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(Circulation. 2000;101:2398.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Heart Rate Dynamics at the Onset of Ventricular Tachyarrhythmias as Retrieved From Implantable Cardioverter-Defibrillators in Patients With Coronary Artery Disease

Etienne Pruvot, MD; Gilles Thonet, PhD; Jean-Marc Vesin, PhD; Guy van-Melle, PhD; Karlheinz Seidl, MD; Herwig Schmidinger, MD; Johannes Brachmann, MD; Werner Jung, MD; Ellen Hoffmann, MD; René Tavernier, MD; Michael Block, MD; Andrea Podczeck, MD; Martin Fromer, MD

From Centre Hospitalier Universitaire Vaudois (E.P., G.v.-M., M.F.), Lausanne, Switzerland; Ecole Polytechnique Fédérale de Lausanne (G.T., J.-M.V.), Lausanne, Switzerland; Klinikum der Stadt (K.S.), Ludwighafen, Germany; Allgemeines Krankenhaus (H.S.), Wien, Austria; Landkrankenhauses (J.B.), Coburg, Germany; Friedrich-Wilhems University (W.J.), Bonn, Germany; Klinikum Grosshadem (E.H.), München, Germany; Pacemaker Clinic (R.T.), UZ, Gent, Belgium; Stiftsklinik Augustinum (M.B.), München, Germany; and Wilhelminenspital (A.P.), Wien, Austria.

Correspondence to Dr Etienne Pruvot, Division of Cardiology, BH16, CHUV, 1011 Lausanne, Switzerland. E-mail etienne.pruvot{at}chuv.hospvd.ch

	Abstract

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Background—The recent availability of implantable cardioverter-defibrillators (ICDs) that record 1024 R-R intervals preceding a ventricular tachyarrhythmia (VTA) provides a unique opportunity to analyze heart rate variability (HRV) before the onset of VTA.

Methods and Results—Fifty-eight post–myocardial infarction patients with an implanted ICD for recurrent VTA provided 2 sets of 98 heart rate recordings in sinus rhythm: (1) before a VTA and (2) during control conditions. Three subgroups were considered according to the antiarrhythmic (AA) drug regimen. A state of sympathoexcitation was suggested by the significant reduction in HRV before VTA onset compared with control conditions. ß-Blockers and dl-sotalol enhanced HRV in control recordings; nevertheless, HRV declined before VTA independent of AA drugs. A gradual increase in heart rate and decrease in sinus arrhythmia at VTA onset were specific findings of patients who received dl-sotalol.

Conclusions—The peculiar heart rate dynamics observed before VTA onset are suggestive of a state of sympathoexcitation that is independent of AA drugs.

Key Words: tachyarrhythmia • Fourier analysis • nervous system, autonomic • coronary disease

	Introduction

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The heart rate (HR) displays spontaneous variations that result from interaction of the sympathetic and parasympathetic systems with the sinus node.¹ HR variability (HRV) analysis measures the frequency and amplitude of these variations, yielding valuable information on the activity of autonomic components. Low HRV has recently been recognized as an independent risk factor of cardiac events after myocardial infarction,^{1 2 3} and it has also been used to assess changes in the dynamics before the onset of ventricular tachyarrhythmia (VTA).^{4 5 6 7 8 9 10 11} Although some studies have reported significant changes in HRV within the minutes preceding VTA onset,^{5 6 7 9 10 11} others have not.^{4 8} To address this issue, we conducted a study on HRV at the onset of ventricular tachycardia and fibrillation (HRVF Study), with the purpose of analyzing the HRV preceding spontaneous episodes of VTA retrieved from implantable cardioverter-defibrillators (ICDs). The study hypothesis was that the HR dynamics might significantly change in the minutes preceding the onset of ICD-treated VTA.

	Methods

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Study Design
The HRVF Study was a European multicenter investigation conducted at 8 university hospitals with experience in ICD therapy.

Patient Characteristics
All patients had an earlier myocardial infarction and were implanted with an ICD (Medtronic 7218/7220) due to life-threatening VTA. Thirteen patients were excluded due to diabetes mellitus, atrial fibrillation, paced rhythm, frequent ectopic beats (>5%), or unknown drug therapy. The remaining 58 patients formed the study sample (mean age 63 years, mean left ventricular ejection fraction [LVEF] 0.34), and 85% had congestive heart failure (CHF) (New York Heart Association functional class II-IV). The main indications for ICD implantation were sustained ventricular tachycardia (sVT)and aborted sudden cardiac death. None of the patients had an acute ischemic event at the time of VTA recording (Table 1).

