY 11201.
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Abstract |
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Background Bradycardia is commonly found in individuals at risk for paroxysmal atrial fibrillation (AF). However, a clear relationship between lengthening of basic cyclic length (BCL) and AF has not been demonstrated.
Methods and Results In 20 open-chest dogs, atrial refractoriness, AF vulnerability, and atrial activation times (ACTs) were determined in sinus rhythm and at BCLs of 400, 300, and 200 ms, and the findings at the same coupling intervals and stimulus strengths were compared. As BCL increased, AFV zone lengthened, and its outer limit occurred later in diastole. The outer limit of the AF vulnerability zone for a BCL was its relative refractory period; the inner limit, however, was not its effective refractory period. A border zone, defined by the inner limit of the AF vulnerability zone and the effective refractory period for a BCL, decreased as BCL lengthened, offsetting the increase in the AF vulnerability zone. The border zone was characterized by paradoxical stimulus current strength propagation relations and features suggesting supernormal conduction. ACT also increased with BCL lengthening. When AF induced by rapid atrial burst pacing was contrasted with AF induced by an extrastimulus, it tended to have a more disorganized pattern and lasted longer.
Conclusions Lengthening of BCL increases the AF vulnerability zone, extending its outer limit later in diastole and comprising an increasing component of the total duration of the relative refractory period. Very short BCLs create conditions that also favor AF vulnerability.
Key Words: fibrillation • heart rate • pacing electrophysiology
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Introduction |
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Atrial bradyarrhythmias are commonly found in individuals at risk for atrial fibrillation (AF).1 2 Although morphological abnormalities, affecting both the sinoatrial node and atrium,3 and functional effects, such as vagotonia that slows the heart rate and independently enhances AF,4 have been demonstrated, a clear electrophysiological relationship between bradycardia and the occurrence of AF has eluded investigators. Experimental studies have suggested a basis for the association: slowing of the heart rate tends to increase the heterogeneity of the recovery of atrial excitability,5 a condition that would favor fractionation of impulse propagation6 7 and the formation of multiple reentrant circuits that characterize AF.8 Clinical electrophysiological studies, however, have not supported this association; instead, these investigations have suggested that shortening of basic cycle length (BCL) enhances atrial vulnerability.9 10 11
The atrium, unlike the ventricle (for which a zone of vulnerability to fibrillation can be related to the T wave12 ), has no ECG marker for repolarization; therefore, definition of the zones of atrial vulnerability is more difficult to derive. To obtain such information, elaborate testing generally is required.13 14 In this article, the findings of experiments undertaken to demonstrate the zones of atrial vulnerability and to determine their relationship to BCL are described.
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Methods |
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Preparation
Twenty conditioned mongrel dogs weighing between 23 and 27 kg were anesthetized with
-chloralose 100 mg/kg IV. The dogs were intubated and ventilated with a Harvard respirator; tidal volume and respiratory rate were adjusted, and the lungs were expanded periodically to keep oxyhemoglobin saturation >90%. Ringer's lactate (500 to 1000 mL) supplemented with 20 mEq potassium chloride and 8 mEq magnesium sulfate was administered during preparatory surgery to mitigate the changes in hemodynamics and electrolytes. Blood samples were obtained periodically during an experiment to confirm that arterial blood gases, pH, and electrolytes were within physiological ranges. Body temperature was maintained by heating pads and monitored by intravascular thermistors. A right lateral thoracotomy was performed, and the heart was suspended in a pericardial cradle. An intravascular sheath was positioned in the right femoral artery for arterial blood sampling and continuous pressure measurements with an electronically calibrated strain gauge, with the midchest as the zero reference. A quadripolar catheter was attached to the epicardial surface of the right atrial appendage with two fine sutures; the distal pair was used for electrical stimulation, and the proximal pair was used to record local electric activity. A second quadripolar catheter was passed through the right femoral vein and positioned in the right atrium, providing "high" and "low" intracavitary electrograms. A bipolar catheter was attached to the right ventricular outflow tract for recording a right ventricular electrogram. (Catheters had 1.5-mm-long electrodes with 5-mm separation.) Femoral artery pressures, ECGs, and epicardial and cavitary electrograms, at a frequency response of 30 to 250 Hz, were displayed and recorded on a multichannel oscillograph at paper speeds of 100 to 150 mm/s. A dual-channel custom-designed programmable stimulator (Bloom Associates) was used to deliver separate rectangular pulses of 1-ms duration of variable current strengths (oscilloscopically calibrated) through an isolation transformer. One channel was used to deliver the drive stimuli; the other delivered the test stimuli. Drive stimuli, delivered as a train of eight, had 1-mA current strength and BCLs of 400, 300, and 200 ms, whereas the current strength of the test stimuli varied between 1 and 10 mA. When testing was performed in sinus rhythm, at least eight spontaneous atrial depolarizations (A1) were sensed before the test stimuli were delivered.
