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(Circulation. 2005;112:465-470.)
© 2005 American Heart Association, Inc.
Arrhythmia/Electrophysiology |
From Medicina Interna II and Dipartimento Scienze Cliniche, Ospedale "Luigi Sacco" (S.G., E.B., P.E.G., E.C., N.M., C.C., A.M.), and Dipartimento Scienze Precliniche, LITA di Vialba (A.P.), Universita degli Studi di Milano, Milano, Italy; Centro Cardiologico, Fondazione Monzino, Milano, Italy (P.D.B.); and Division of Cardiovascular Disease, Mayo Clinic College of Medicine, Rochester, Minn (V.K.S.).
Correspondence to Dr Stefano Guzzetti, Medicina Interna II, Ospedale "L. Sacco," Via GB Grassi 74, 20157 Milano, Italy. E-mail stefanog{at}fisiopat.sacco.unimi.it
Received November 3, 2004; revision received April 8, 2005; accepted April 12, 2005.
| Abstract |
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Methods and Results We propose a symbolic analysis series to quantify the prevalence of sympathetic or parasympathetic cardiac modulation. This analysis decomposes the heart rate variability series in patterns lasting 3 beats and classifies them into 3 categories: nonvariable, variable, and very variable patterns referred to as 0V, 1V, and 2V patterns. First, we applied this method to experimental and pharmacological conditions characterized by sympathetic activation (tilt test, handgrip, nitroprusside, and high-dose atropine administration) or parasympathetic activation (phenylephrine and low-dose atropine administration) in 60 healthy subjects. An increase in sympathetic modulation and a vagal withdrawal elicited a significant increase in 0V patterns and a decrease in 2V patterns, whereas parasympathetic dominance induced the opposite, reflecting a reciprocal sympathovagal balance. The second part of the study considered a series of 300 beats before the onset of major arrhythmic events in patients with an implantable cardioverter-defibrillator. Symbolic analysis detected an increase in the percentage of 0V patterns before the onset of major arrhythmias compared with baseline (41.6±3.9% and 24.4±2.9%, respectively; P<0.01), indicating a sympathetic prevalence. On the other hand, the 2V patterns did not decrease before major arrhythmias, suggesting the presence of nonreciprocal autonomic modulations.
Conclusions Symbolic analysis of 3 beat sequences takes into account the different time course of sympathetic and parasympathetic cardiac modulations and seems appropriate for elucidating the neural pathophysiological mechanisms occurring during the short periods that precede acute cardiac events.
Key Words: arrhythmia heart rate nervous system, autonomic
| Introduction |
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The aim of the present study was to test the ability of a nonlinear tool based on symbolic analysis of 3-beat sequences to distinguish sympathetic and parasympathetic cardiac modulation. First, a specific protocol modifying the activity of the 2 branches of the autonomic nervous system was used to verify this method. Second, this technique was then applied to evaluate the role of the autonomic system before the onset of major arrhythmias, because sympathetic activation is considered one of the factors implicated in life-threatening arrhythmias.7 The symbolic analysis method adopted consists mainly of the transformation of a time series (RR intervals) into short patterns (3 beats long), their classification, and the evaluation of their rates of occurrence.8 This type of nonlinear analysis takes into account short patterns distributed in the RR series and would seem appropriate for studying the short HRV instabilities that precede sudden cardiac events such as major arrhythmias. Although previous studies proposed other nonlinear algorithms to stratify arrhythmic risk in cardiac patients,9,10 our method provides new interpretative insights into the role played by autonomic modulation in triggering major arrhythmic events.
| Methods |
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Patients With an Implantable Cardioverter-Defibrillator
We collected 28 series of 300 RR periods (intervals between 2 RR waves of intracavitary ECG recordings) preceding ventricular tachycardia (VT) or ventricular fibrillation (VF) in patients with an implantable cardioverter-defibrillator (ICD; Medtronic Inc). The RR series were automatically stored in the device when an arrhythmic event required an internal DC shock. The intracavitary ECG was sampled at 100 Hz; up to 1000 beats were collected before each episode. The 300 beats before the onset of major arrhythmias were analyzed. All enrolled patients had experienced previous episodes of major arrhythmia before ICD implantation.
The 20 men and 8 women had a mean age of 53±3 years (range, 25 to 73 years). None of the patients were receiving ß-blockers at the time of recordings. Three patients were on amiodarone therapy; no other antiarrhythmic drugs were being used.
The results were compared with control time series collected at rest in the same patients during the periodic ICD check (the last 300 beats recorded up to 2000 beats).
