Autonomic nervous system and paroxysmal atrial fibrillation: a study based on the analysis of RR interval changes before, during and after paroxysmal atrial fibrillation

Federico Lombardi*, Diego Tarricone, Fabrizio Tundo, Federico Colombo, Sebastiano Belletti and Cesare Fiorentini

Cardiologia, Dipartimento di Medicina, Chirurgia e Odontoiatria, Osp. San Paolo, Università di Milano, via A. di Rudinì 8, 20142 Milan, Italy

* Corresponding author. Tel./fax: +39-02-50323145
E-mail address: federico.lombardi{at}unimi.it

Received 21 February 2004; revised 7 May 2004; accepted 18 May 2004

Abstract

Aims To evaluate the presence of an abnormal autonomic modulation before, during and immediately after paroxysmal atrial fibrillation (PAF).

Methods and results We analysed Holter recordings of 65 patients with 110 PAF episodes lasting more then 30 s. Mean RR interval, co-efficient of variation and short-term heart rate variability were measured before, during and after PAF episodes. We observed a significant correlation between the coupling interval and both the cycle length measured from 30 min up to few cycles before PAF onset, and ventricular response. When comparing the heart rate variability (HRV) before and after PAF we observed a significant reduction of the low frequency/high frequency components (LF/HF) ratio (from 6.2±7.4 to 3.2±4.1). A short–long–short cycle sequence was detectable in 37 PAF onsets associated with a greater incidence of atrial ectopic beats and a greater LF component (62±25 vs. 53±27 normalised units) in comparison to the remaining episodes. When onsets were divided for a LF/HF ratio cut-off value of >=2 to separate episodes with a predominant sympathetic, as opposed to those with a prevailing vagal (LF/HF<2) modulation, we observed opposite changes (from 9.1±7.8 to 4±3.7 and from 0.8±0.5 to 2±3.6, respectively) consistent with a recovery of a more physiological sympatho-vagal balance immediately after recovery of sinus rhythm. No changes in co-efficient of variation of ventricular response were detectable before PAF termination.

Conclusions A predominant sympathetic modulation characterises the majority of PAF onsets whereas a vagal predominance was detectable in about 30% of episodes. These patterns are no longer detectable after recovery of sinus rhythm.

Key Words: Autonomic nervous system • Heart rate variability • Sympathetic activation • Vagal mechanisms • Atrial arrhythmias

Introduction

Atrial fibrillation is a major clinical problem involving a growing number of patients with different arrhythmia-related symptoms and causing a significant social and economic impact. From a clinical point of view, atrial fibrillation has been classified as paroxysmal or persistent in relation to the modality of termination, and permanent when the efforts to restore sinus rhythm become ineffective. It is a common opinion that the time frame elapsing from the paroxysmal to the permanent form may be extremely variable and influenced by several factors such as the presence or absence of structural heart disease, atrial dimension and the duration of the arrhythmia. All these factors are recognised as a major determinant of the extent of electrical, mechanical and anatomical remodelling.1–4

An additional factor, which is often not adequately considered, is the role of the autonomic nervous system and, in particular, the pro-arrhythmic effects of sympathetic or vagal activation.5 In experimental models of atrial fibrillation, it has been possible to observe that both sympathetic and vagal activations were capable of reducing atrial refractoriness and therefore to favour re-entry. The effect on atrial refractoriness was noticed during either an increase of atrial cycle length secondary to vagal activation or during a shortening of atrial cycle length secondary to sympathetic activation.5–8 Changes in action potential duration and refractoriness could produce pro-arrhythmic effects not only in the induction but also in the perpetuation of atrial fibrillation. In addition, it cannot be excluded that the continuous and non-physiological variations of cardiac cycle duration during atrial fibrillation episodes might affect autonomic control mechanisms and atrial and ventricular remodelling, thus favouring arrhythmia maintenance.3

In the past, a few clinical studies5,7–10 were made in order to verify the existence of a link between atrial fibrillation episodes and autonomous nervous system. In most instances, particularly in subjects with paroxysmal atrial fibrillation (PAF), a pro-arrhythmic role of sympathetic or vagal activation was recognised. The inference, however, was mainly based on the analysis of the environmental context in which atrial fibrillation initiated. Accordingly, exercise-induced atrial fibrillation was considered to depend upon sympathetic activation, whereas arrhythmic episodes occurring during rest or night time were classified as of vagal origin.5 More recently, by applying heart rate variability analysis, signs of abnormal autonomic modulation of sinus node have been described in patients with episodes of atrial fibrillation during Holter recordings or after DC cardioversion.9–17

The aims of the present study were to analyse the relationship between patterns of onset of paroxysmal atrial fibrillation (PAF) and autonomic tone and to evaluate whether spontaneous recovery of sinus node could be associated with changes in indices of autonomic modulation in ambulatory patients who presented PAF episodes during Holter recording.

