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(Circulation. 1995;92:3415-3423.)
© 1995 American Heart Association, Inc.

Articles

Evaluation of Importance of Central Effects of Atenolol and Metoprolol Measured by Heart Rate Variability During Mental Performance Tasks, Physical Exercise, and Daily Life in Stable Postinfarct Patients

Ype S. Tuininga, MD; Harry J.G.M. Crijns, MD; Jan Brouwer, MD; Maarten P. van den Berg, MD; Arie J. Man in't Veld, MD; G. Mulder, PhD; K.I. Lie, MD

From The Thorax Center (Y.S.T., H.J.G.M.C., J.B., M.P.v.d.B.), Department of Cardiology, University Hospital Groningen; Cardiovascular Research Institute COEUR (A.J.M.i.V.), Department of Internal Medicine, University Hospital Rotterdam; and the Department of Experimental Psychology (G.M.), University of Groningen, The Netherlands.

Correspondence to Dr Y.S. Tuininga, The Thorax Center, Department of Cardiology, University Hospital Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands.

	Abstract

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Background Physical exercise and mental work cause alterations in cardiac autonomic control. ß-Blockers protect the heart against stress, and this effect may be in part centrally mediated. In this context, the lipophilicity of the drug would be clinically relevant.

Methods and Results Thirty postinfarct patients were randomized to receive 100 mg atenolol or 200 mg metoprolol CR in a double-blind, crossover manner, each for a 6-week period. Heart rate (HR) variability was used to study autonomic effects during mental and physical stress and to study circadian variations. Mean 24-hour HR decreased from 77±7 to 60±6 beats per minute after atenolol and to 62±6 beats per minute after metoprolol (P=.046). At baseline, mental performance tasks did not affect HR, but decreased HR variability (SDNN index from 51±26 to 30±13 milliseconds [ms], P<.001; high-frequency power from 130±143 to 110±125 ms², P=.046; and low-frequency power from 538±447 to 290±275 ms², P<.001). Both ß-blockers decreased HR during mental performance tasks (P<.001) and increased SDNN index and high-frequency power. Before treatment, bicycle exercise decreased HR variability; root-mean-square of successive difference decreased from 21±8 to 15±10 ms (P=.004). ß-Blockade could not prevent this decrease. No differences between atenolol and metoprolol were observed for absolute high- and low-frequency power or after adjustment for HR. Vagal blockade with methylatropine during chronic ß-blocker treatment nearly abolished all components of spectral power. HR was found to be the parameter most strongly affected by ß-blockade but not by an influence on vagal tone. No differences were found between atenolol and metoprolol.

Conclusions In stable postinfarct patients, chronic treatment with metoprolol and atenolol attenuates the reduction in HR variability induced by mental performance tasks, but the effects during exercise are limited. ß-Blockers do not appear to increase vagal tone in this stable patient group. The point of action in these patients is mainly a reduction in HR, probably due to a reduction in stress-induced sympathetic activation. Clinically significant differences between atenolol and metoprolol were absent, indicating that the degree of lipophilicity does not distinguish among the ß-blockers what their salutary effects are on HR variability during the specific challenges used.

Key Words: exercise • heart rate • infarction

	Introduction

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Treatment with ß-blocking drugs reduces the sudden death rate by 30% in postinfarct patients,¹ but the mechanisms involved are not clear. Changes in autonomic activity such as sympathetic activation and vagal withdrawal facilitate the occurrence of ventricular tachyarrhythmias,^{2 3 4 5} in particular when combined with myocardial ischemia.⁶ ß-Blockers may reduce the risk of sudden death, not only by correcting myocardial ischemia but also by correcting deranged autonomic status associated with stress.⁶ This contention is supported by experimental observations showing that ß-receptor blockade in the central nervous system prevents ischemia-induced ventricular fibrillation.^{7 8} Therefore, it has been suggested that ß-blockade prevents ventricular fibrillation through central processes. During high sympathetic stress, one effect of ß-blockade would then be a better maintained vagal tone.

