Elucidating the Mechanisms of Atrial Flutter Cycle Length Variability Using Power Spectral Analysis Techniques
Background The mechanism of the small beat-to-beat variations in cycle length of atrial flutter in humans has not been fully explained. We investigated the beat-to-beat control of atrial flutter cycle length using time and frequency analysis techniques.
Methods and Results Mean, SD, and power spectra of atrial cycle lengths were calculated from atrial recordings in 28 patients with type I atrial flutter. In control patients, mean and SD values of atrial cycle length were 265±37 and 4.9±1.7 ms. Power spectra contained two or three major peaks with 10.6±9.2% in band 1 (0.0 to 0.18 Hz), 26.7±15.9% in band 2 (0.18 to 0.6 Hz), and 63.1±17.7% in band 3 (0.6 to 2.2 Hz). Isoproterenol infusion (n=8) increased percentage of total power in band 1 (7.1±5.6% to 25.7±18.9%, P<.001). Percentage of total power in band 1 was less in patients receiving (n=5) versus not receiving (n=18) oral β-blockers (2.2±1.9% versus 10.6±9.2%, P=.003). Standard deviation (2.5±1.3 versus 4.9±1.7 ms, P=.009) and total power (2025±1350 versus 9768±8874 ms2, P=.005) were less in heart transplant recipients (n=5) than control patients. Increases in respiratory rate (n=6) shifted band 2 frequency peak to higher frequencies (0.26±0.13 to 0.38±0.18 Hz, P<.05). Atrial cycle length was longer and monophasic action potential duration was shorter during inspiration than during expiration. Band 3 frequency peak was correlated with heart rate (r=.797, P<.0001).
Conclusions Atrial flutter cycle length variability has an underlying periodic pattern that is detected by spectral analysis. Atrial flutter is modulated on a beat-to-beat basis by an interplay between the autonomic nervous and respiratory systems and the ventricular rate.
The presence of small beat-to-beat variations in the atrial cycle length of atrial flutter has been well described.1 2 3 4 5 6 Lammers et al,5 Ravelli et al,6 and Waxman et al7 suggested that these oscillations in cycle length can be accounted for by a mechanism related to atrial stretch after ventricular contraction. These studies, however, relied solely on time domain measures to characterize the mechanisms of atrial cycle length oscillations and did not fully consider the role of other potentially important control mechanisms, including the respiratory and autonomic nervous systems. Increases in cycle length variability have been observed to occur before termination of atrial flutter and other reentrant tachyarrhythmias.8 9 10 11 Elucidation of the mechanisms that govern cycle length oscillations during stable, sustained atrial flutter may provide insight into the alterations that lead to spontaneous tachycardia termination.
Power spectral analysis is a powerful technique with which to study and quantify heart rate variability during sinus rhythm, but it has not been applied to other rhythms, such as atrial flutter. With this approach, heart rate variability during sinus rhythm has been shown to be composed of several periodic oscillations. A low-frequency component centered at 0.1 Hz is modulated by both sympathetic and parasympathetic tone, and a high-frequency component between 0.2 and 0.3 Hz is synchronous with respiratory activity and is controlled by parasympathetic outflow.12 13 14 15 16 17
We used time and frequency analysis techniques to investigate the beat-to-beat variation of atrial flutter cycle length. Modulation of the frequency peaks in the power spectra was evaluated by examining their response to physiological and pharmacological interventions. The role of short-term changes in sympathetic and parasympathetic tone was examined by studying the effects of intravenous isoproterenol and edrophonium, and the influence of long-term alterations in autonomic tone was investigated by examining atrial flutter cycle length variability in patients receiving oral β-adrenergic blockers and in heart transplant recipients. The effects of changes in the respiratory rate were evaluated during metronomically controlled breathing, and the effect of ventricular contraction on the atrial flutter cycle length power spectrum was also assessed.