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of the Entire Sample

Data Collection
Patient drug regimen, symptoms, and circumstances (sleep or awake state) related to VTA episodes were noted on a follow-up form. The 58 patients provided 2 sets of 98 HR recordings prospectively retrieved from the ICDs. The first set consisted of 1024 sinus interbeat (R-R) intervals stored immediately before the onset of VTA ("before VTA"), and the second set of 1024 R-R intervals not related to a VTA was acquired at the next follow-up visit ("control conditions"). For some patients, up to 4 separate episodes were analyzed. Unlike other investigators,⁶ we did not average the results of repetitive episodes because the conditions and times of VTA onset were different. Three subgroups of patients were considered according to their unique antiarrhythmic (AA) drug regimen (Table 2): dl-sotalol (sotalol subgroup, 14 patients, 2 sets of 22 recordings), ß-blockers (ß-blocker subgroup, 16 patients, 2 sets of 25 recordings), and no AA drugs (no AA subgroup, 23 patients, 2 sets of 43 recordings). The 3 subgroups included only 53 of the 58 patients because 5 patients (representing 8 VTA recordings) had combined AA drug therapy, including amiodarone. By definition, AA subgroups included only patients treated with 1 AA drug. Drug regimens were not discontinued during the study. The accuracy of ICD VTA detection was checked through visual inspection of the memory-retrieved right ventricular electrogram.

View this table: [in this window] [in a new window]   Table 2. Characteristics of the 3 Subgroups of Patients

R-R Interval Signals
Endocavitary ECGs are sampled online at 128 Hz with use of the ICD, and threshold detection of QRS complexes was performed. Medtronic model 7218/7220 ICDs store R-R-interval signals in binary format that are retrieved with use of the Medtronic programmer (model 9790c). Binary signals are then converted into ASCII format for analysis with the use of dedicated software. All recordings were in sinus rhythm with 5% of ectopic beats. This threshold value of 5% was shown to yield reliable HRV analysis results after ectopic beat interpolation.^{4 6} R-R interval signals were first passed through a filter based on a threshold detection that replaced ectopic beats with a local averaged value (linear interpolation) and then were visually checked before HRV analysis. For spectral analysis only, R-R signals were linearly detrended to remove trends that could affect power spectrum estimation.^{4 6}

HRV Analysis
We computed the mean R-R interval (mR-R), defined as the mean value of normal-to-normal R-R intervals. For spectral analysis, a fast Fourier transform was used to estimate the power spectral density with a 512-sample length and a Hanning window. Because R-R signals are sampled on an irregular basis, they were sampled again at 4 Hz.¹² Spectral powers (ms²) were determined in 4 frequency bands¹ : total power (0.008 to 0.40 Hz), high-frequency power (HF, 0.15 to 0.40 Hz), low-frequency power (LF, 0.04 to 0.15 Hz), and very LF power (VLF, 0.008 to 0.04 Hz). Relative power (normalized unit) was not calculated because its ability to measure cardiac variability was recently questioned.¹³ The power spectral density estimation performed with a 128-Hz ECG sampling rate was assessed with surrogate data; the signal-to-noise ratio was >10 dB at 0.40 Hz, an acceptable threshold for HRV analysis. All indices were computed on the entire duration of both control conditions and before VTA recordings and within the 4 windows of 2-minute duration before VTA onset.

Statistical Analysis
Because of the skewness of the distribution of spectral indices, log-transformation [ie, ln(1+x)] was performed before statistical analysis. Differences between recording conditions were assessed with the use of paired t test for spectral indices and Wilcoxon’s signed rank test for mR-R values. To analyze a possible trend over the 4 windows of 2 minutes before VTA onset, a linear regression was used for spectral indices, and the nonparametric Page test for the mR-R, a variant of the Friedman ANOVA, was used for dependent samples specifically directed toward ordered alternatives.¹⁴ Linear and stepwise regression analyses were used to evaluate associations. A value of P<0.05 was considered statistically significant.