To study the clinical relevance of the above hypothesis, we used Holter monitoring to evaluate whether ß-blockers are able to affect HR variability under various kinds of stress in postinfarct patients. Previously, this method was reported to be a valuable tool to study cardiac autonomic control, and it was recommended for risk stratification after myocardial infarction.^{9 10} In the present study, we investigated the effects of two widely used ß-blocking agents—metoprolol and atenolol, of which metoprolol is known for its favorable effect on sudden death rate.¹¹ The two drugs differ in their degree of lipophilicity. Lipophilic metoprolol might have a more marked influence on the central nervous system than hydrophilic atenolol because of a different degree of penetration.^{7 8} Because in daily life the occurrence of various stressors is not exceptional, we studied the effects of both ß-blockers during different kinds of stress. End points of the study were HR and its variability during mental performance tasks and physical stress, after autonomic blockade, and during 24-hour Holter monitoring.

	Methods

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Patients
Male or female patients between 18 and 75 years of age were eligible for the study if 3 to 12 months had elapsed since their infarct and if they had a left ventricular ejection fraction of >0.30 and no signs of overt heart failure. The period of 3 to 12 months postinfarction was chosen because during this period, the recovery of HR variability after acute myocardial infarction is considered to be stable.¹² Only patients who were in NYHA class I or II for angina pectoris were included. Exclusion criteria were congestive heart failure class II NYHA, moderate-to-severe angina, atrial fibrillation, sick sinus syndrome or second- or third-degree AV conduction block, sinus bradycardia of <40 beats per minute, and chronic lung disease.

Study Protocol
The protocol was performed in conformance with the guidelines established in the Declaration of Helsinki and was approved by the institutional review board. Written informed consent was obtained from each patient before entry into the study. The study was designed as a randomized, double-blind, crossover study. After an off-drug baseline period (exceptions were short-acting nitrates and anticoagulants), patients were randomized to receive 200 mg metoprolol controlled-release or 100 mg atenolol daily for a 6-week period. After that period, patients were crossed over to receive the other drug for an additional 6 weeks. At the end of each of the three periods, a complete 24-hour ambulatory ECG recording (Holter) was made, during which two versions of a mental performance task and a bicycle exercise test were done. All patients underwent these tests once before baseline evaluation to familiarize them with the study procedure. The effects of autonomic blockade were studied during the two treatment periods in a subgroup of patients (n=14).

ECG Assessment
One resting 12-lead ECG was made at baseline, and one was made during treatment with both ß-blockers. The QT intervals were measured by two observers who were unaware of the treatment code. QT_c was calculated with Bazett's formula.¹³ Also, QT dispersion was measured as the longest minus the shortest QT interval in a 12-lead ECG.

Holter recordings were made with a three-channel recorder (series 8500, Marquette Electronics) and were analyzed by an experienced analyst who was unaware of the treatment modality (with a Marquette Laser XP analyzer).

HR Variability
The data base of RR intervals was transported to a personal computer. A postprocessor developed at our institution¹⁴ was used for HR variability analysis to analyze HR variability as divided in 288 segments of 5 minutes for a total 24-hour recording. Time domain and frequency domain parameters were studied; time domain analysis gave an impression of the total amount of HR variability, whereas frequency domain analysis was used to investigate various rhythms generated by different biological regulating systems. Time domain parameters used are depicted in Table 1. These included the mean NN interval, the mean of the SDNN for all 5-minute segments (SDNN index), the CV, and the rMSSD. The latter is the time-domain parameter that is the least affected by HR. Frequency domain (spectral) parameters were also calculated over 5-minute segments. Before this calculation, episodes with noise and ectopics were substituted by keeping the previous NN interval constant throughout that period. Segments with more than 15% noise or ectopic beats were excluded from analysis. Twelve 5-minute segments were averaged to obtain hourly mean values of HR variability parameters. The average value of the interval series was subtracted before spectral analysis was performed using a discrete Fourier transformation algorithm. In contrast to fast Fourier transformation, discrete Fourier transformation does not require a stationary continuous signal because there is no resampling with this technique (resampling in fast Fourier causes considerable loss of power). Total frequency power was calculated as the power between 0.03 and 0.40 Hz. LF and HF components were calculated as power between 0.04 and 0.15 Hz and between 0.15 and 0.40 Hz, respectively. Furthermore, the ratio of LF to HF was calculated, which gives an indication of the percentage of vagal modulation within the total autonomic system. Normalized LF and HF were calculated as LFx100%/TF>0.03 Hz and HFx100%/TF>0.03 Hz (in NU). A second normalization method was also calculated: the CCV=square root of power/mean RR interval. The CCV of the HF component is considered a pure parameter of the efferent discharge rate in cardiac vagal nerves and is not affected by sympathetic stimulation.¹⁵