Definitions
S1 is the stimulus artifact for the basic drive; A1 is the atrial electrogram of the basic drive. S2 is the stimulus artifact for the test beat; A2 is the atrial electrogram of the premature beat. A1A1 is the basic cycle length, spontaneous or driven; (A)S1S2 is the coupling interval of the test stimulus; and A2A3 is the first return cycle after the atrial premature stimulus. Atrial diastolic threshold is the minimal current resulting in consistent atrial capture at A1A1 of 300 ms by use of an up-down-up format. AF is defined as a burst of repetitive atrial impulses having varying morphology and cycle lengths averaging <120 ms and lasting >1 second. (In preliminary experiments, the duration of AF was found to be enhanced when the hypokalemia that develops acutely in the preparation of this model is not corrected. Because short episodes of AF that spontaneously revert permit repeated studies with less hemodynamic and autonomic confounding, correction of this abnormality was felt to be desirable.) Zone of atrial vulnerability (for a given A1A1) is the interval beginning in late diastole (outer limit) and extending into early diastole (inner limit) in which AF can be induced by a single test stimulus (S2). Atrial activation time, S2-A2, of a premature beat is the interval beginning with S2 and extending through A2 recorded by electrodes close (5 mm) to the test stimulus, reflecting both latency (interval from S2 to A2) and local atrial depolarization time. Atrial relative refractory period (for a given A1A1) is taken as the longest (A)S1S2 that fails to elicit a propagated response at 1-mA current strength. Atrial effective refractory period (for a given A1A1) is the longest (A)S1S2 that fails to elicit a propagated response at a 10-mA current strength after a stepwise progression of current strengths from 1 to 10 mA and a stepwise reduction of (A)S1S2. The total duration of the relative refractory period for a given A1A1 is taken as the interval extending from the relative refractory period to the effective refractory period; the duration of the border zone is taken as the interval extending from the inner limit of zone of atrial vulnerability to the effective refractory period.
Protocol
After the atrial diastolic threshold was determined, a strength-interval curve was defined in sinus rhythm. Beginning at a coupling interval of 25 ms less than the BCL, a stimulus with a current strength of 1 mA was introduced after at least eight spontaneous atrial depolarizations. The coupling interval was then decreased at 10-ms decrements until propagation failed. When propagation failed, the coupling interval was increased by 5 ms. If the longer coupling interval also failed, it was considered to be the relative refractory period; if not, the shorter interval was so defined. This format was followed at 1-mA steps from 1 to 10 mA until the longest coupling interval that failed to propagate at 10 mA was determined. Whenever repetitive atrial depolarizations occurred, testing was repeated at the same settings. If criteria for AF were met and could be replicated at least once, the interval was included in the zone of vulnerability. In seven dogs in which AF could not be induced with this format, 10-mA stimuli were used to scan early diastole at 5-ms increments for the 50 ms above the atrial effective refractory period; the occurrence (or lack) of propagation of one or more atrial depolarizations was noted. If failure to propagate or repetitive atrial depolarizations ensued, testing was repeated at the same settings.
