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(Circulation. 1997;96:1209-1216.)
© 1997 American Heart Association, Inc.

Articles

Heart Rate Variability in Patients With Atrial Fibrillation Is Related to Vagal Tone

Maarten P. van den Berg, MD; Jaap Haaksma, BSc; Jan Brouwer, MD; Robert G. Tieleman, MD; G. Mulder, PhD; ; Harry J. G. M. Crijns, MD

From The Thorax Center, Department of Cardiology, University Hospital Groningen, and the Department of Experimental Psychology (G.M.), University of Groningen, Groningen, the Netherlands.

Correspondence to Dr M.P. van den Berg, The Thorax Center, Department of Cardiology, University Hospital Groningen, PO Box 30.001, 9700 RB, Groningen, Netherlands. E-mail J.Haaksma{at}thorax.azg.nl

	Abstract

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Background Analysis of heart rate variability (HRV) has thus far not been applied in patients with atrial fibrillation, probably because of the presumed absence of any form of patterning of the ventricular rhythm, particularly vagally mediated respiratory arrhythmia. However, such patterning is theoretically conceivable given the function of the atrioventricular node in atrial fibrillation and its susceptibility to autonomic influences.

Methods and Results Sixteen patients (mean age, 56±4 years) with long-term atrial fibrillation on fixed doses of digoxin or verapamil were studied; 12 healthy men in sinus rhythm were used as control subjects. HRV (standard deviation of RR intervals [SD], coefficient of variance [CV], the root-mean-square of successive difference [RMSSD], and low-frequency [LF] and high-frequency power [HF]) was analyzed during 500 RR intervals at baseline, after administration of propranolol (0.2 mg/kg IV), and after subsequent administration of methylatropine (0.02 mg/kg IV). HRV at baseline and changes in HRV after methylatropine were then related to vagal tone (vagal cardiac control), quantified as the decrease in mean RR after methylatropine. Baseline HRV was higher in the atrial fibrillation group than in the control group; after propranolol, HRV increased in both groups; after methylatropine, HRV neared zero in the control group, whereas it returned to baseline values in the atrial fibrillation group. SD, RMSSD, LF, and HF at baseline were significantly (P<.05) correlated with vagal tone in the control group but also in the atrial fibrillation group (correlation coefficients of .60, .61, .57, and .64, respectively). Even stronger correlations were observed between changes in these parameters after methylatropine and vagal tone, particularly in the atrial fibrillation group (correlation coefficients of .89, .87, .72, and .90, respectively).

Conclusions This study shows that HRV in patients with atrial fibrillation is related to vagal tone.

Key Words: fibrillation • atrioventricular node • heart rate • nervous system, autonomic

	Introduction

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In recent years, analysis of heart rate variability (HRV) has emerged as a valuable noninvasive tool for assessment of autonomic status. It has become increasingly clear that various cardiovascular disease states are associated with typical changes in HRV. For instance, heart failure is characterized by HRV changes indicative of sympathetic activation as well as vagal withdrawal.^{1 2 3} The same holds true for coronary artery disease⁴ and valvular heart disease.⁵ Moreover, HRV has a prognostic value,⁶ and pharmacological interventions may improve HRV, in particular the vagal components.^{7 8 9}

The above findings, however, pertain only to patients in sinus rhythm. A paucity of data exists as to HRV in patients in atrial fibrillation. In fact, atrial fibrillation is generally considered an exclusion criterion for analysis of HRV. Presumably, the apparent total irregularity of ventricular rhythm in atrial fibrillation has daunted most investigators. Yet, atrial fibrillation is very common, particularly in patients with heart failure, and also in patients with coronary artery disease and valvular heart disease.¹⁰ In a single study, the prognostic value of several commonly used HRV parameters was analyzed in patients with valvular disease and atrial fibrillation; interestingly, a decreased HRV was associated with an adverse clinical course.¹¹ However, basic methodological and mechanistic aspects were not addressed. In particular, it is unknown whether at all, let alone to what extent, the established time and frequency domain HRV parameters reflect autonomic status in patients with atrial fibrillation. In the present study we addressed this issue, focusing on the vagal limb of the autonomic nervous system. Sequential pharmacological autonomic blockade was performed in 16 patients with atrial fibrillation by first administering propranolol and then methylatropine; after thus eliminating confounding sympathetic effects, vagal tone and the relation of vagal tone with HRV could be determined. Twelve healthy men served as control subjects.