View this table: [in this window] [in a new window]   Table 1. Time and Frequency Domain Measures of HR Variability

HR variability was measured during a 5-minute rest period with the patient sitting. Then, two mental performance tasks with different levels, each during 5 minutes, and a bicycle exercise test were performed. In a subgroup, HR variability was measured after autonomic blockade. All tests were performed at the same time of the day, in the afternoon, when the degrees of cardiac ß-blockade after 200 mg metoprolol controlled-release and 100 mg atenolol are similar.¹⁶ After measurement of the effects of mental performance tasks and physical stress, circadian patterns over 24 hours were measured.

Mental Performance Tasks
Mental tasks were presented in a quiet room at a constant temperature of 20°C. Patients were in a sitting position and were instructed not to talk during the tests. Two test levels were used. In test 1, three different randomly chosen characters were presented, and patients were asked to remember these. Subsequently, one character was shown on a PC screen for 3 seconds; then, this character was replaced by another; and so on. If a character matched one of the three characters in mind, patients were instructed to react by using the keyboard and to count the number of recognized characters in mind.^{17 18} The total test duration was 5 minutes. In test 2, the same protocol was used, but new characters were presented and patients were instructed to count the three characters apart, instead of together. The duration of test 2 was also 5 minutes. Both tests place a heavy load on the mental components memory, attention, and time pressure; therefore, they measure, in particular, mental work but not emotional stress.

Exercise Stress Testing
Exercise tests were performed with patients on a bicycle ergometer (Quinton Instruments Company) according to a previously described protocol.¹⁹ Briefly, a 12-lead ECG was recorded with a Marquette Case 12 ECG. The protocol consisted of an initial work load of 50 W, gradually built up during the first 30 seconds of the test, and thereafter a stepwise increase of the work load of 10 W every 30 seconds.

Vagal blockade was performed in 14 patients. Intravenous injection of methylatropine was used to further investigate the sympathovagal balance. The test was performed during each treatment period while patients were chronically treated with one of the two ß-blocking agents. After a 5-minute supine rest, 0.02 mg/kg methylatropine was injected intravenously, and RR intervals were recorded continuously for 15 minutes.

Statistical Analysis
Data are given as mean±1 SD. Statistical calculations were conducted with standardized biomedical algorithms using SPSS-PC+ and SPPSSWIN (SPSS Inc). Differences between values at baseline and for the two treatment modalities and between the two ß-blockers were assessed for HR, SDNN index, and normalized spectral parameters using Student's t test for paired samples. For other variables, Wilcoxon's matched-pairs test was used. A value of P<.05 was considered statistically significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Patients
Thirty patients, of whom 24 were male (mean age, 58±7 years), were included in the study. Sixteen patients had had an inferior infarction, 6 had had an anterior infarction, and 8 had had a non–Q-wave infarction. Their mean left ventricular ejection fraction was 56±9%. Three patients were excluded from analysis because of symptomatic hypotension, inappropriate compliance, and >15% noise due to a high prevalence of premature supraventricular beats, respectively.

ECG Monitoring
Data concerning HR and QT intervals are given in Table 2. QT interval increased during metoprolol without an increase in QT dispersion, whereas atenolol prolonged both. Mean 24-hour HR was decreased by 24% by treatment with metoprolol and by 27% with atenolol (Table 2). The average maximal HR over 24 hours decreased with both drugs by 24%, and the 24-hour minimal HR decreased by 14% and 16%, respectively.

View this table: [in this window] [in a new window]   Table 2. Effects on HR and QT Intervals Before and After Treatment With Metoprolol and Atenolol

HR Variability
HR variability was measured during mental and physical stress, after vagal blockade with atropine (Fig 1), and for a 24-hour period.