	Results

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Patient Characteristics
The ß-blocker subgroup patients were older than patients without AA drugs (Table 2). The LVEF was significantly lower in patients without AA drugs (0.28) than in patients in the ß-blocker (0.38) and sotalol (0.36) subgroups. The mean VTA cycle length (CL) was 316 ms, a value indicative of VT episodes rather than ventricular fibrillation events. We observed a trend toward a higher value of VTA CL in the sotalol subgroup compared with patients without AA drugs (P=0.06). For the overall sample and for the 3 subgroups, no correlation was found between VTA CL and LVEF or time of VTA onset. Figure 1 displays the circadian pattern of the 98 VTA episodes. A peak of events was noticed between 8 AM and 6 PM. Only 12% of the episodes occurred during sleep. Symptoms at the time of VTA consisted of dizziness, syncope, or palpitations in 57%, whereas 43% of the episodes were asymptomatic. No angina pectoris or dyspnea was mentioned.

View larger version (10K): [in this window] [in a new window]   Figure 1. Circadian distribution of VTA in overall sample.

HRV for the Overall Population
Before VTA, the mean HR computed from the 1024 R-R intervals increased significantly compared with control conditions. Total power was reduced, and the decrease was significant in each of the 3 frequency bands (Table 3). A significant progressive increase in HR but no consistent evolution of spectral indices was noticed in the last windows of 2-minute duration before VTA onset (Table 4). Figure 2 shows 2 recordings of 1024 R-R intervals retrieved from ICD memory. Most of the power is located in the VLF band in both recording conditions, with a further reduction in spectral power in all frequency bands before VTA onset.

View this table: [in this window] [in a new window]   Table 3. Comparison of HRV Results Between Control Conditions and Before VTA Recordings

View this table: [in this window] [in a new window]   Table 4. Temporal Evolution of HRV Results Before VTA Onset

View larger version (16K): [in this window] [in a new window]   Figure 2. Left, Illustrative signals of 1024 R-R intervals as retrieved from ICDs. Short-long sequences are single ectopic beats. Right, HR spectra computed from these 2 signals. Top, Control conditions. HF peak (top right) represents respiratory sinus arrhythmia seen as fluctuations of high amplitude in R-R signal (top left). Bottom, recording before VTA onset. Sudden decrease at end of R-R signal illustrates VTA onset. Note reduced amplitude of both respiratory sinus arrhythmia and LF fluctuations (bottom left), which manifest as decreased power in overall spectrum (bottom right) compared with control conditions (top right).

In a stepwise regression analysis that included LVEF, age, and weight, LVEF was the only positively correlated predictor of mean R-R interval, total power, and VLF power values during control conditions.

HRV for Patients Without AA Drugs
A comparison of both recording conditions revealed no change in mean HR but a significant decrease in total power before VTA onset. The latter resulted from a significant reduction in both LF and HF power and from a borderline decrease in VLF power (Table 3). No trend in indices was noticed in the minutes preceding VTA onset (Table 4).

HRV for the AA Subgroups
The ß-blocker and sotalol subgroups displayed a significant increase in mean HR before VTA compared with control conditions. A decrease in total power was also noticed resulting from a significant reduction in VLF power for the ß-blocker subgroup and from a significant reduction in VLF and LF power for the sotalol subgroup (Table 3). For the ß-blocker subgroup, no trend in indices was noticed in the minutes preceding VTA onset, whereas the sotalol subgroup showed a significant gradual increase in mean HR and a decrease in HF power (Table 4).

Comparison of HRV Results During Control Conditions
During control conditions, the sotalol and ß-blocker subgroups indices were not different. In patients without AA drugs, the mean HR was significantly higher and total power was lower than both AA subgroups values. The lower total power was due to lower LF and HF powers compared with the sotalol subgroup and to lower VLF power only compared with the ß-blocker subgroup. To determine the contribution of the AA drugs to the differences in HRV between subgroups, indices were compared in selected patients with similarly low LVEF (range 0.26 to 0.39). In patients without AA drugs, the mean HR was higher and total, LF, and HF powers were significantly lower (P<0.05) compared with the other subgroups.

Comparison of HRV Results Before VTA
Before VTA, no difference was observed between subgroups except for the mean HR: the mean HR of the sotalol subgroup was significantly lower than the mean HR of patients without AA drugs but similar to the ß-blocker subgroup value (Table 4).