	Methods

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Patients
Male or female patients 18 years of age or older who were hospitalized for elective electrical cardioversion of long-term atrial fibrillation were eligible for the study. Patients with suspected or documented atrioventricular (AV) nodal conduction disturbances were excluded as well as patients with contraindications for administration of propranolol and atropine. Healthy men were used as control subjects; exercise testing and echocardiography were performed to exclude cardiovascular disease in these subjects. The study was approved by the institutional review board, and written informed consent was obtained from each participant before entry into the study.

Experimental Protocol
The patients were in the postabsorptive, unsedated state and lying supine. During the experiment, ventricular rhythm was continuously recorded with a Marquette Holter recorder (Series 8500). Three ECG leads were used: modified leads V₁, V₅, and aVF. After recording of baseline rhythm for 15 minutes, sequential pharmacological autonomic blockade was performed; a bolus of propranolol (0.2 mg/kg IV) was administered to achieve complete ß-blockade, and, after 15 minutes, a bolus of methylatropine (0.02 mg/kg IV) was added for complete vagal blockade, thus also obtaining complete autonomic blockade.¹² The administration of propranolol and methylatropine was unblinded. After the experimental protocol, patients underwent electrical cardioversion as described previously.¹³ Recordings and autonomic blockade were performed in a similar fashion in the control subjects.

Data Analysis
The recordings were processed by an experienced analyst using a Marquette Laser Holter system (Series 8000XP). Thereafter, three episodes of atrial fibrillation (baseline, after propranolol, and after methylatropine), each containing 500 ventricular intervals, were transferred to a postprocessor developed at our institute.¹⁴ To ensure stable conditions, particularly after drug administration, in each instance the last 500 intervals near the end of each 15-minute recording period were selected. To verify stability, mean heart rate during the first 50 intervals and the last 50 intervals during each period were compared; a mean difference <5% was considered acceptable. HRV analysis was then performed as described previously^{8 9 14} and in accordance with the recommendations from the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.¹⁵ Discrete Fourier transformation was used for the analysis of the frequency (spectral) domain parameters. Inherent to the purpose of the study, we could not use normal-to-normal (NN) intervals in the atrial fibrillation group; instead, ventricular-to-ventricular (RR) intervals were used. Furthermore, since changes in heart rate per se such as occur after administration of propranolol and methylatropine may affect HRV, at least during sinus rhythm, two additional parameters were calculated: (1) the coefficient of variance (CV), defined as the standard deviation of RR intervals/mean RR, and (2) the coefficient of component variance (CCV), defined as the square root of power/mean RR.^{4 16} The time and frequency domain parameters thus studied are listed in Table 1. HRV in the control subjects was analyzed in the same way. Obviously, NN intervals could be used in the control subjects.

View this table: [in this window] [in a new window]   Table 1. Definitions of Time and Frequency Domain Parameters of Heart Rate Variability

Vagal tone was assessed with the use of a previously described method.^{16 17 18} According to this method, vagal tone, referred to as vagal cardiac control (VCC), can be quantified as the cardiac response to additional vagal blockade in the setting of ß-blockade, that is, after elimination of sympathetic effects. VCC was thus calculated as mean RR after propranolol minus mean RR after methylatropine.

Finally, we sought to account for the effect of digoxin on HRV because it was argued that the established vagomimetic effect of digoxin in atrial fibrillation^{19 20} constituted a possible confounding factor. Hence, the above analyses were also performed comparing the patients with and those without digoxin.

Statistical Analysis
Data are given as mean±1 SEM, unless indicated otherwise; medians with range are given in case of non-normally distributed values. Pearson's test and Spearman's rank correlation test were used to calculate correlation coefficients between HRV parameters at baseline and VCC. Similarly, correlations between changes in HRV parameters after administration of methylatropine and VCC were calculated. Findings in patients with and without digoxin were compared with the use of ANOVA. Statistical analyses were conducted with SPSS-PC, version 5.01 (SPSS Inc); values of P<.05 were considered to be significant.

	Results

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Patients
Sixteen patients were included in the study. Clinical characteristics are presented in Table 2. Thirteen patients used digoxin, verapamil, or a combination for control of the ventricular rate. Three patients used no such drugs. There were no significant differences in clinical characteristics between the patients with and those without digoxin. The control group consisted of 12 men (mean age, 33±2 years). Besides transient, mild blurring of vision and dryness of the mouth in some subjects, administration of propranolol and methylatropine was uneventful both in patients and control subjects. Cardioversion of atrial fibrillation to sinus rhythm was achieved in 13 patients. All these patients had a PR interval <0.22 second. All recordings were technically adequate (<1% noise or ventricular ectopic beats) and stationary.