Methods

Study population
We analysed Holter recordings of 75 consecutive patients (mean age 67±10 years; range from 47 to 87 years, gender: 57 male) who presented 148 PAF episodes lasting at least 30 s. The clinical characteristics of individual patients were: systemic hypertension 35%, coronary artery disease 19%, sick sinus syndrome 8%, valvular heart disease 8%, no-organic heart disease 30%. Smoking habit was reported in 25 of 75 subjects. The pharmacological therapy included digoxin in four patients, Calcium antagonists in seven patients, ß-blockers in eight patients, class Ic anti-arrhythmic drugs in 17 patients, and class III anti-arrhythmic drugs in 13 patient. No therapy was given in 29 subjects.

The study was approved by the Ethical Committee of our institution and the research was conducted according to the principle of the Declaration of Helsinki.

Holter analysis
Two-channel 24-h electrocardiographic recordings were analysed using a commercially available digital scanner (Synetec, V 1.20, Ela Medical, Paris, France). The electrocardiogram was digitally sampled at 128 samples per second and inter-beat (RR) interval time series were computed and exported to an IBM PC compatible computer for further analysis. To account for the pro-arrhythmic effect of atrial ectopies and the consequent changes in atrial repolarisation, the arrhythmic episodes were classified in type 1 (T1) and type 2 (T2) according to the presence or absence of a "short–long–short" sequence before atrial fibrillation initiation. PAF episodes were also divided in day time (6:01–21:00 h) and night time episodes (21:01–6:00 h) based on the moment of onset.

The following periods were considered: 30 min of sinus rhythm before atrial fibrillation onset and 5 min of sinus rhythm immediately after spontaneous recovery of sinus rhythm. In 42 episodes lasting more then 15 min, the initial, central and final 5-min periods were also analysed.

RR interval analysis
RR interval time series were visually inspected to detect abrupt changes in cycle length due to artefacts or premature atrial or ventricular contractions. The latter could be easily recognised when the cycle interval became higher or smaller of a user-defined threshold.17 These irregularities were linearly interpolated based on the last and first cycle interval before and after the artefact, respectively, thus performing a low pass filtering procedure. Thirty-eight out of 148 PAF episodes were excluded for noise in the tracings () or for the absence of an adequate sinus rhythm period before or after the arrhythmic event. As a result 10 patients were excluded from the study.

The corrected RR interval time series were used to compute: RR interval trends before AF, short term heart rate variability (HRV) analysis before and after AF episodes, standard deviation of RR intervals and co-efficient of variations during AF. In particular, we measured the average cycle length of the 5-min period starting 30, 15, 10 and 5 min before arrhythmia onset as well as of 60th, 45th, 30th, 15th, 10th, fifth, third, second and first cycle before atrial fibrillation onset. The coupling interval was defined as the interval between the last sinus and first atrial fibrillation QRS.

Autoregressive algorithms were used to provide the number, centre frequency and associated power of the oscillatory components that characterise spectral analysis of short-term recording.17–20 Adequacy of analysis was verified by formal statistical criteria such as the Anderson's test (which verifies that all the information contained in the time series is extracted in the computation) and Akaike's criterion (which indicates the optimal order fitting the data).21 In the present study, the order of the model used to estimate power spectrum ranged between 9 and 14. As previously reported,17–20 spectral analysis of short-term recordings is characterised, in addition to a very low frequency component (VLF, 0–0.03 Hz) whose physiological meaning remains uncertain, by two major components at low (LF: 0.03–0.15 Hz) and high (HF: 0.15–0.40 Hz) frequency. LF component has been proposed18,19 and utilised, particularly when expressed in normalised units (nu), as an index of sympathetic modulation, although it might be influenced by parasympathetic modulation and baroreflex activity.19 HF, which is a measure of respiratory sinus arrhythmia, is an accepted index of vagal modulation. The ratio between the absolute power of the LF and HF component was also calculated and LF/HF ratio was used as an index of sympatho-vagal interaction. Values >2 were considered to reflect a sympathetic predominance and a reduced vagal modulation.17–20

Statistics
The data are shown as means±SD for the continuous variable or median and interquartile ranges (IQR) for skewed distributions, and as absolute or relative frequencies for categorical variables. Due to the fact that different characteristics in relation to time and type of onset, duration and autonomic pattern before PAF onsets were observed in 25 patients with multiple (range 2–8) episodes, data were analysed per event rather than per patient number. Student's t test and ANOVA were utilised for the analysis of continuous variables (overall comparison). Post-hoc pair-wise comparisons were assessed by the Bonferroni test. The Mann–Whitney U test for unpaired comparisons was used for continuous variables with a non-normal distribution. Multiple linear correlation and regression analysis were performed to evaluate the relationship between the coupling interval and either the length of pre-selected cycles before atrial fibrillation onset or the mean ventricular response of the first 30 cycles of atrial fibrillation.