A similar format was followed at paced BCLs of 400, 300, and 200 ms. However, test stimuli were introduced after eight driven beats beginning at 390 ms for a BCL of 400 ms (when the spontaneous rate permitted). At coupling intervals of <300 ms, testing also was conducted at the same current strength and coupling interval with a BCL of 300 ms; at coupling intervals of <200 ms, testing also was conducted at the same settings with a BCL of 200 ms. When two or more BCLs were being tested, the order of BCLs was alternated. Whenever repetitive atrial depolarizations ensued, testing was repeated and contrasted with the findings at the other BCLs. With this format, for stimulus strengths ranging from 1 to 10 mA with 1-mA incremental steps, and at 10-ms decrements, and at 5-ms increments, strength-interval curves were determined for the three BCLs. After the strength-interval curve for a BCL of 400 ms was defined, those for BCLs of 300 and 200 ms were derived. For a BCL of 300 ms, the strength-interval curve was begun at 1 mA and at the shortest coupling already shown to capture at this current strength. The format described above was repeated and accompanied by duplicative settings at BCLs of 400 (when possible) and 200 ms. After the strength-interval curve for a BCL of 300 ms was defined, that for a BCL of 200 ms was derived, beginning at 1 mA and at the shortest coupling interval already shown to capture at this current strength. Thus, for BCLs of 400, 300, and 200 ms, strength-interval curves and zones of atrial vulnerability were compared at the same time with the same current strengths and coupling intervals (when mathematically and electrophysiologically possible).
In nine dogs, diastole also was scanned with 10-mA stimuli at 5-ms increments for the 50 ms above the effective refractory periods for these BCLs. At this stimulus strength, the BCLs were tested at the same coupling intervals, the order of BCLs was alternated, and testing at the same settings was repeated whenever repetitive atrial depolarizations or an unexpected nonpropagation occurred.
Testing of the effects of burst pacing of eight stimuli at BCLs of 400, 300, 200, 100, and 50 ms (for a single dog in which AF could not be induced at 100 ms) at current strengths of 1 to 10 mA was done after the studies with a single extastimulus were completed.
Statistical Analyses
Values are presented as mean±SEM. Statistical differences were analyzed with Fisher's exact test for categorical variables and the paired t test for continuous variables. A value of P<.05 was considered significant for single comparisons and the value after the Bonferonni adjustment—(0.05/{[k(k-1)]/2}), where k is the number of groups—for multiple comparisons. When P was <.05 but was greater than the adjusted value, the findings were considered to be of borderline statistical significance.
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General Considerations
Table 1
summarizes the values of the salient variables describing the experimental conditions of the study. Relative and effective refractory periods shortened as BCL decreased; all differences were statistically significant (P<.008) except for the relative refractory period at a BCL of 400 ms compared with that at 300 ms.
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In 19 of the 20 dogs (95%), AF was produced by a train of eight stimuli at a cycle length of 
100 ms with a current of 
10 mA. In 16 dogs (80%), AF was induced with a single extrastimulus at a BCL of 200 ms; in 11 dogs (55%), at 300 ms; and in 9 dogs (45%), during spontaneous beating. AF also was evoked at a BCL of 400 ms in 9 of 15 dogs (60%) in which the spontaneous rate permitted reliable pacing at this cycle length. When AF was induced by a single extrastimulus at a BCL other than 200 ms, it also was induced at 200 ms. Although overall AF was evoked more readily by an extrastimulus when the heart was driven than when it was beating spontaneously (80% versus 45%; odds ratio, 4.9; 95% CI, 1.0 to 26.5; P=.048), there was no difference in the subset of experiments in which atrial diastole was scanned with a 10-mA stimulus incrementally and decrementally: 100% induction of AF in spontaneously beating hearts, 100% at a BCL of 200 ms, and 60% at a BCL of 300 and/or 400 ms.
Zones of Atrial Vulnerability
The induction of AF generally occurred in sharply defined, reproducible periods. Fig 1 shows a representative example of the zone of atrial vulnerability. Fig 1B shows the induction of AF at a coupling interval of 135 ms (the outer limit of zone); Fig 1E, at 120 ms (the inner limit of zone). Fig 1F and 1G displays atrial stimulation within the border zone at a coupling interval less than the inner limit of the atrial vulnerability zone, which results in atrial activation without induction of AF.
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Cycle Length Relationships
Table 2 and Fig 2 summarize the relationships of AF zones to BCL. Figs 3 through 7 show the relationships found in one experiment. In the figures, at BCLs of 400, 300, and 200 ms, the effects of a single extrastimulus at the same coupling intervals and current (1 mA) are compared. Figs 3 through 5 show that the zone of atrial vulnerability extends from 140 to 125 ms at a BCL of 400 ms, whereas at a BCL of 300 ms, AF is observed only at a coupling interval of 140 ms. As shown, at a BCL of 200 ms, AF is not induced at these coupling intervals. Only at the shortest coupling interval (125 ms) in this sequence are repetitive atrial depolarizations observed at a BCL of 200 ms and then just four beats having an interectopic interval averaging >200 ms.