Twenty-eight patients (all men; mean±SD age, 67±10 years; age range, 44 to 82 years) with spontaneous, sustained, type I atrial flutter who had been referred for cardioversion composed the study population. In the present study, type I atrial flutter was diagnosed when the inferior leads of the surface ECG contained the characteristic sawtooth appearance of flutter waves and the atrial cycle length was >176 ms.2 Patients with atrial flutter and long atrial cycle lengths (ie, >240 ms) were not excluded from this study provided that the surface ECG morphology was consistent with typical atrial flutter. The range of mean atrial flutter cycle lengths among patients in this study was 203 to 353 ms. Six of the subjects in the present study had been part of a previous report on conversion of atrial flutter with ibutilide, and eight of these subjects had been part of a previously reported study on the effects of pharmacologically induced alterations in atrial flutter cycle length and monophasic action potential duration.8 18
For the purpose of analysis, patients in the present study were divided into three groups (Table 1⇓): control subjects (n=18), β-blocker recipients (n=5), and heart transplant recipients (n=5). The control group was defined as patients with atrial flutter who had not undergone heart transplantation and were not receiving β-adrenergic blockers. The β-blocker group was defined as patients with atrial flutter who were receiving oral β-adrenergic blockers and had not undergone heart transplantation. The heart transplant group was defined as patients with atrial flutter who had undergone orthotopic heart transplantation.
The clinical characteristics of the patients are summarized in Table 1⇑. Patients in this study had established atrial flutter with a duration of 2 to 150 days. All patients had associated heart disease, including coronary artery disease, hypertension, cardiomyopathy, sick sinus syndrome, Wolff-Parkinson-White syndrome, valvular heart disease, or heart transplantation. Heart transplant recipients had received their transplanted heart at a mean of 4.9 years before the study (range, 1 to 9 years). Two of the five heart transplant patients were clinically suspected of having acute or chronic rejection. Patients were receiving atrioventricular node–blocking drugs (digoxin, β-adrenergic blockers, and/or calcium antagonists), but no patients were receiving class I or III antiarrhythmic drugs. Patients receiving β-adrenergic blockers were on chronic maintenance oral therapy with no recent change in their dose for 48 hours before the study and were not receiving digoxin. Heart transplant recipients were not receiving β-adrenergic–blocking drugs or digoxin. The left atrial diameter was enlarged (>3.5 cm) on echocardiography in 17 of 23 patients (74%). Left atrial size was not assessed in the five heart transplant recipients. The study protocol was approved by the Committee on the Conduct of Human Research of the Virginia Commonwealth University and the McGuire VA Medical Center, and all patients gave written informed consent.
Atrial recordings were obtained in the electrophysiology laboratory under quiet conditions with patients in the fasting, nonsedated state in the supine position. A steerable 7F catheter with a pair of Ag-AgCl electrodes at the distal tip and a pair of platinum ring electrodes located adjacent to the catheter tip was used for recording atrial monophasic action potentials and atrial electrograms, respectively (EP Technologies). This catheter was inserted through the femoral vein and positioned in the lateral right atrium or atrial appendage to obtain stable atrial recordings. Three or more standard ECG leads, atrial monophasic action potential recordings obtained with a DC-coupled preamplifier, and atrial bipolar electrograms were digitized at a sampling rate of 1024 Hz, displayed simultaneously on a monitor, stored on optical disk, and recorded at speeds of 100 to 200 mm/s (Cardiolab, Prucka Engineering). Respiratory activity was monitored with a bellows-type respirometer to indicate inspiratory and expiratory movements and was recorded in six patients. Right atrial pressure tracings with respiratory activity were recorded in two patients.
After baseline recordings were obtained, the following protocols were instituted in control patients to assess the effects of short-term interventions on atrial flutter cycle length variability: (1) in eight patients, recordings were made after a 10-minute intravenous infusion of placebo (D5W) at a rate of 3 mL/min; (2) in eight patients, recordings were made 3 minutes after the initiation of an intravenous infusion of isoproterenol at a dosage of 0.03 μg·kg−1·min−1; (3) in seven patients, recordings were obtained 3 minutes after a 10-mg intravenous bolus of edrophonium; and (4) in six patients, recordings were made during controlled, metronomic respiration. Patients were trained to breathe in synchrony with the sound of a ventilator placed near their head with tidal volume set at 15 mL/kg, and they controlled their respiration for 2 minutes each in random order at 12, 16, 20, or 24 breaths/min.
Data Measurement and Analysis
Data from 2-minute, continuous recordings were transferred via high-level input channels to a commercially available heart rate variability system (Predictor I, Arrhythmia Research Technology) and were redigitized at a sampling rate of 2000 Hz with analog-to-digital gain of 8000. The atrial cycle lengths were computed from the intra-atrial electrogram signal using a template-matching criterion. After manual selection of the template, atrial cycle length intervals were identified automatically based on a cross-correlation algorithm with the template. This routine resulted in 98.0% of beats being accepted as matching the template. The atrial cycle lengths also were randomly verified manually and edited using electronic calipers with recordings at 200 mm/s.