A two-sided p-value <0.05 was defined as statistically significant.

Results

We analysed 110 paroxysmal atrial fibrillation episodes with a median duration of 154 min (IQR 0.5–1020 min). Sixty-five episodes (59%) started during the day time; 45 episodes (41%), started during night time. PAF episodes had a sudden onset in 73 cases (T2) whereas a short–long–short sequence was detectable in 37 cases (T1). These latter episodes were also characterised by a greater number of premature atrial contractions in the last 10 cycles before PAF (median: 2±1.8 vs. 0.9±1.5; ).

When considering all cycle length variations before T1 and T2 onset (Fig. 1), there was a small progressive, but not significant, reduction in mean RR interval. When comparing values measured 30 min and three cycles before PAF onset, mean RR interval decreased from 921±163 to 883±279 ms (). To evaluate whether the autonomic modulation could affect sinus node and atrioventricular node properties to a similar extent, we analysed the relationship between RR interval preceding PAF, the coupling interval and ventricular response during PAF. There was a significant correlation between the coupling interval and both the average RR interval values measured 30, 15, 10, and 5 min before PAF onset and the interval corresponding to the 60th, 45th, 30th, 15th, 10th, fifth, third, second, and first cycle before PAF onset. For example, the correlation co-efficient values between the coupling interval and average 10-min or the third cycle before PAF onset were, respectively, 0.44 and 0.52. There was also a significant correlation between coupling interval and the average cycle length of the first 30 cycles of PAF (; ).



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Fig. 1 Mean RR interval changes before, during and after type 1 (open triangle) and type 2 (filled symbols) paroxysmal atrial fibrillation (PAF) episodes. SR, sinus rhythm. CI, coupling interval. Corresponding times and cycle numbers are indicated on x axis.

 
HRV analysis before and after PAF episodes
Spectral analysis of HRV of the 5 min preceding and following PAF episodes is presented in Table 1. Before PAF, the mean RR interval and total power were 909±181 ms and 1685±225 ms2, respectively. LF was greater than HF with a LF/HF ratio of 6.2±7.4. After spontaneous recovery of sinus rhythm we observed, in absence of major differences in mean RR interval and total power, significant changes in LF and HF components. Consequently, LF/HF ratio significantly decreased (3.2±4.1). Neither the different pharmacological regimens nor the faster or slower (> or <600 ms) mean ventricular response to PAF were associated with a significant alteration of this pattern.


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Table 1 Spectral analysis of HRV before and after PAF episodes

 
The analysis of the HRV in relation to the type of onset revealed a greater LF component in T1 in comparison to T2 onset (62±25 vs. 53±27 nu; ). Furthermore, the duration of AF episodes with T1 onset was significantly shorter than that with T2 onset (69±98 vs. 197±238 min; ).

To better characterise autonomic modulation before PAF episodes, we divided all episodes according to a LF/HF ratio cut-off value of >=2, known to reflect a predominant sympathetic and reduced vagal modulation of sinus node. A LF/HF ratio<2 was present in 37 episodes; 20 of these started during the night time (Table 2). A LF/HF ratio >=2 was present in the majority of episodes (). Among them, 80% started during day time. A LF/HF>2 pattern characterised 78% of type 1 onset, whereas a LF/HF<2 pattern was detectable in 53% of night time episodes. The mean duration of PAF episodes divided according to LF/HF ratio was similar (180±186 vs. 141±221 min). Of interest was the finding that, when comparing short term HRV before and after PAF according to the above predefined cut-off value, a significant increase (from 0.8±0.5 to 2±3.6) or reduction (from 9.1±7.8 to 4±3.7) of LF/HF ratio was, respectively, observed (Fig. 2).


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Table 2 Number and percentage of PAF episodes in relation to time of onset, LF/HF ratio and modality of onset

 


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Fig. 2 Mean RR interval and LF/HF ratio before and after paroxysmal atrial fibrillation episodes divided according to a LF/HF cut-off ratio of >>2. This value has been used to separate episodes preceded by signs of sympathetic activation from those with signs of vagal predominance. After recovery of sinus rhythm, a more physiological sympatho-vagal balance was indicated by the reduction or increase in LF/HF ratio detectable, respectively, in both patterns of onset.