View this table: [in this window] [in a new window]   Table 2. Clinical Characteristics

Heart Rate Variability
Effect of Autonomic Blockade on HRV
The results of the sequential administration of propranolol and methylatropine on heart rate and the time and frequency domain HRV parameters are shown in Fig 1 and Fig 2. Baseline mean RR was short compared with baseline mean NN. Nevertheless, mean RR and mean NN prolonged comparably after propranolol. In contrast, the response to methylatropine differed; although both mean NN and mean RR shortened after methylatropine was added, the effect on mean NN was more marked. Whereas mean RR returned to baseline, mean NN reached a value well below baseline. Baseline HRV parameters, both time and frequency domain, were high in the atrial fibrillation group compared with the control group. Increases in HRV parameters were observed after propranolol in both groups, although the extent varied. After addition of methylatropine, HRV parameters decreased again; however, values in the control group virtually neared zero, whereas values in the atrial fibrillation group returned to near baseline. Representative examples of the power spectra at baseline and after drug administration in a single atrial fibrillation patient and a control subject are shown in Fig 3.

View larger version (18K): [in this window] [in a new window]   Figure 1. Mean ventricular interval (mean RR) and time domain parameters of heart rate variability (standard deviation of RR intervals [SD], coefficient of variance [CV], and root-mean-square of successive difference [RMSSD]) at baseline (BL) and the effects of sequential administration of propranolol (P) and methylatropine (M) in the atrial fibrillation group (dotted lines) and the control group (solid lines). Note: Error bars in the control group after methylatropine were too small to be depicted with the exception of the mean ventricular interval.

View larger version (20K): [in this window] [in a new window]   Figure 2. Frequency domain parameters of heart rate variability (high-frequency power [HF], low-frequency power [LF], and coefficient of component variance of high-frequency power [CCVHF] and low-frequency power [CCVLF]) at baseline (BL) and the effects of sequential administration of propranolol (P) and methylatropine (M) in the atrial fibrillation group (dotted lines) and the control group (solid lines). Note: Error bars in the control group after methylatropine were too small to be depicted.

View larger version (36K): [in this window] [in a new window]   Figure 3. Power spectra at baseline (BL) and after sequential administration of propranolol (P) and methylatropine (M) in a representative patient with atrial fibrillation (left panels) and a control subject (right panels). Note that the scale on the y-axis is adjusted in the lower right panel. Total spectral power at baseline is clearly higher in the patient with atrial fibrillation. After ß-blockade is obtained by propranolol, spectral power increases in both the patient and the control subject. Adding methylatropine to propranolol, thereby obtaining complete autonomic blockade, results in almost total diminution of spectral power in the control subject. It also causes a substantial decrease in spectral power in the patient with atrial fibrillation, although spectral power does not near zero as in the control. Importantly, diminution of spectral power includes the high-frequency range (0.15 to 0.40 Hz), although the change is not confined exclusively to this range.

Correlation Between HRV and Vagal Tone
Correlations between individual parameters of HRV at baseline and VCC are given in Table 3. As expected, in the control group significant correlations existed between various parameters of HRV and VCC. In fact, all except the CV and CCV of low-frequency power (CCVLF) were correlated with VCC. More importantly, significant correlations between multiple HRV parameters and VCC were also found in the atrial fibrillation group. These included the standard deviation of RR intervals (SD), root-mean-square of successive difference (RMSSD), low-frequency power (LF), and high frequency power (HF). Correlation coefficients ranged from .57 to .64, with HF showing the strongest correlation. Correlations between changes in individual HRV parameters after administration of methylatropine and VCC are given in Table 4. Significant correlations were again observed in the control group for most parameters. Also, significant correlations were once more found in the atrial fibrillation group; with the exception of CCVLF, changes after administration of methylatropine in all other HRV parameters were correlated with VCC. Correlation coefficients ranged from .72 to .90, with HF again showing the strongest correlation. Data in individual patients with respect to HF and CCVHF are shown in Fig 4.

View this table: [in this window] [in a new window]   Table 3. Correlations Between Heart Rate Variability Parameters at Baseline and Vagal Cardiac Control

View this table: [in this window] [in a new window]   Table 4. Correlations Between Changes in Heart Rate Variability Parameters After Administration of Methylatropine and Vagal Cardiac Control

View larger version (21K): [in this window] [in a new window]   Figure 4. Relation in individual patients between baseline high-frequency power (HF) (upper left panel) and coefficient of component variance of high-frequency power (CCVHF) (upper right panel) and vagal cardiac control (VCC) and the change in high-frequency power (delta HF) (lower left panel) and coefficient of component variance of high-frequency power (delta CCVHF) (lower right panel) and vagal cardiac control after methylatropine.