	Discussion

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The main finding in the present investigation was that the HR dynamics were deeply depressed before VTA onset regardless of the AA drug regimen. In contrast to the HR, the spectral analysis showed important modifications related to VTA onset in patients without AA drugs. Furthermore, AA drugs seem to alter the HR dynamics according to their specific AA property: (1) in control recordings, ß-blockers and dl-sotalol increased the HRV compared with patients without AA drugs, and (2) dl-sotalol, but not the ß-blockers, was associated with a gradual increase in HR and a decrease in sinus arrhythmia before VTA.

The HF component of the HR spectrum (ie, the sinus arrhythmia) depends on the parasympathetic activity.¹ The LF component results from combined sympathetic and parasympathetic activities,¹ whereas the VLF component depends at least on the parasympathetic system.¹³ Both vagal withdrawal^{13 15} and exercise¹⁶ decrease total power and power in the VLF, LF, and HF bands. In CHF, spectral power is decreased and predominantly located in the VLF band.¹⁷ In these patients, a negative correlation was found between sympathetic activity and total, LF, or HF power.^{17 18 19} Under both recording conditions and regardless of AA, most spectral power was located in the VLF band, which is consistent with the high proportion of CHF in our patients. Moreover, the reduction in HRV before VTA onset compared with control conditions suggests a state of additional sympathoexcitation, which is supported by a peak of arrhythmic events during awake hours (Figure 1).

Linear Detrending Before HRV Analysis
The HRV has been analyzed before the onset of VTA with linear and nonlinear techniques.^{4 5 6 7 8 9 10 11} Vybiral et al⁸ did not observe any trend in HR and in its standard deviation in the minutes preceding the onset of ventricular fibrillation. In some studies, an increase in HR but no evolution of spectral indices before sVT was noted,⁴ whereas other researchers have reported a decrease in HRV within 1 hour preceding sVT compared with non-sVT⁶ or with 24-hour values.^{6 9 11} In a recent work, we observed an increase in HR but a gradual rise in VLF power and a decline in HF power before VTA onset⁷ that have not been reported by others. These findings are partially validated by the present study: a gradual decrease in HF power but no change in VLF power are noted. This may be explained by the following differences. First, our present observations show that the gradual increase in HR and the decline in HF power are specific of dl-sotalol–treated patients. Second, unlike in our previous work,⁷ we performed a linear detrending of R-R signals before spectral analysis. Linear detrending attenuates the spectral power in the VLF band computed on R-R signals with a linear trend, and in the presence of nonlinear trends, it may change the temporal evolution of this band. This led us to formulate the following hypotheses: (1) R-R signals before VTA contain a nonlinear increase whose power is concentrated in the VLF band, and (2) linear detrending on a nonlinear signal may change the temporal evolution of VLF power. We synthesized a negative exponential signal that simulated a nonlinear increase in HR before VTA onset. Before detrending, the VLF power progressively increased in a manner similar to our previous results,⁷ whereas after detrending, the VLF power displayed no trend, as observed in the present study. This suggests that linear detrending, a common practice in HRV analysis,^{6 7} substantially affects the temporal evolution of VLF power in HR recordings with nonlinear trends.

Patients Without AA Drugs
In patients without AA drugs, we, like others, show that no trend in HRV indices is observed in the minutes before VTA.^{4 8 9} Although frequently reported,^{4 6 9} a significant rise in HR was not observed for this subgroup. Two factors may have accounted for this discrepancy. First, our parameters were measured in the last 4 windows of 2-minute duration before VTA, whereas others computed these indices with 5- to 30-minute windows.^{4 6 9 11} In the present study, the absence of HR rise may be due to shorter windows. Second, the mean LVEF of our subgroup without AA drugs (0.28) is lower than the mean LVEF (0.34 to 0.43) in previous studies.^{4 6 9 11} The HR is known to be inversely correlated with LVEF,²⁰ which was confirmed in the present study. The low LVEF may have prevented a further increase in HR within this very short period.

In contrast to the mean HR, depressed 24-hour spectral indices have been reported to be predictive of VT occurrence.⁴ Low HRV is also known to be more strongly associated with cardiac mortality rates after myocardial infarction than the 24-hour mean HR.^{1 2} In patients without AA drugs, all spectral components were depressed before VTA compared with control conditions, whereas the mean HR was not (Table 3). Therefore, spectral analysis is more sensitive than the mean HR in the identification of arrhythmogenic conditions on a short-term time scale.