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Table 2 and Fig 2 display the average values of the defining features of the zones of atrial vulnerability in all dogs in which AF was induced. Table 2 gives the results of the analyses in which the variables are compared for those dogs in which AF was induced at more than one cycle length. The limits of the zones increased as BCL lengthened, with a significant difference occurring when outer zone limits at 200 ms were compared with those at 400 ms. The duration of the AF zones also lengthened as BCL increased, with a significantly longer duration occurring with spontaneous beating, which had an average cycle length of 440 ms, compared with that at 200 ms. In contrast, the border zone between the inner limit of the AF zone and the effective refractory period decreased. The result of the differing trends was that the overall interval from the outer limit of the zone of AF to the effective refractory period did not change for the BCLs studied.
Relation of Borders of the AF Zone to Atrial Refractoriness
Table 3 summarizes the relationship of the AF zone borders to the relative and effective periods of the atrium. The outer limits of the zone are shown to be about the same as the relative refractory periods for all cycle lengths. Small but not statistically significant differences were evident, consistent with the expected variation related to the definitions of refractoriness and the techniques of the testing method. The actual relative refractory period begins when a stimulus fails to elicit a response at atrial diastolic threshold, whereas the relative refractory period in this study was taken as the interval at which a response was not elicited at 1 mA, an intensity more than two times this value. The small and directionally opposite differences between spontaneously beating AF outer border limits and the relative refractory periods may relate to issues of sensing and conduction when a test stimulus is coupled to a spontaneous atrial impulse.
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In contrast, the inner limit of the zone was not the atrial effective refractory period. As noted, the differences between the AF vulnerable period inner limit and the atrial effective refractory period created a distinct border zone that increased as cycle length decreased.
Atrial Activation Times
The time at which a delay between the stimulus artifact and local atrial depolarization (latency) occurs can serve as a marker for the beginning of the relative refractory period15 and therefore can be viewed as a surrogate for the development of atrial vulnerability. Figs 6 and 7 illustrate the relation between atrial activation time (latency and local depolarization) and atrial vulnerability. When atrial activation time is 110 ms, AF occurs at a coupling interval of 115 ms with a BCL of 200 ms (Fig 6A) or at a coupling interval of 130 ms with a BCL of 400 ms (Fig 7A); AF is not observed with a shortening of atrial activation time, which occurs despite a reduction of coupling interval at the same BCL (Fig 6B), or at the same coupling interval but different BCLs (Fig 7B and 7C).
The relation of atrial activation time to BCL is demonstrated in Fig 7 and summarized in Fig 8. As Fig 7 shows, at a coupling interval of 130 ms and a BCL of 400 ms, atrial activation time is 110 ms, and a burst of repetitive atrial depolarizations ensues (Fig 7A); at the same coupling interval but with shorter BCLs, atrial activation times are shorter, and atrial repetitive responses are less evident (Fig 7B and 7C). Fig 8 shows the average atrial activation times for BCLs of 400, 300, and 200 ms at a coupling interval of 141±3 ms and a current intensity of 2.9±0.4 mA. The atrial activation times are longer with increased BCLs (all P<.001).
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P<.001 vs 200 ms; 
P<.001 vs 300 ms.
Characteristics of the Border Zone
The hallmark of the AF border zone was the abrupt cessation of AF inducibility by stimuli still able to evoke atrial extrasystoles at shorter coupling intervals. Although the explanation for this occurrence was not always evident (Fig 1F and 1G), two paradoxical phenomena were often observed: local excitation appeared to improve despite shorter coupling intervals (Fig 6), and low-intensity stimuli produced excitatory responses when those of a higher intensity failed. Fig 9 shows that stimuli with an intensity of 1 and 2 mA delivered at a coupling interval of 90 ms, falling within the border zone at a BCL of 200 ms, produced an extrasystole, whereas a 5-mA stimulus did so intermittently and a 10-mA stimulus did not produce an extrasystole.