Role of Digoxin
HRV parameters at baseline in patients with and those without digoxin did not differ significantly. Also, the responses of these parameters to drug administration were comparable. Finally, correlations of the individual HRV parameters with VCC did not differ between patients with and those without digoxin. Findings are summarized in Table 5.

View this table: [in this window] [in a new window]   Table 5. Effects of Propranolol and Methylatropine on Heart Rate Variability Parameters in Patients With and Without Digoxin

	Discussion

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The principal finding of this study is that HRV in patients with atrial fibrillation is significantly related to vagal tone. Whereas numerous studies have already demonstrated that HRV is a meaningful method to assess vagal tone in patients in sinus rhythm, this study is the first to show that the same holds true for atrial fibrillation patients. It may be surmised that our finding has potentially important clinical implications.

Ventricular Rhythm in Atrial Fibrillation
The clinical hallmark of atrial fibrillation is an irregularly irregular ("random") ventricular rhythm.²¹ However, controversy exists as to whether the ventricular rhythm in atrial fibrillation is truly random. Whereas some investigators contend that it is,²² others, using a variety of mathematical techniques, have shown that a certain degree of "patterning" may be present.^{23 24 25 26} Still others have investigated respiratory variations of the ventricular rhythm in atrial fibrillation.^{27 28 29 30} However, results were conflicting, both within and between the studies; respiratory patterning was an infrequent finding, and in the individuals in whom a certain degree of patterning could be demonstrated, respiration exerted inconsistent effects on ventricular rhythm. Presumably, differences in methodology played a role; it is noteworthy that in none of the studies was spectral analysis performed, this technique being very well suited for the analysis of respiratory patterning. Moreover, the role of the autonomic nervous system was not addressed. Important questions were thus left unanswered, particularly the possibility of respiratory patterning of the ventricular rhythm due to respiratory fluctuations in autonomic, that is, vagal tone. Yet, this is theoretically conceivable, given the electrophysiological principles governing ventricular rhythm in atrial fibrillation and the importance of autonomic tone. According to the prevailing concept, the principal determinant of ventricular rhythm in atrial fibrillation is the AV node, the refractoriness of the node restricting AV transmission of the atrial fibrillatory impulses.^{31 32} The irregularity of the ventricular rhythm is considered to be due to the varying degree of penetration of the atrial impulses into the AV node, thereby causing varying degrees of refractoriness ("concealed conduction").^{33 34} In addition, although direct electrophysiological data are scarce, clinical experience provides abundant evidence for a substantial effect of autonomic tone on AV nodal refractoriness. Thus, the ventricular rhythm in atrial fibrillation follows a circadian pattern,³⁵ with rates being higher during daytime, for example, during physical exercise, due to vagal withdrawal and sympathetic activity. Lowest rates are attained during the night due to high vagal tone. A depressant effect of vagal activation on AV transmission during atrial fibrillation is also apparent from the effect of vagal maneuvers, for instance, carotid sinus activation,³⁶ as well as from the rise of heart rate after administration of atropine.^{25 37}

Present Study
On the basis of the above premises, we hypothesized that analysis of HRV might be a meaningful method for assessment of vagal tone in patients with atrial fibrillation, analogous to analysis of HRV in subjects with sinus rhythm. The results of the study confirmed our hypothesis. As expected, both time and frequency domain parameters of HRV at baseline were clearly higher in the patients with atrial fibrillation than in the subjects with sinus rhythm. This reflects the overall higher degree of irregularity of ventricular rhythm in atrial fibrillation. As outlined above, irregularity of the atrial fibrillatory process per se, causing varying degrees of concealed conduction in the AV node, undoubtedly plays a crucial role in this connection. Yet, the data suggest that "hidden" within the apparent totally irregular rhythm, vagally mediated respiratory patterning of ventricular rhythm is present. Pertinent to this conclusion is the finding that vagal tone, calculated as VCC, was found to be related to multiple parameters of HRV, in particular to HF. Furthermore, changes in HRV parameters as occurred after vagal blockade with methylatropine showed even stronger relations with vagal tone. Again, HF, that is, change in HF, showed the strongest relation, the correlation coefficient being as high as .90. To put it differently, it thus appears that a substantial part of the high-frequency (0.15 to 0.40 Hz) fluctuations of the ventricular rhythm in atrial fibrillation is due to respiratory fluctuations in vagal tone. As such, our study suggests that atrial fibrillation behaves like sinus rhythm. In fact, correlation coefficients at baseline were on the average only slightly lower in the atrial fibrillation group than in the control group in sinus rhythm. At this stage, however, it should be pointed out that HRV does not appear to be an absolute measure of vagal tone in patients with atrial fibrillation. This would have required HRV to near zero after complete autonomic blockade, like HRV in the control group. Instead, a substantial degree of HRV persisted after complete autonomic blockade, which, as pointed out earlier, reflects the "inherent" irregularity of the ventricular rhythm in atrial fibrillation. Hence, HRV would appear to be a relative measure of vagal tone in patients with atrial fibrillation, with changes in HRV being significantly related to changes in vagal tone. However, having said that, it should be realized that even in subjects in sinus rhythm, HRV is not an absolute measure of vagal tone, that is, autonomic tone; it is generally recognized that HRV merely reflects fluctuations in autonomic tone rather than reflecting the mean level of autonomic tone.^{15 38} Thus, HRV, by its very underlying physiological and mathematical principles, can never provide an absolute measure of autonomic tone irrespective of the type of cardiac rhythm, for example, atrial fibrillation or sinus rhythm.