Patients With AA Drugs
Sotalol is a ß-blocker with class III AA property²¹ that is known to increase HRV in patients with organic heart disease.²² During control conditions, patients treated with either ß-blockers or dl-sotalol showed similar HRV, but it was more pronounced than that in patients without AA drugs. Differences between AA subgroups appeared in the minutes before VTA onset. Both drugs were associated with a progressive increase in HR, but the difference was not significant for the ß-blocker subgroup. During the last 8 minutes before VTA onset, the sotalol subgroup gradually decreased its HF power together with an increase in HR, whereas the ß-blocker subgroup did not. Experimental and clinical data have shown that reduced vagal activity is associated with an increased risk of sudden death during chronic ischemia.^{2 3} Our results suggest that during control conditions, dl-sotalol enhanced the vagally mediated modulation of the HR, as expressed with the HF power, and that a gradual reduction in vagal tone was involved in VTA triggering.

Conclusions
With the use of HR recordings retrieved from ICD memory, a state of sympathoexcitation was observed as expressed by the reduction in HRV before VTA onset. ß-Blockers and dl-sotalol enhanced HRV; nevertheless, HRV declined before VTA regardless of the AA. A gradual increase in HR and a decrease in the vagally mediated sinus arrhythmia at VTA onset were seen in patients treated with dl-sotalol. Due to the limited capacity of ICD memory, on the basis of the present study, we cannot conclude whether predictive parameters of VTA onset have been identified. We also observed that linear detrending before HRV analysis may substantially affect the temporal evolution of VLF power in HR signals.

Study Limitations
The respiratory dynamics can affect HRV over the entire spectrum.^{1 13} In our study, as in previous studies,^{4 6 9 11} respiratory rates could not be controlled because of the unpredictability of VTA occurrence.

sVTA and non-sVTA could not be differentiated because the average number of beats before ICD termination was equal to 20. Total HRV seems to increase before non-sVT but apparently decreases or remains unchanged before sVT.^{4 6 9 11} In our study, a gradual decrease or no change in HRV indices was noticed before VTA onset. The removal of non-sVTA episodes should have enhanced the value of our findings rather than diminish it. It has been reported that HRV before sVT decreased for sVTs with an initial complex that had a waveform identical to subsequent complexes (type 2), whereas HRV remained unchanged for sVTs triggered by morphologically distinct early cycle (type 1).¹¹ Due to limited ICD memory, these data were not available in the present study. For some patients, up to 4 VTA episodes were included in the analysis. The analysis has been redone, with only the first episode kept (chronologically). Despite weaker levels of significance, the results remained essentially unchanged.

We did not match the time of control recording acquisition to the time of VTA recordings. The control set was, however, acquired between 8 AM and 6 PM, which was also the case for 66% of VTA recordings. In addition, a limited number of VTA episodes (12%) occurred during sleep, a state of vagal predominance. Even though for the 88% remaining VTA the time was not strictly equal to the time of control recordings, they generally occurred during the awake state. Nevertheless, this dissimilarity might have contributed to the difference in HRV results reported in the present study. Repetition of the statistical analysis after the withdrawal of events that happened during sleep did not modify the results. Recordings of 10-minute duration were used as controls for comparison with HR recordings before VTA. Our control recordings might not be sufficiently representative of the patients’ overall (24-hour) HRV state, even though it has been established that correlations between short-term and long-term HRV measures were high in postinfarction patients.²³

	Acknowledgments

 
This work was supported by grants from the Fondation Vaudoise de Cardiologie (Lausanne, Switzerland), Swiss Society of Cardiology (Working Group on Cardiac Pacing and Electrophysiology), Swiss National Foundation for Scientific Research (Bern, Switzerland), and Bakken Research Center (Maastricht, the Netherlands). We acknowledge the contributions of B. van Veen, J. Milne, G. Lefthériotis, and D. Latchem. The HRVF study was endorsed by the Working Group Pacing and Arrhythmias of the European Society of Cardiology.

Received August 18, 1999; revision received November 30, 1999; accepted December 22, 1999.

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