The mean, SD, range, and maximum-minimum difference of atrial flutter cycle lengths were used as time domain measures of atrial cycle length variability. Power spectra were computed automatically from the digitized interval tachogram using autoregressive techniques with a model order of 16.19 20 DC filtering was performed to remove the DC component of the signal before the data were passed to the spectral analysis routine. Power spectra were divided into three spectral bands based on a visual inspection of the location of the major peaks in the spectra. Band 1 was from 0.00 to 0.18 Hz, band 2 was from 0.18 to 0.60 Hz, and band 3 was from 0.6 to 2.2 Hz (Figs 1 and 2⇓⇓). In patients in the control group, a distinct spectral peak was present in 10 of 18 patients in band 1 and in all 18 patients in bands 2 and 3. The abscissa of the power spectrum was expressed as cycles per beat because spectral analysis was carried out on the interval tachogram. Conversion from cycles per beat to hertz was performed by dividing the frequency scale by the mean atrial cycle duration. Spectral power was expressed as milliseconds squared and as a normalized value by dividing power by the number of intervals in the recording. The power component of each spectral band, the percentage of total power in each band, and the spectral peak amplitude and frequency were calculated. The ratio of the power in band 1 to band 2 was determined analogous to studies of sinus rhythm heart rate variability in that the ratio of low- to high-frequency power provides an assessment of sympathovagal balance.16 17
In five patients in whom the effects of metronomic respiration were assessed, the beat-to-beat atrial cycle length and atrial monophasic action potential duration during atrial flutter were determined from an average of ≥25 cycles during inspiration and expiration. The monophasic action potential duration was measured with recordings at 200 mm/s from the action potential upstroke to the point at which repolarization was 90% complete.
Repeated measures ANOVA or a Student's two-tailed t test for paired data was used where appropriate to determine the significance of differences in atrial flutter cycle length variability in control patients during short-term interventions (placebo, isoproterenol, and edrophonium infusions and controlled respiration). Differences in atrial flutter cycle length variability among control, β-adrenergic blockade recipient, and heart transplant recipient groups were evaluated with the unpaired Student's two-tailed t test. When the difference in SDs between groups was significant, data were logarithmically transformed. Linear regression analysis was used to examine the relation between the mean atrial flutter cycle length and the SD of atrial cycle lengths and between the frequency of the peak in band 3 and the mean heart rate during the data recording. A value of P<.05 was considered statistically significant, and data are reported as mean±1 SD.
The spontaneous beat-to-beat variability of atrial flutter cycle lengths from a patient in the control group is shown in Fig 1⇑. The 30-second atrial cycle length–versus–time series plot demonstrates that atrial flutter is not a strictly regular rhythm. The mean atrial flutter cycle length in this patient during the 2-minute recording was 215 ms, with a 15-ms range of cycle lengths from a minimum of 208 ms to a maximum of 223 ms and a SD of atrial flutter cycle lengths of 3.7 ms. In the 18 patients in the control group, the mean atrial flutter cycle length was 265±37 ms, and the SD of atrial flutter cycle lengths was 4.9±1.7 ms (SD range, 2.7 to 8.0 ms). The amount of beat-to-beat variability in the cycle length of atrial flutter was not dependent on the atrial cycle length. The SD of atrial cycle lengths during atrial flutter was not significantly correlated (r=.290, P=.2427) by linear regression analysis with the mean atrial flutter cycle length. Patients with short atrial cycle lengths had a similar degree of atrial flutter cycle length variability as those with long cycle lengths. There was no significant difference (P=.3215) in the SD of atrial cycle lengths between those with an atrial flutter cycle length of <240 ms (mean cycle length, 228±8 ms; mean SD, 4.3±1.0 ms) and those with an atrial cycle length of >240 ms (mean, 289±26 ms; SD, 5.3±2.0 ms).
The time series in Fig 1⇑ demonstrates that in this patient, there was a periodic pattern to cycle length variability. In addition to the beat-to-beat variability, there also is a much lower frequency oscillation, which repeats every 3 to 4 seconds, or approximately eight times during this 30-second recording. The power spectrum of atrial flutter cycle lengths obtained from this patient is shown in Fig 1⇑. In this patient, the beat-to-beat variability of atrial cycle lengths is composed of two main peaks: a midfrequency peak at 0.24 Hz and a high-frequency peak at 1.16 Hz. In this patient, band 1 (0.0 to 0.18 Hz) (expressed as a percentage of total spectral power) accounted for 2.4%, band 2 (0.18 to 0.60 Hz) accounted for 54.9%, and band 3 (0.60 to 2.20 Hz) accounted for 42.9% of total spectral power.