 
RR interval changes during PAF episodes
In 42 PAF episodes lasting more than 15 min, we analysed the mean RR interval, the standard deviation and co-efficient of variation in the initial, central and final 5-min segments. As indicated in Table 3, no significant changes were detectable during PAF, thus indicating that the spontaneous termination of the arrhythmic episodes was not preceded by detectable changes in ventricular response or in its variability.


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Table 3 Analysis of RR interval, standard deviation and co-efficient of variation before, during and after PAF episodes

 
Discussion

This study indicates that signs of an abnormal modulation of the sinus node precedes the onset of PAF. In the majority of cases, a predominant sympathetic and reduced vagal modulation were reflected by the presence of heart rate acceleration, predominance of LF component and increased LF/HF ratio, whereas in about one-third of cases a vagal predominance was detectable. In both instances, recovery of sinus rhythm was associated with a more physiological autonomic control of sinus node. No pseudo-regularisation of ventricular response was detectable before spontaneous termination of PAF episodes.

Autonomic activity and atrial fibrillation onset
Several studies have suggested the existence of a link between atrial fibrillation and the autonomic nervous system.5–17 Initially,5 the inference was mainly based on the analysis of the environmental context in which atrial fibrillation initiated. Accordingly, exercise-induced atrial fibrillation was considered to depend upon sympathetic activation, whereas arrhythmic episodes occurring during rest or night time were classified as of vagal origin. The multiplicity of neural and non-neural factors involved in PAF is reflected by the analysis of circadian variation of the incidence of PAF onset, maintenance and termination. Yamashita et al.22 observed different patterns during 24 h; they reported a double peak of increases of onset incidence after lunch and at midnight, whereas maintenance showed a sharp decline in the morning where most of the episodes terminated. These findings were interpreted as indirect evidence of a determinant role of vagal mechanisms for AF initiation. A similar conclusion was also inferred by Mitchell et al.23 who analysed the onset of atrial tachyarrhythmia in patients with an atrial defibrillator. In this as well as in other studies11,14–16,22,23 most the episodes occurred during night time.

In the present report, we observed a greater prevalence of PAF onset during the day time. This difference was related, in our opinion, to both patients' characteristics and inclusion criteria, which required PAF initiation and termination within the same 24-h Holter recording, rather then to a specific autonomic pattern.

Sympathetic and vagal mechanisms, by reducing atrial effective refractory period, may facilitate arrhythmia initiation.6–8 Sympathetic activation may exert an additional pro-arrhythmic role, by increasing atrial automaticity.7 This effect is not limited to the appearance on a surface electrocardiogram of frequent ectopic atrial beats but, as recently reported,24 may also cause an increase in the spontaneous or pacing-induced activity of ectopic foci at the pulmonary vein-atrial junction. This latter experimental finding is of great potential interest. Indeed, whereas radiofrequency ablation of the pulmonary veins has clearly emphasised the triggering role of these foci,25–27 the clinical significance of their sensitivity to adrenergic activation remains to be evaluated.

The simultaneous occurrence of frequent premature atrial beats that produce short–long–short RR interval sequence, diurnal prevalence and signs of sympathetic activation at spectral analysis of HRV in type 1 onset indicates, in our opinion, an important link between adrenergic activity, atrial automaticity and atrial fibrillation initiation. Moreover, the finding of a significant correlation between the coupling interval and both the sinus cycle length before, and the ventricular response during PAF, reflects the determinant role of the autonomic nervous system in conditioning not only sinus node activity during sinus rhythm but also atrioventricular node function during the initial minutes of PAF episodes.

HRV analysis before an after PAF
HRV analysis immediately before and after PAF indicates the presence of a major difference in spectral components known to reflect an autonomic modulation of sinus node. Signs of a predominant sympathetic, and reduced vagal, modulation of sinus node were detectable in most PAF episodes that started during the day time and were characterised by the presence of atrial ectopies, whereas a more physiological autonomic modulation of sinus node was associated with spontaneous recovery of sinus rhythm. This pattern was even more evident when comparing spectral indices of autonomic modulation in relation to a pre-selected cut-off value of LF/HF ratio used to separate episodes with a prevailing sympathetic, from those with a prevailing vagal, modulation. Two findings were worthy of interest: first, vagal predominance in the minutes preceding PAF onset was limited to about 30% of cases mainly occurring during night time; second, most of the patients presented signs of a more physiological sympatho-vagal modulation immediately after recovery of sinus rhythm, independently of the spectral pattern before PAF onset. A finding that, in our opinion, indicates that the figures of spectral components observed before PAF onset were likely to reflect a transient condition rather than the chronic effects of an underlying heart disease.