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AF Produced by an Extrasystole Versus Rapid Burst Pacing
As noted, AF was almost invariably produced by rapid atrial stimulation. Compared with AF produced by a single extrasystole, AF produced by burst pacing was faster and appeared to have more disorganized and longer-lasting episodes. This is illustrated in Fig 10; under the same conditions, eight 10-mA stimuli with a BCL of 100 ms evoke AF, with the atrial electrogram showing more rapidly occurring and more disorganized waveforms than AF produced by a single impulse of 10 mA delivered 130 ms after an eight-beat drive with a BCL of 300 ms.
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Discussion |
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The present study demonstrates that zones of atrial vulnerability can be defined experimentally and that the duration and borders of these zones can be related to heart rate. As heart rate decreases (BCL lengthens), the outer limit (the latest time in diastole when AF can be evoked with a single extrastimulus) and the duration of the zone increase. The outer limit of the zone approximates the relative refractory period for the BCL, but the inner limit (the earliest time in diastole when AF can be evoked with a single extrastimulus) is not the effective refractory period for the BCL. A border zone can be defined that is bounded by the inner limit of the zone of atrial vulnerability and the effective refractory period for a BCL. The border zone tends to shorten as BCL lengthens; the magnitude of this decrease appears to be comparable to the increase in the duration of the atrial vulnerability zone so that the interval from the beginning of the border zone to the end of atrial vulnerability (the total duration of the relative refractory period) remains constant (at least for the BCLs studied).
The development of a delay in local atrial activation time (the interval defined by the stimulus artifact of the test stimulus and the apparent end of the local atrial electrogram), which reflects primarily an increase in latency (the interval defined by the stimulus artifact and the apparent beginning of the local electrogram), can be viewed as a marker for the beginning of the relative refractory period15 and therefore could be taken as a surrogate for the development of atrial vulnerability. Not unexpectedly, the duration of atrial activation times for the same coupling interval was also found to be longer as BCL increased, providing further evidence, albeit indirect, for the extension of the zones of atrial vulnerability with an increase in BCL.
Seemingly paradoxical electrophysiological phenomena were observed within the border zone. The loss of atrial vulnerability with the persistence of excitability that occurred with shortening of the coupling interval is itself surprising. However, in early investigations of AF and in studies in which atrial and ventricular strength-interval and strength-duration relations were defined, transient "dips," lower stimulus intensity requirements to elicit an extrasystole, were observed at short coupling intervals.14 15 Improvement of conductivity at short test intervals, like those observed in our studies, also have been described in animals16 and humans17 and have been considered manifestations of "supernormal" conduction. The failure of high-intensity stimuli to elicit an atrial extrasystole when one of a lower intensity is successful also has been described and referred to as the "disappearance phenomenon"13 14 ; this occurrence has been observed with stimuli having intensities considerably higher than those used in this study at a time when AF could still be induced.13 14 Thus, during the interval defined by the border zone, the threshold of excitation and for eliciting the disappearance phenomenon might decrease and local conductivity might improve, conditions that would protect against the development of AF.6 7 8 The reason for the shortening of this border zone of reduced AF vulnerability as cycle length increases, which would enhance the risk of early diastolic extrasystoles evoking AF, is not clear.
Despite the extensive body of clinical and laboratory investigations of AF, this study is the first to show the presence of clearly defined, cycle-length–related zones of AF. Several factors may account for this. Unlike the ventricle, for which the zone of vulnerability is clearly defined by the T wave,12 the atrium lacks such an ECG marker, relegating studies of atrial vulnerability to the electrophysiology laboratory. Early electrophysiological investigations modulated test stimulus intensity and duration but did not compare the effects of BCL on the occurrence and timing of AF.13 14 Although more recent investigators have studied the effects of BCL on AF, they have failed to modulate pulse duration and intensity,9 10 generally delivering stimuli of an intensity insufficient to evoke AF over a broad range of coupling intervals. Moreover, as we found in our initial experiments in this investigation, merely modulating stimulus intensity is insufficient to define the zones. Because of the complexity of the relationships between stimulus intensity and the thresholds for evoking an extrastimulus or AF, atrial diastole must be scanned with stimuli of different intensities to determine the zones of atrial vulnerability. In our study, only a 1-ms pulse duration, which was held constant for all studies, was used. Strength-interval relations were determined by use of an up-down protocol, and BCL was changed for the same coupling intervals and stimulus strengths. Because pulse duration was held constant and a maximum stimulus current intensity of only 10 mA was used, it is possible that zones of different durations and borders for the BCL studied would have emerged if a more elaborate protocol had been used. However, the concept that develops from these investigations, that atrial vulnerability zones lengthen and extend later in diastole with increased BCL and occupy an increased percentage of the total duration of the relative refractory period, is not likely to change with additional perturbations, at least not for the BCLs studied.