In the 18 control group patients, mean total spectral power was 9768±8874 ms2, or 21.0±18.1 ms2/beat when normalized for the mean number of beats in each recording. The characteristics of each of the spectral bands of atrial flutter cycle length variability are reported in Table 2⇓. Bands 1, 2, and 3 accounted for a mean of 10.6%, 26.7% and 63.1%, respectively, of total spectral power, and the mean frequency peak in each of the bands was 0.006, 0.30, and 1.25 Hz, respectively.
The reproducibility of time and frequency domain measures of atrial flutter cycle length variability was assessed in eight patients by repeating recordings and measurements after a 10-minute intravenous infusion of placebo (D5W). The mean atrial flutter cycle length (267±29 versus 267±29 ms), the SD of atrial cycle length (5.5±1.8 versus 5.4±1.7 ms), and the percentages of total power in each of the bands (15.3±13.2%, 35.0±20.2%, and 48.9±18.1% versus 17.1±15.3%, 31.6±15.9%, and 50.2±20.0%) were not significantly different at baseline before versus after placebo.
The effects of sympathetic stimulation with isoproterenol on atrial flutter cycle length variability were examined in eight subjects, and the effect of isoproterenol in one of these subjects is shown in Fig 2⇑. In eight patients, isoproterenol significantly decreased the mean atrial flutter cycle length from baseline (from 258±34 to 249±33 ms, P=.0024) and significantly increased the power in band 1 (from 1219±2157 to 4364±5823 ms2, P<.001), the percentage of total power in band 1 (from 7.1±5.6% to 25.7±18.9%, P<.001), the amplitude of the spectral peak in band 1 (from 41±44 to 286±246 ms2/Hz, P<.01), and the ratio of the power in band 1 to band 2 (0.31±0.25 to 1.71±1.9, P=.0153). Isoproterenol did not significantly alter the SD of atrial flutter cycle lengths, total spectral power, or the spectral characteristics of band 2 or 3.
The effects of β-adrenergic blockade on atrial flutter cycle length variability were examined in five patients receiving chronic oral β-adrenergic blockers, and the atrial flutter cycle length power spectrum from one patient receiving a β-blocker is shown in Fig 3⇓. The time and frequency domain measures of atrial flutter cycle length variability in patients receiving oral β-adrenergic blockers were compared with those of the control group, who were not receiving β-blockers. Spectral power in band 1 (276±357 versus 1191±1647 ms2, P=.0162), percentage of total spectral power in band 1 (2.2±1.9% versus 10.6±9.2%, P=.0025), and band 1–to–band 2 power ratio (0.14±0.13 versus 0.54±0.52, P=.0292) were significantly smaller in patients receiving β-adrenergic blockers compared with control patients. The atrial flutter cycle length, SD of atrial flutter cycle lengths, total spectral power, and spectral characteristics of band 2 and 3 did not differ significantly between patients receiving β-adrenergic blockers and patients in the control group.
In seven subjects, edrophonium was given as an intravenous bolus to examine the effects of an acute increase in vagal tone on atrial flutter cycle length variability but did not produce significant changes in time or frequency domain measures. The mean flutter cycle length (257±37 versus 256±38 ms, P=.6184), power in band 2 (3323±4134 versus 1500±1047 ms2, P>.05), percentage of total power in band 2 (34.1±17.8 versus 30.6±18.5%, P>.05), amplitude of the spectral peak in band 2 (263±341 versus 271±310 ms2/Hz, P>.05), and the ratio of the power in band 1 to band 2 (0.27±0.23 versus 0.45±0.54, P=.4199) were not significantly different at baseline before versus during edrophonium. Heart rate also was not altered significantly by edrophonium (76±16 versus 78±21 bpm, P=.7066), so the absence of significant changes in cycle length variability may have been due to the lack of a significant increase in vagal tone. Four of the seven patients administered edrophonium were receiving oral digoxin.