View larger version (31K): [in this window] [in a new window]   Figure 1. Bar graphs of effects of 200 mg metoprolol CR (shaded bars) and 100 mg atenolol (filled bars) compared with baseline (open bars) on mean RR interval (ms), SDNN index (msx10), rMSSD (msx10), LF (ms2), HF (ms2), and LF-to-HF ratio (x100). A, HR variability parameters during 5 minutes of complete rest. B, Same HR variability parameters measured during mental performance task 1 (results of second test were comparable). C, Effects of exercise stress testing on HR variability. D, Effects of autonomic blockade with intravenous methylatropine on HR variability. In general, HR variability was decreased during mental and physical stress testing. ß-Blockade increased HR variability during mental performance tasks but not during exercise (*P<.05).

Mental performance tasks. Both mental tasks showed HR variability changes in the same direction, in which the second showed larger changes in HF power. Mental work did not affect the mean RR interval compared with the preceding 5-minute rest period before treatment with ß-blockers. Both metoprolol and atenolol increased the mean RR interval during mental performance (from 714±118 to 963±144 and 1010±137 ms, respectively; P<.001 for both drugs). The SDNN before treatment decreased during mental performance from 52±26 at rest to 30±13 ms (P<.001). After metoprolol, the SDNN during mental performance increased to 37±19 ms, and after atenolol, the SDNN increased to 37±16 ms (P=.043 and P=.013, respectively). Mental performance tasks also reduced the spectral HR variability parameters of TF, LF, and HF power (Table 3). Both metoprolol and atenolol increased TF (P=.04 and P=.004, respectively) but did not significantly affect LF during mental performance. HF was increased by both ß-blockers (P=.001 and P<.001). Adjustment of LF for both HR and TF showed a reduction after ß-blockade during mental performance (P<.001 for both ß-blockers). Adjusted HF, however, retained the same pattern as absolute HF, ie, an increase after ß-blockade. The second mental performance tasks showed a similar pattern. Absolute LF was slightly higher and HF was slightly lower compared with the first mental test, reflecting the higher degree of difficulty and of subsequent psychological performance.

View this table: [in this window] [in a new window]   Table 3. Spectral HR Variability Parameters and Effects of Mental Performance Tasks, Physical Exercise, and Autonomic Blockade in Postinfarction Patients

Exercise stress testing. Physical exercise reduced the mean RR interval from 685±114 to 518±86 ms (P<.001). Metoprolol and atenolol attenuated exercise-induced shortening of the mean RR interval: 645±105 and 669±97 ms, respectively (P<.001 for both drugs compared with exercise at baseline). The SDNN did not change from rest to exercise (51±26 to 51±21 ms, P=NS). Both metoprolol and atenolol increased the SDNN during exercise to 64±26 and 77±41 ms (P=.018 and P=.007, respectively). However, a parameter less sensitive to changes in HR, rMSSD, decreased during exercise from 21±8 to 15±10 ms (P=.004), and the addition of ß-blockade could not prevent this decrease (Fig 1). The effects on spectral parameters are shown in Table 3. Briefly, TF, LF, and HF were reduced by exercise, and this reduction was not significantly affected by ß-blockade. Also, adjusted LF and HF were only slightly affected by ß-blockade during exercise.

Vagal blockade. Injection of methylatropine had the most striking effects on HR variability parameters. Not only mean RR interval and SDNN also CV and rMSSD fell dramatically. The same pattern was found after spectral analysis (Table 3): LF and HF fell dramatically. No differences could be demonstrated between metoprolol and atenolol.

Circadian patterns. The circadian pattern of the mean NN interval is shown in Fig 2. ß-Blockade increased the mean NN interval, particularly in the daytime, although the effect was also found at night. Day-versus-night data before and during ß-blockade are shown in Table 4, in which day is considered to be 8:00 AM to 12:00 midnight and night is considered to be 12:01 AM to 8:00 AM. Both ß-blockers reduced the day-night differences in all HR variability parameters. No difference in HR variability was found between atenolol and metoprolol over the mean 24 hours. However, from 8:00 AM to 4:00 PM, the NN interval during atenolol was more prolonged than during metoprolol (967±97 and 929±109 ms, P=.006, respectively). During the night (12:01 AM to 8:00 AM), no differences were found between the two ß-blockers. The SDNN over 24 hours showed a small increase in daytime after ß-blockade but none at night (Fig 3). No differences were found between atenolol and metoprolol regarding their effects on the circadian pattern of SDNN. TF power increased due to ß-blockade, and this was paralleled by an increase in HF (Fig 4) and LF. No significant differences between atenolol and metoprolol in spectral parameters (absolute values) were found. After normalization for TF power, the increase in HF (NU) remained present, but the LF power showed a decrease during ß-blockade. The CCV HF, a parameter affected little by sympathetic activity, showed no differences between ß-blockade and baseline (Fig 5A), whereas CCV LF decreased after ß-blockade (Fig 5B). Again, the effects in daytime were most clear.