The findings of the present study are consistent with the expectations based on recent investigations that substantiated the multiple wavelet theory of AF with activation maps6 7 and demonstrated that the induction and persistence of AF can be related to the "wavelength of the cardiac impulse."8 18 With increasing BCL, the outer limit of the zone of AF occurs later in diastole, as expected from the lengthening of the relative refractory period with an increase in cycle length.19 During this period, conduction slows, which is reflected in some measure by the lengthening of the atrial activation time, as observed in our study. Moreover, as BCL increases, recovery of excitability is less homogeneous.5 Thus, as heart rate slows, a premature atrial impulse is more likely to encounter conditions that favor multiple reentry. A competing influence is the lengthening of the functional refractory period with an increase in BCL, which would tend to increase the wavelength of the impulse.18 At very rapid heart rates, the heterogeneity of recovery of excitability also increases.5 As shown in our study, when AF was induced with rapid burst atrial stimulation in contrast to that induced by a single atrial extrastimulus at a longer BCL, the waveforms were more disorganized and AF lasted longer, which is consistent with the presence of an increased number of wavelets. Of interest, AF induced with a single extrastimulus at a long BCL often began with regular waveforms before degenerating into a more typical pattern; regular repetitive depolarizations also have been observed to precede the development of experimental ventricular fibrillation.20 21 These findings might be explained by the initial development of a focal reentry created by the electrophysiological conditions. In the presence of a functionally disturbed electrophysiological environment, fractionation of impulses from such a reentrant circuit might quickly result in multiple reentrant circuits with the typical ECG pattern of AF.
Clinical Implications
Our findings appear to dispute earlier clinical investigations. In one of these studies, atrial flutter was found to be inducible when BCL was reduced.11 Typical atrial flutter, however, is mechanistically different from AF; atrial flutter is usually characterized by a single reentrant circuit with an "excitable gap,"22 which may require a critical array of electrophysiological conditions to evoke. In contrast, the milieu that favors AF, a heterogeneity of the recovery of excitability and a short wavelength of the atrial impulse, may be created by myriad combinations of BCLs and coupling intervals. In the two clinical studies in which shortening of the BCL favored AF, the findings during spontaneous beating were contrasted with those obtained with pacing at a faster rate.9 10 As we found when a limited protocol for inducing AF was used, AF was more readily evoked with an extrastimulus if the BCL was electrically driven. Perhaps this is related to the persistence of some electric effects of the driven beats.15 Nevertheless, when only electrically driven BCLs are compared, basic cycle lengthening favored induction of AF later in diastole and increased the duration of the zone of atrial vulnerability for the same coupling interval and stimulus current strength.
A potential limitation of cycle length relationship studies is the observation that a steady state for myocardial refractoriness may not occur for a few hundred beats after BCL has been changed.23 However, those studies also demonstrate a plateau of the interval–heart rate curves evident at eight beats, the number of beats after which test stimuli could be introduced reliably.23 Also, our observations do not dispute the notion that tachycardia itself creates conditions that favor AF. In fact, our own findings, particularly those in which AF induced by an extrastimulus is contrasted with those produced by rapid burst pacing, support such a relationship. Thus, slowing heart rate creates conditions that favor the occurrence of AF; some of these conditions are replicated at rapid heart rates.