Methodological Considerations
The fact that patients were hospitalized for cardioversion to restore sinus rhythm permitted us to obtain some impression of AV nodal conduction. In all patients in whom sinus rhythm was restored, the PR interval was normal (<0.22 second). Although the presence of a normal PR interval excludes gross AV conduction disturbances, particularly in the patients with rheumatic and ischemic heart disease, the AV node may have been diseased. In addition, most patients used drugs that affect AV nodal electrophysiological properties for control of ventricular rate. These drugs included digoxin, which is also known for its vagomimetic effects.^{19 20} These factors hamper the interpretation of our findings. On the other hand, the results are even more remarkable considering these confounding factors. Correlation coefficients in the control group were somewhat lower than those reported by Hayano et al,¹⁶ who also studied healthy men. In that study, the atropine dose was individualized by carefully titrating the dose against heart rate. Also, these investigators used a metronome to control breathing. Still, our model yielded significant correlations between HRV and VCC in the control group, supporting its validity. More importantly, despite the free breathing, significant correlations were also found in the atrial fibrillation group, which in fact adds to the importance of our findings and adds to the clinical applicability of our approach. Another methodological issue is also related to respiration: Because respiration as such was not recorded, it cannot be formally ascertained that the observed high-frequency patterning of ventricular rhythm was indeed to some extent related to respiration. Finally, the use of VCC (ie, mean RR after propranolol minus mean RR after methylatropine) as a measure of vagal tone in the setting of atrial fibrillation may be subject to criticism because the cited studies^{16 17 18} referred only to sinus rhythm. Given the complex interplay discussed earlier between AV nodal input and AV nodal conduction in atrial fibrillation, the analogy between atrial fibrillation and sinus rhythm with respect to the validity of VCC may not be simply assumed. However, both experimental and clinical data support the analogy. Moe and Abildskov³⁹ have shown in a dog model of atrial fibrillation that vagal stimulation lowers ventricular rate through a concerted effect on AV nodal input and concealed conduction in addition to a direct effect on AV nodal refractoriness, with all three factors acting in the same direction. Importantly, the effect on ventricular rate was stronger when the frequency of stimulation of the vagal nerve was increased. Also, as alluded to earlier, direct vagal stimulation through the carotid sinus nerve in a patient with atrial fibrillation was shown to exert a reproducible lowering effect on ventricar rate.³⁶ These findings indicate that vagal stimulation lowers ventricular rate in atrial fibrillation in a unidirectional manner, proportional to the strength of stimulation, and hence support the validity of VCC as a measure of vagal tone in atrial fibrillation.

Conclusions and Implications
Using a simple noninvasive model, we were able to show for the first time that HRV in patients with atrial fibrillation is related to vagal tone. The potential value of this finding is substantial, considering the value of HRV in patients in sinus rhythm. The potential prognostic value of HRV in atrial fibrillation has already been demonstrated.¹¹ It should, however, be realized that underlying mechanisms may differ because we used rather short recordings whereas Stein et al used 24-hour recordings, thus accounting for long-term modulating factors. Analysis of HRV in atrial fibrillation might also provide important clinical information. In particular, repeated measurements comparing HRV at different times seem to be of interest. For instance, such an approach would allow for assessment of the effect of drugs with neurohumoral modulating activity,^{2 4} although one should be careful not to study drugs with concomitant, direct effects on the atrium or the AV node because these might affect HRV independent of any autonomic effect.

Received December 3, 1996; revision received February 26, 1997; accepted March 9, 1997.

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