Heart Transplant Recipients
The effects of cardiac denervation on atrial flutter cycle length variability were evaluated in heart transplant recipients (n=5), a group in which cardiac autonomic innervation is known to be diminished.21 22 A 30-second atrial cycle length–versus–time series plot and the power spectrum from a transplant patient with atrial flutter are shown in Fig 4⇓. In the heart transplant recipient, there was significantly less beat-to-beat variability in atrial flutter cycle length compared with the control patient shown in Fig 1⇑. The low-frequency cycle length oscillations seen in the time series and power spectrum from the control patient were not apparent in the recordings from the transplant patient. Comparison of time and frequency domain measures of atrial flutter cycle length variability between heart transplant and control patients revealed significantly less atrial flutter cycle length variability in heart transplant recipients. This was demonstrated by a significantly smaller SD of atrial flutter cycle length (2.5±1.3 versus 4.9±1.7 ms, P=.0089) and lower total spectral power (2025±1350 versus 9768±8874 ms2, P=.0053) in transplant recipients. Transplant recipients compared with control patients exhibited an overall reduction in power in each of the spectral bands without a significant or consistent change in the distribution of spectral power among the bands. Spectral band power was significantly less in bands 2 and 3 (429±350 versus 2417±2723 ms2, P=.0041 and 982±922 versus 6199±5461 ms2, P=.0025) and tended to be less in band 1 (629±1002 versus 1191±1647 ms2, P=.2302), but the percentages of total power in each of the bands (25.6±29.6%, 15.7±13.1%, and 59.4±32.3% versus 10.6±9.2%, 26.7±15.9%, and 63.1±17.7%) were not significantly different between transplant and control patients.
The effects of respiratory activity on atrial flutter cycle length variability were investigated in six control patients during metronomic breathing at 12, 16, 20, and 24 breaths/min. As illustrated in Fig 5⇓, increases in respiratory rate progressively shifted the frequency peak in band 2 of the power spectrum to the right to higher frequencies (from 0.26±0.13 to 0.38±0.18 Hz, P<.05). To examine whether a relation exists between variations in atrial flutter cycle length, respiratory activity, and right atrial pressure, intra-atrial pressure was recorded together with the respiratory signal and electrical activity during atrial flutter in two patients. The time course of the changes in the respiratory signal was associated with similar changes in right atrial pressure (Fig 6⇓). Right atrial pressure decreased during inspiration and increased during expiration. The beat-to-beat changes in atrial flutter cycle length and monophasic action potential duration were assessed during inspiration and expiration in five patients. The mean atrial flutter cycle length was significantly longer (263±54 versus 258±53 ms, P<.05), and the mean atrial monophasic action potential duration was significantly shorter (160±45 versus 172±50 ms, P<.05) during inspiration compared with expiration (Fig 7⇓).
Linear regression analysis was used to examine the relation between the frequency of the peak in band 3 and the ventricular contraction or heart rate. The spectral activity in band 3 was significantly correlated (r=.797, P<.0001) with mean heart rate during the 2-minute recording (Fig 8⇓).
This study analyzed the spontaneous oscillations of human atrial flutter cycle length interval on a beat-to-beat basis. The spontaneous variability was characterized in the time domain and in the frequency domain using a technique that has not been applied previously to atrial flutter. Frequency domain analysis was performed by calculating spectra using an autoregressive model that both provided the power spectral density distribution and automatically calculated the number, amplitude, total power, and peak frequency of each of the oscillatory components. This spectral analysis technique allowed quantitative comparison between interventions for the purposes of physiological interpretation.
Comparison With Previous Studies
The existence of spontaneous oscillations in the atrial flutter cycle length has been demonstrated in previous studies. The mean SD for atrial flutter cycle lengths of 4.9 ms in the control group in the present study is similar to the average cycle length variation of 4.3 ms reported by Wells et al,2 of 5 ms reported by Lammers et al,5 and of 4.8 ms reported by Ravelli et al.6 In contrast to previous studies, none of the patients in the present study were receiving class I or III antiarrhythmic drugs.
The mechanisms responsible for these interval oscillations have not been fully explained. Previous studies in animals and humans have shown that spontaneous atrial cycle length interval variations are not randomly distributed but rather occur on a beat-to-beat basis in association with the QRS complex.3 4 5 6 7 These results were obtained by plotting the beat-to-beat cycle length of atrial flutter in relation to the onset of the QRS complex or by examining the effects of changes in atrioventricular conduction on atrial flutter cycle length. This approach, however, failed to recognize the presence of lower-frequency oscillations that also control the periodicity of atrial flutter cycle length on a beat-to-beat basis. The use of spectral analysis techniques in the present study disclosed the presence of two or three main oscillations controlling atrial flutter cycle length variability. In addition to the component related to the ventricular contraction (band 3), the present study also demonstrated the existence of two lower-frequency oscillations that correlated with respiratory activity and sympathetic tone.