Our findings may have relevance in the treatment of AF. Drugs used for paroxysmal AF that slow heart rate, such as ß-blockers or calcium channel blockers, might increase the risk of AF recurrence. There is some evidence to suggest that verapamil may actually do this.24 Conversely, atrial underdrive pacing may be of value in individuals with bradycardia-related AF.25 Of course, the implications of our studies must be tempered by the limitations of extrapolating the findings of an acute animal study to humans, particularly because the anesthetized dog is not a bradycardic model. Nevertheless, the strength-interval relations of the human atrium, at least for BCLs of 300, 450, and 600 ms, conform to the findings in our study: relative and effective refractory periods relate positively to BCL, and the total duration of the relative refractory period does not change for these BCLs.26
If slowing heart rate in the presence of nearly physiological conditions with an otherwise normal heart produces functional changes that favor AF, bradycardia might be especially detrimental when the atrium is abnormal. Some individuals with sinoatrial dysfunction have sinus bradycardia for decades before they develop paroxysmal AF.27 When individuals with bradycardia undergo the cardiac sclerodegenerative changes associated with aging,3 which might produce shortening of atrial refractoriness,28 29 30 loss of rate adaptation of the atrial refractory period,31 and abnormalities of atrial conduction,30 32 33 they might become especially at risk for AF. These speculations, however, can be tested only in a clinical setting.
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Acknowledgment |
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We express our appreciation to Daisy Frankson, Heidi Kleinbart, and Jane Parkenton for their secretarial assistance and to Charla Puryear for preparing the illustrations.
Received January 9, 1996; revision received March 13, 1996; accepted March 26, 1996.
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References |
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1. Rubenstein JJ, Schulman CL, Yurchak PM, DeSanctis RW. Clinical spectrum of the sick sinus syndrome. Circulation.. 1972;46:5-13.
2. Mazuz M, Friedman HS. Significance of prolonged electrocardiographic pauses in sinoatrial disease: sick sinus syndrome. Am J Cardiol.. 1983;52:485-489.[Medline] [Order article via Infotrieve]
3.
Davies MJ, Pomerance A. Pathology of atrial fibrillation in man. Br Heart J.. 1972;34:520-525.
4. Le Heuzey JY, Boutjdir M, Gagey S, Lavergne T, Guize L. Cellular aspects of atrial vulnerability. In: Attuel P, Coumel P, Janse MJ, eds. The Atrium in Health and Disease. Mount Kisco, NY: Futura Publishing; 1989:81-94.
5. Han J, Millet D, Chizzonitti B, Moe GK. Temporal dispersion of recovery of excitability in atrium and ventricle as a function of heart rate. Am Heart J.. 1966;71:481-487.[Medline] [Order article via Infotrieve]
6. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am Heart J.. 1959;58:59-70.[Medline] [Order article via Infotrieve]
7. Moe GK. On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Phamacodyn Ther.. 1962;140:183-188.
8. Allessie MA, Rensma PL, Lammers WJEP, Kirchoff CJHJ. The role of refractoriness, conduction velocity, and wavelength in initiation of atrial fibrillation in normal conscious dogs. In: Attuel P, Coumel P, Janse M, eds. The Atrium in Health Disease. Mount Kisco, NY: Futura Publishing Co, Inc; 1989:27-41.
9.
Wyndham CRC, Amat-Y-Leon F, Wu D, Denes P, Simpson R, Rosen KM. Effects of cycle length on atrial vulnerability. Circulation.. 1977;55:260-267.
10. Engel TR, Gonzalez AD. Effects of digitalis on atrial vulnerability. Am J Cardiol.. 1978;42:570-576.[Medline] [Order article via Infotrieve]
11. Watson RM, Josephson ME. Atrial flutter, I: electrophysiologic substrates and modes of initiation and termination. Am J Cardiol.. 1989;45:732-741.
12. King BG. The Effect of Electric Shock on Heart Action With Special Reference to Varying Susceptibility in Different Parts of the Cardiac Cycle. New York, NY: Columbia University; Aberdeen Press; 1934. Thesis.
13. Orias O, Gilbert JL, Siebens AA, Suckling EE, Brooks CM. Effectiveness of single rectangular electrical pulses of known duration and strength in evoking auricular fibrillation. Am J Physiol.. 1950;162:219-225.
14. Brooks CM, Orias O, Gilbert JL, Siebens AA, Hoffman BF, Suckling EE. Auricular fibrillation: relationship of `vulnerable period' to `dip' phenomenon of auricular excitability curve. Am J Physiol.. 1951;164:301-306.