Of 28 consecutive series, 21 were considered for the analysis; 7 were excluded for the following reasons: 2 for atrial fibrillation, 3 for >10% of arrhythmic beats, and 2 for a pacemaker-driven rhythm. In the presence of ectopic beats (<10%), HRV series was linearly interpolated between the preceding/successive normal RR intervals.
Symbolic Dynamics
The method was fully described and validated previously.8 Briefly, RR interval sequences of length n=300 were selected. The length (L) was kept fixed in all analyses. The full range of the sequences was uniformly spread on 6 levels (from 0 to 5), and patterns of length L=3 were constructed as in Figure 1. Therefore, each subject and each experimental condition had its own range of RR intervals. The Shannon entropy11 of the distribution of the patterns was calculated to provide a quantification of the complexity of the pattern distribution. All possible patterns (ie, 216) were grouped without any loss into 3 families referred to as (1) patterns with no variation (0V; ie, all 3 symbols were equal), (2) patterns with 1 variation (1V; ie, 2 consequent symbols were equal and the remaining symbol was different), and (3) patterns with 2 variations (2V; ie, all symbols were different from the previous one). Examples of patterns are given in Figure 2. The percentage of the patterns 0V and 2V is reported in the Results section.
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To test the presence of deterministic structures in the series, we carried out a surrogate data analysis.12 Fifteen surrogate series for each original series were created by shuffling the temporal order of the samples. The percentages of 0V and 2V patterns derived from the original series were compared with those derived from surrogate series. If the percentages derived from the original series were significantly larger than those calculated from the surrogate series,8,12 the relevant patterns could not be considered present by chance.
Spectral Analysis
Frequency domain analysis of HRV was performed with an autoregressive algorithm6,13 on the same sequences used for symbolic dynamics. Briefly, the power spectral density was calculated for each RR series. Three spectral components were considered: very low frequency, from 0 to 0.03 Hz; low frequency, from 0.03 to 0.15 Hz; and high frequency, from 0.15 to 0.40 Hz. The spectral components were expressed in absolute (ms2) and normalized units and as the ratio of low to high frequency. Normalization consisted of dividing the power of a given spectral component by the total power minus the power below 0.03 Hz and multiplying the ratio by 100.6,13
Statistical Analysis
Data are presented as mean±SE. The differences in percentage of 0V and 2V patterns before major arrhythmic events and during control periods were tested with a 2-tailed paired Student t test or the Wilcoxon signed-rank test when the data were not normally distributed (SigmaStat for Windows, version 2.03). One-way ANOVA for repeated measures and Dunnetts method for multiple comparisons were used to compare the different experimental and pharmacological conditions with resting state in healthy subjects. If the data were not normally distributed, the Friedman rank test for multiple comparisons was used. Correlation values (r) were assessed by the Pearson
2 test statistic. A value of P<0.05 was considered statistically significant.
| Results |
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After high-dose atropine (parasympathetic blockade), a significant increase in 0V patterns and a decrease in 2V patterns were detectable, whereas low-dose atropine (parasympathetic agonist effect) produced no significant changes (Figure 3, middle).
The infusion of phenylephrine (reflex increase of cardiac parasympathetic modulation) determined a significant increase in 2V percentage, whereas nitroprusside infusion (reflex increase in cardiac sympathetic modulation) caused a significant increase in 0V dynamics (Figure 3, bottom). The changes in 1V patterns did not achieve the threshold of significance during autonomic tests. The results of Shannon entropy analysis in healthy subjects are shown in Figure 4.
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In Table 1, the results of time and frequency domain analyses of the same series (300 beats) during the different physiological and pharmacological experimental conditions are reported as differences from resting conditions. The correlations between 0V or 2V patterns and mean RR or spectral components during tilt test, which represented the more numerous experimental condition (43 subjects), did not reach statistical significance.
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Patients With an ICD
In 17 of 21 patients, the percentage of nonvariable symbolic patterns (3 beats on the same level; 0V) increased before life-threatening arrhythmias compared with baseline (0V patterns at baseline, 24.4±2.9%; before the onset of VT/VF, 41.6±3.9%; P<0.01; Figure 5, top); on the other hand, the small increase in 2V patterns did not reach statistical significance (2V patterns at baseline, 1.5±0.6%; before the onset of VT/VF, 3.2±1.0%; P=0.14; Figure 5, middle). Noteworthy, the percentages of both 0V and 2V patterns were substantially unchanged in the RR surrogate series at baseline and before the onset of major arrhythmias (0V patterns, 24.4±3.4% and 29.6±3.9%; 2V patterns, 3.0±1.0% and 2.5±1.1%, respectively). The percentage of 1V patterns was not significantly reduced before arrhythmic events compared with baseline. Shannon entropy, a measure of complexity, was significantly reduced in periods preceding major arrhythmias compared with control periods (3.19±0.08 and 3.59±0.07, respectively; P<0.05; Figure 5 bottom). Finally, heart rate increased in periods preceding major arrhythmia, whereas variance and spectral components did not change substantially (Table 2), even when the powers are expressed in a logarithmic scale. The increase in heart rate was correlated with the increase in 0V patterns before the onset of major arrhythmias (r=0.70; P<0.01). Moreover, a slight but significant positive correlation was found between high frequency (in ms2), as well as in logarithmic scale and the percentage of 2V patterns before arrhythmias (r=0.43, P<0.05; and r=0.54, P<0.05, respectively).