View larger version (13K): [in this window] [in a new window]   Figure 2. Plot of mean 24-hour circadian NN interval pattern before () and after 6-week treatment with 200 mg metoprolol CR () and 100 mg atenolol (). Both ß-blockers increased the mean NN interval, particularly in the daytime, although the effect was also found at night. Both ß-blockers reduced the day-night differences. Between 8:00 AM and 4:00 PM, the NN interval during atenolol was more prolonged than during metoprolol (967±97 and 929±109 ms, P=.006, respectively). During the night (12:01 AM to 8:00 AM), no differences were found between the two ß-blockers.

View this table: [in this window] [in a new window]   Table 4. Day and Night HR Variability Data Before and After Metoprolol and Atenolol Treatment for 6 Weeks

View larger version (17K): [in this window] [in a new window]   Figure 3. Mean 24-hour circadian SDNN index before () and after 6-week treatment with the ß-blockers 200 mg metoprolol CR () and 100 mg atenolol ().

View larger version (16K): [in this window] [in a new window]   Figure 4. Mean 24-hour circadian HF component before () and after 6-week treatment with the ß-blockers 200 mg metoprolol CR () and 100 mg atenolol ().

View larger version (14K): [in this window] [in a new window]   Figure 5. Circadian pattern of CCV of HF (A) and LF (B) power before () and after 6-week treatment with 200 mg metoprolol CR () and 100 mg atenolol ().

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This report details the effects of mental performance tasks and physical exercise on HR variability after myocardial infarction and the modulation of the various stressor effects by ß-blockade. The data indicate that the challenges used were effective in reducing HR variability in stable postinfarct patients. Six-week treatment with a ß-blocker enhanced HR variability during daily life and mental performance tasks. This effect of ß-blockers may play an important role in the prevention of sudden death in postinfarct patients. Because in this context vagal activation is generally viewed as protective²⁰ and increased sympathetic activity predisposes to ventricular fibrillation,^{21 22} ß-blockers are considered either to reduce sympathetic tone or to enhance vagal activity. In this respect, our data suggest that modulation of sympathetic rather than parasympathetic tone was important as effects on vagal activity were less pronounced. On the other hand, HR variability during physical stress was not strongly affected by ß-blockade, indicating that exercise overrules ß-blocker–induced HR variability effects. With the described challenges, the present study could not detect relevant differences between metoprolol and atenolol on HR variability, suggesting that lipophilicity is not an important property in stable postinfarction patients during daily life, mental performance, exercise, and vagal blockade. Whether this holds true for other stressors, such as emotional stress and ischemia, remains to be established.

Mental Performance Tasks and Exercise Stress Testing
Mental activity is indissolubly related to daily life. In healthy subjects, it has been shown to induce changes in the sympathovagal balance, in the direction of sympathetic predominance.²³ ß-Blockade is thought to reduce the sympathetic influence and attenuate vagal withdrawal.²⁴ In healthy subjects, our test is known to increase HR, but the data for the present postinfarction group showed no change in the mean RR interval during mental performance tasks, indicating an altered reaction of postinfarction patients to mental performance due to a different autonomic control. Although HR was not affected, mental performance tasks decreased all measures of HR variability in the postinfarction patients. During ß-blockade, SDNN and CV were still reduced by mental performance tasks, but the reduction was attenuated. Spectral analysis showed that ß-blockade enhanced power in all frequency components during mental performance.

Exercise depressed most HR variability parameters strongly. However, SDNN and CV increased, suggesting an increase in HR variability. This seems paradoxical but can be explained by the fact that HR changes profoundly during exercise, being low at rest and high at peak exercise, causing high SD. Therefore, these HR variability parameters are less useful in assessing autonomic control during standard clinical exercise tests. The parameters rMSSD and HF power were markedly decreased by exercise, both at baseline and during ß-blockade. In summary, ß-blockers may maintain normal autonomic balance during mental performance but cannot prevent or significantly attenuate adrenergic effects during exercise in this patient group.