15. Orias O, Brooks CM, Suckling EE, Gilbert JL, Siebens AA. Excitability of the mammalian ventricle throughout the cardiac cycle. Am J Physiol.. 1950;163:272-282.
16.
Childers RW, Merideth J, Moe GK. Supernormality in Bachmann's Bundle: an in vitro and in vivo study in the dog. Circ Res.. 1968;22:363-370.
17.
Agha AS, Castillo CA, Castellanos A, Myerburg RJ, Tessler MP. Supernormal conduction in the human atria. Circulation.. 1972;46:522-527.
18.
Rensma PL, Allessie MA, Lammers WJEP, Bonke FIM, Schalij MJ. Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circ Res.. 1988;62:395-410.
19. Mendez C, Gruhzit CC, Moe GK. Influence of cycle length upon refractory period of auricles, ventricles, and A-V node in the dog. Am J Physiol.. 1956;184:287-295.
20. Moe GK, Harris SA, Wiggers CJ. Analysis of the initiation of fibrillation by electrographic studies. Am J Physiol.. 1941;134:473-492.
21. Harris SA, Moe GK. Idioventricular rhythms and fibrillation induced at the anode or the cathode by direct currents of long duration. Am J Physiol.. 1942;136:318-331.
22.
Shimizu A, Nozaki A, Rudy Y, Waldo AL. Multiplexing studies of effects of rapid atrial pacing on the area of slow conduction during atrial flutter in canine pericarditis model. Circulation.. 1991;83:983-994.
23.
Janse MJ, van der Steen ABM, van Dam RT. Refractory period of the dog's ventricular myocardium following sudden changes in frequency. Circ Res.. 1969;24:251-262.
24. Shenasa M, Kus T, Fromer M, LeBlanc RA, Dubuc M, Nadeau R. Effect of intravenous and oral calcium antagonists (diltiazem and verapamil) on sustenance of atrial fibrillation. Am J Cardiol.. 1988;62:403-407.[Medline] [Order article via Infotrieve]
25. Coumel P, Friocourt P, Mugica J, Attuel P, Leclercq JF. Long-term prevention of vagal atrial arrhythmias by atrial pacing at 90/minute: experience with 6 cases. Pacing Clin Electrophysiol.. 1983;6:552-560.[Medline] [Order article via Infotrieve]
26.
Buxton AE, Marchlinski FE, Miller JM, Morrison DF, Frame LH, Josephson ME. The human atrial strength-interval relation: influence of cycle length and procainamide. Circulation.. 1989;79:271-280.
27.
Rokseth R, Hatle L. Prospective study on the occurrence and management of chronic sinoatrial disease, with follow-up. Br Heart J.. 1974;36:582-587.
28. Cosio FG, Palacios J, Vidal JM, Cocina EG, Gomez-Sanchez MA, Tamargo L. Electrophysiologic studies in atrial fibrillation: slow conduction of premature impulses: a possible manifestation of the background of reentry. Am J Cardiol.. 1983;51:122-130.[Medline] [Order article via Infotrieve]
29. Buxton AE, Waxman HL, Marchlinski FE, Josephson ME. Atrial conduction: effects of extrastimuli with and without atrial dysrhythmia. Am J Cardiol.. 1984;54:755-761.[Medline] [Order article via Infotrieve]
30.
Capucci A, Biffi M, Boriani G, Ravelli F, Nollo G, Sabbatani P, Orsi C, Magnani B. Dynamic electrophysiological behavior of human atria during paroxysmal atrial fibrillation. Circulation.. 1995;92:1193-1202.
31. Attuell P, Childers R, Cauchemez B, Poveda J, Mugica J, Coumel P. Failure in the rate adaptation of the atrial refractory period: its relationship to vulnerability. Int J Cardiol.. 1982;2:179-197.[Medline] [Order article via Infotrieve]
32. Simpson RJ, Foster JR, Gettes LS. Atrial excitability and conduction in patients with interatrial conduction defects. Am J Cardiol.. 1982;50:1331-1337.[Medline] [Order article via Infotrieve]
33. Simpson RJ. Clinical electrophysiology of the normal and diseased human atria. In: Falk RH, Podrid PJ, eds. Atrial Fibrillation Mechanisms and Management. New York, NY: Raven Press Ltd; 1992:321-331.
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