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| Discussion |
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We proposed a nonlinear method of HRV analysis (3-beat symbolic analysis) to quantify the prevalence of sympathetic or parasympathetic cardiac modulation in conditions in which the use of a linear HRV approach6 is limited or even disputable. The method was validated by experimental and pharmacological protocols characterized by specific changes in sympathovagal balance. In these experimental conditions, the percentage of symbolic patterns changed in clear directions, consistent with expected changes in sympathetic or vagal cardiac modulation. Specifically, an increase in sympathetic modulation and vagal withdrawal elicited both an increase in 0V patterns and a decrease in 2V patterns, whereas parasympathetic prevalence induced opposite changes: an increase in 2V patterns and a decrease in 0V patterns. Our method of analysis was able to take into account short instabilities in the HRV series that may provide insights into autonomic cardiac regulation, considering the different latencies and time courses of the fast parasympathetic and slow sympathetic modulations.13
Wessel et al25 recently showed, using a symbolic methodology based on a "word" of 6 symbols, that symbolic dynamics of RR series forecasted life-threatening arrhythmias. Shusterman et al26 recognized disturbances in "core" patterns, indicating progressive destabilization of cardiac rhythm, which would predict the onset of spontaneous sustained ventricular tachyarrhythmias. In our patients with ICDs, the period before the onset of major arrhythmias was characterized by an increase in flat symbolic (0V) patterns, suggesting that a sympathetic prevalence could facilitate the onset of these arrhythmias. Although an increase in 0V patterns was associated with a decrease in 2V patterns during experimental and pharmacological tests in healthy subjects, the significant increase in 0V before the onset of major arrhythmias was not coupled with a decrease in 2V patterns in ICD patients. The possible concomitance of both vagal and sympathetic actions, most likely on a reflex basis, could facilitate arrhythmias by a complex interplay.27 Symbolic analysis seems able to detect the coexistent excitation of the 2 systems, weakening the concept that vagal and sympathetic outflows in pathophysiological conditions work exclusively in a sort of reciprocal arrangement. Alternatively, a trend to increased 2V patterns may be due to nonautonomic mechanisms affecting heart rate dynamics and resulting from alternating patterns of RR intervals.28 Moreover, electric alternation of ST segment and T wave has been previously described to precede the VT/VF events.29 Inhomogeneity of ventricular repolarization might explain both RR and repolarization alternating patterns,30 which, in turn, might be facilitated by sympathetic stimulation.31
Other nonlinear approaches such as Shannon entropy, which clearly decreased before the onset of arrhythmic events, were less able than symbolic dynamics to identify the experimental changes in cardiac autonomic modulation. Finally, we stress the simplicity of the method used for symbolic analysis. In a previous study,8 we verified that 6 levels for a sequence of 3 beats is the most appropriate compromise to best detect the relative changes induced by the autonomic modulation on HRV. The presence of ectopic beats influences the results of classification by reducing the number of different patterns (ie, complexity). Therefore, the application of a proper correction procedure is mandatory in the presence of ectopic beats.
Study Limitations
We compared recordings preceding the onset of major arrhythmias with basal recordings obtained at rest with the same device during a periodic ICD check. Consequently, we have no data to assess whether sympathetic activation is greater before a major arrhythmic event compared with other periods throughout the day, particularly during activity.
Moreover, our symbolic analysis is based on normal functioning of the SA node and does not provide a measure of repolarization properties of myocardial substrate, which is directly involved in the genesis of life-threatening ventricular arrhythmias.
Conclusions
As shown in the first part of the study (autonomic tests), an increase in sympathetic cardiac modulation determines the rise in 0V and the decrease in 2V patterns, whereas opposite results are observed during an increase in parasympathetic cardiac modulation. Reciprocal changes are observed in the normalized power of low- and high-frequency spectral components of HRV. As reported in the second part of the study, before the onset of major arrhythmias, the symbolic pattern possibly related to prevalent sympathetic modulation increases, and the pattern possibly related to vagal modulation does not decrease in a reciprocal way. Standard HRV analysis does not detect any significant change in these conditions.
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