Effects of Respiratory Activity
In the present study, it was demonstrated that the midfrequency component of atrial flutter cycle length variability, centered at 0.30±0.10 Hz, was related to respiratory activity. During controlled respiration from 12 to 24 breaths/min, increases in respiratory rate shifted the midfrequency peak to the right to slightly higher frequencies. The time course of the changes in right atrial pressure correlated with changes in the respiratory signal. As has been previously observed, right atrial pressure decreased during inspiration and increased with expiration.23 24 The reduction in right atrial pressure during inspiration that results from a decrease in intrathoracic pressure produces an acceleration of venous return to the right atrium and an increase in atrial stretch.23 24 Thus, cyclic variations in intrathoracic pressure during respiration were transmitted to the right atrium and were associated with fluctuations in flutter cycle length. Atrial flutter cycle length prolonged and atrial monophasic action potential duration shortened during inspiration when atrial stretch was increased and atrial pressure was reduced. The shortening of action potential duration as an effect of transient stretch has been observed in previous studies.25 26 27 This finding implies that beat-to-beat prolongation of atrial flutter cycle length during inspiration was not related to changes in action potential duration but was the result of changes in conduction time secondary to either increases in path length or slowing of conduction velocity. This is consistent with our previous observations that type I atrial flutter in humans has a fully excitable gap and that action potential duration is not a direct determinant of atrial flutter cycle length.18 Diminished atrial flutter cycle length variability was found in patients with orthotopic heart transplantation, a clinical model of autonomic denervation. Thus, atrial stretch resulting in an increase in path length of the reentrant circuit may not entirely account for the effect of respiratory activity on flutter cycle length. A neural mechanism may also have a role in these oscillations, possibly related to the Bainbridge reflex, in which atrial stretch results in inhibition of vagal tone.28 29 30
Role of Autonomic Tone
It is widely recognized that sinus rhythm is modulated on a beat-to-beat basis by changes in either sympathetic or parasympathetic tone.12 13 14 15 16 17 Previous reports have suggested that atrial flutter cycle length variability is independent of autonomic tone.3 4 5 6 7 These conclusions were primarily based on the time course of the spontaneous oscillations of atrial flutter cycle length and on studies that reported in six patients that autonomic blockade did not significantly alter the flutter cycle length or the effects of tilt, Valsalva maneuver, or respiratory activity on the changes in flutter cycle length.4 5 6 In contrast, the findings of the present study on the effects of autonomic interventions support the conclusion that similar to sinus rhythm, autonomic tone modulates atrial flutter cycle length on a beat-to-beat basis. Compared with patients with preserved autonomic control, heart transplant recipients and patients receiving β-adrenergic blockade had diminished beat-to-beat variability in atrial flutter cycle length as exhibited by the significantly smaller SD of atrial flutter cycle length and/or spectral band power. Isoproterenol shortened atrial flutter cycle length and altered the spectral characteristics of the low-frequency components (band 1) of the power spectra. The effects of isoproterenol to shorten the atrial flutter cycle length were likely mediated through changes in conduction velocity because shortening of atrial refractory period or action potential duration would not be expected to shorten the cycle length of atrial flutter in a reentrant circuit with a fully excitable gap.18 The changes induced by sympathetic stimulation were of very low frequency. Thus, it is not surprising that previous studies that used only time domain measures such as SD failed to recognize this effect on beat-to-beat cycle length variability. Vagal stimulation with intravenous edrophonium, a cholinesterase inhibitor, did not produce a statistically significant change in atrial flutter cycle length or cycle length variability. This may have been related to the short duration of action or weak vagomimetic effects of this agent or the dependence of its action on the level of vagal tone.