In this regard, it is important to recall that different patterns of HRV were observed before PAF onset. For example, Herweg et al.11 reported an increase in HF, reflecting an enhanced parasympathetic activity, in the minutes preceding PAF episodes occurring during night time and in young subjects with structurally normal hearts. Dimmer et al.12 analysed changes in sympatho-vagal balance in the hour preceding atrial fibrillation in patients who underwent coronary artery bypass surgery. LF/HF progressively increased in the minutes immediately preceding atrial fibrillation onset as a result of a reduction in the power of HF component. These findings led the authors to conclude that a shift in the autonomic balance with a loss of vagal tone and a moderate increase in sympathetic tone characterised the period before atrial fibrillation onset. Wen et al.13 who studied 12 patients with paroxysmal atrial flutter also reported similar findings; the analysis of the HRV in the frequency domain demonstrated an increase in the normalised value of the low frequency (LF) component and in the LF/HF ratio and a decrease in the normalised value of the HF component. These changes initiated 6 min before the onset of episodes of paroxysmal atrial flutter, thus suggesting a shift of sympatho-vagal balance toward a sympathetic predominance. Similar results were reported by Tomoda et al.14 who observed a progressive increase in LF/HF ratio from about 30 min to just before the PAF onset, in the absence of major changes in the HF component.

More relevant to the present study are the results of two recent studies.15,16 Bettoni and Zimmermann15 analysed 147 PAF episodes lasting more than 30 min and observed a phasic change in spectral indices of HRV. The LF/HF ratio showed a linear increase until 10 min before paroxysmal atrial fibrillation, followed by a sharp decrease immediately before the arrhythmia onset. This pattern was interpreted as an evidence of a primary increase in adrenergic tone followed by a late parasympathetic activation buffering the adrenergic predominance. This possibility is not in disagreement with the results of our study. Indeed, the values of LF/HF ratio measured immediately before PAF onset were the same in both our study and that of Bettoni. None of the above reports, however, analysed HRV during and after spontaneous recovery of sinus rhythm. Tomita et al.16 analysed HRV before and after PAF in patients without structural heart disease. Signs of sympathetic activation were observed before PAF episodes occurring during the day whereas a gradual increase of both LF and HF was detectable before PAF episodes occurring at night. Our results not only substantiate the pro-arrhythmic role of adrenergic activation during day time episodes but also indicate that in about 30% of PAF episodes, signs of a predominant vagal modulation are well detectable. In addition, when considering patients with multiple PAF episodes, different modality of onset in relation to the presence or absence of ectopies, time of onset and autonomic pattern were detectable. This finding confirms, in our opinion, not only the multiplicity of factors involved in PAF onsets but also that the changes in autonomic indices are transient and may vary within the same patient.

RR interval changes during PAF
In the electrophysiology laboratory, slowing or pseudo-regularisation of atrial activity often precedes spontaneous termination of induced AF episodes. To evaluate whether such a phenomenon could also occur in the clinical setting, we analysed the RR interval during the initial, central and final part of PAF episodes with the assumption that a less disorganised atrial activity could be reflected by a pseudo-regularisation of ventricular response. Our results indicate that neither mean RR interval nor its variability is reduced before PAF termination. It therefore seems unlikely that neither an improvement in haemodynamic conditions and consequent changes in autonomic activity, nor a variation in autonomic control of the atrioventricular node might play a major role in facilitating arrhythmia termination.

Study limitations and conclusions
The heterogeneity of patients enrolled in the study in relation to the underlying heart disease and drug treatment represents one of the major limitations of this study. In addition, Holter recordings were performed without documentation of physical activity or synchronisation of feeding time or of retiring to bed. No information on respiratory pattern during day and night time was available, thus preventing the possibility of determining the influence of breathing pattern on spectral components.19 The effects of specific drugs on the observed results was not individually assessed given the variety of treatments and the impossibility of assessing patient compliance.

Nevertheless, the study indicates the presence of important alterations of autonomic control mechanisms in the minutes preceding PAF onset as well as the recovery of a physiological sympatho-vagal balance immediately after arrhythmia termination. Autonomic mechanisms may also condition the ventricular response of PAF episodes. As to the mechanisms involved in PAF episode termination, no inference on a possible role of autonomic tone was suggested by the analysis of ventricular response before spontaneous recovery of sinus rhythm.

Acknowledgments

This work was partially supported by a 2002 Grant of MIUR.

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