Effects of Ventricular Contraction
The high-frequency component (>0.60 Hz) of atrial flutter cycle length variability accounted for >60% of the oscillatory activity and correlated with the heart rate or ventricular contraction. Using spectral analysis techniques, the present study confirms the findings of previous investigations that used only time domain analysis and focused on the effects of the ventricular beat.3 4 5 6 7 These previous studies suggested that the effect of the ventricular beat to alter the flutter cycle length is mediated via mechanoelectrical feedback caused by atrial stretch after the onset of the QRS complex. In the present study, a component of cycle length variability related to the ventricular contraction was present in heart transplant recipients. This finding supports the conclusion that the effect of the ventricular contraction on flutter cycle length variability is not mediated via a neural mechanism.
Comparison With Sinus Rhythm Heart Rate Variability
The mechanisms identified in the present study that control atrial flutter cycle length variability have many similarities to those that govern sinus rhythm heart rate variability, despite the differing mechanisms of these rhythms: anatomic reentry versus normal automaticity. In addition to the sympathetic and parasympathetic components of sinus rhythm heart rate variability, an effect on sinus node rate related to the ventricular contraction and to changes in atrial pressure and distention has been previously recognized, particularly during atrioventricular block. This effect is termed ventriculophasic sinus arrhythmia; the PP interval containing a QRS complex is shorter than the PP interval without it; and its mechanism has been ascribed to the Bainbridge reflex.31 An increase in atrial pressure and distention during ventricular systole results in transient acceleration of heart rate due to a reflex inhibition of vagal tone. This is also postulated to be the mechanism by which inspiration increases heart rate.24 28 30 Inspiration increases venous return, withdraws vagal tone, and increases the sinus node rate via the Bainbridge reflex. Important differences in direction of the response to this stimulus are seen during sinus rhythm versus atrial flutter. Increases in atrial stretch after the QRS complex or with inspiration are associated with slowing of the atrial rate in type I flutter.4 6 A potential explanation for these differences may be related to the initial atrial rate. Ahmad and Nicoll32 showed that the direction of the response to atrial distention is dependent on the initial heart rate. When the initial heart rate is <140 bpm, intravenous saline infusions result in cardiac acceleration, whereas at more rapid initial rates, infusions slow the heart rate. The mechanism of this differential response based on the atrial rate has not been elucidated.
Spontaneous Tachycardia Termination
The mechanisms that lead a stable, sustained, reentrant tachycardia to suddenly, spontaneously terminate are not well understood. Although in the present study we did not directly examine this issue, it does suggest a potential mechanism that should be examined in future studies. Because in other, previous studies8 9 increases in cycle length variability were observed to occur before termination of atrial flutter, alterations in the control mechanisms mediating atrial flutter cycle length variability may be responsible for spontaneous tachycardia termination. Transient alterations in one of the control mechanisms or an interaction of these mechanisms may perturb the circuit sufficiently to cause increased oscillations that may become unstable and lead to termination of the arrhythmia. The degree of oscillation at a given site of the reentrant circuit forms the basis of beat-to-beat cycle length variability and may be important in the maintenance of the stability of a reentrant tachycardia.11 33 A reentrant tachycardia becomes stable and sustains itself if oscillations dampen and may terminate if oscillations become progressively greater.
The lack of a significant vagomimetic effect with edrophonium limited our ability to determine the vagal dependence of portions of the atrial flutter cycle length power spectra. Changes in atrial size during inspiration and expiration were not directly measured during atrial flutter in patients in this study and were derived from previous studies. Conduction velocity and path length of the reentrant circuit during inspiration and expiration were not evaluated. Techniques to obtain these measures during electrophysiological study in humans have not been established. In heart transplant recipients, the presence of autonomic denervation was assumed and was not directly assessed because this is difficult during atrial flutter. The possibility of reinnervation in some patients cannot be excluded with certainty.34
Spectral analysis is a powerful tool with which to evaluate the oscillatory components of atrial flutter cycle length variability. Power spectral analysis demonstrates that there is an underlying periodic pattern to spontaneous atrial flutter cycle length variability. Atrial flutter is modulated on a beat-to-beat basis by a complex interplay between the ventricular contraction and the respiratory rate possibly mediated via changes in atrial pressure and/or volume and by the autonomic nervous system. Changes in each of these control mechanisms can be detected by alterations in specific bands of the power spectrum. Sympathetic tone primarily modulates the low-frequency band; respiratory activity controls the midfrequency band; and the heart rate determines the high-frequency band. Alterations in the mechanisms mediating atrial flutter cycle length variability may be responsible for spontaneous tachycardia termination.
- Received February 22, 1996.
- Revision received May 31, 1996.
- Accepted June 13, 1996.
- Copyright © 1996 by American Heart Association
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