Circadian Variations
Twenty-four–hour Holter recordings were performed before and after chronic (6 weeks) ß-blockade. Before treatment, the circadian pattern of RR intervals and HR variability was normal and showed a marked difference between day and night. ß-Blockade shifted the circadian distribution of the mean RR interval upward and attenuated the day-night difference. Thus, HR was lower and HR variability indexes in the time and frequency domain were increased compared with pretreatment control values. This effect of ß-blockade corresponds to that previously reported in patients with coronary heart disease^{25 26} and in healthy subjects.^{27 28} The most marked effects compared with control values were found in daytime, the period of the day with the highest sympathetic activity^{29 30} and the highest HR.

Vagal Blockade and Cardiac Vagal Tone
Vagal blockade by methylatropine was used as a method to study the effect of muscarine receptor blockade during chronic ß-blocker treatment. In patients on ß-blockade, this is an indirect way to quantify pure vagal tone. Vagal blockade resulted in increased HR and almost complete elimination of HR variability, including both LF and HF components, emphasizing the fundamental importance of cardiac vagal tone for both the LF and the HF components in these patients. It was postulated that this method, combined with HR variability analysis, may be helpful in discriminating lipophilic from hydrophilic ß-blockers.⁸ However, the response during metoprolol was the same as during atenolol, supporting the above-mentioned lack of lipophilicity-related central effects of metoprolol. Of note, after correction for HR using the CCV, the increase in HF after ß-blockade was abolished, indicating that in our patient group HF increase after ß-blockade was the result of a reduction in HR rather than an enhancement of cardiac vagal tone.

It has been suggested that increased HR variability after ß-blockade reflects an increase in cardiac vagal tone. However, it is important to consider the role of the increase of the mean RR interval per se and how this will change HR variability parameters such as SDNN and HF. Adjustment for HR changes by calculation of the CV for SDNN³¹ or CCV HF power (Fig 5A) resulted in approximately the same values after ß-blockade as in pretreatment control. It is therefore likely that the changes in SDNN and HF power observed during Holter recordings of patients with coronary heart disease on ß-blockade mainly reflect a reduction in HR induced by these agents. There are, however, circumstances during which cardiac vagal tone is low and may be increased by ß-blockade. This may occur during heavy emotional stress, such as the fight-fright-flight reaction.³² The mechanism by which ß-blockers then may exert their action have been ascribed to several factors; these include an increase in impulse activity of cardiac vagal afferent fibers after ß-blockade,³³ a central modulation of autonomic nervous outflow,²⁸ and cardiovascular reflex adjustments, which can be identified by ß-blockade.³⁴ It has been unknown which of these centrally acting mechanisms operates in postinfarction patients with marked depression of left ventricular function, who are known to benefit most from ß-blockade.

Lipophilicity Versus Hydrophilicity
Experimental data suggest that central effects of ß-blockade are more marked with lipophilic drugs.^{7 8} However, our data and the data of a recently reported clinical study²⁵ could not demonstrate differences between lipophilic metoprolol and hydrophilic atenolol with regard to HR variability. Even after complete vagal blockade with atropine, we could not demonstrate any difference between the two drugs. Although in our study the effects of atenolol were somewhat more pronounced during the day, this is probably an effect of the dose used, which was reflected by a slightly greater decrease in HR during the day after atenolol. Several explanations may be given as to why no relevant differences were found. First, the patient group studied, although postinfarction, was very stable and did not have significant ischemia or left ventricular dysfunction. In other words, the patients' overall degree of neurohumoral activity was supposedly (near) normal and the additional central effects of metoprolol other than effects on HR per se could never be striking. This explanation is consistent with observations of Parker et al,³⁵ who showed in psychologically stressed animals that different intracerebral doses of a ß-blocker produced similar effects on cardiovascular parameters but had markedly different effects when the system was adequately challenged. Our data show a maintained cardiac vagal stimulation during the study period. The marked changes in HR and HR variability after vagal blockade induced by methylatropine support this notion. It therefore cannot be excluded that a difference might have been observed if the patients had been studied under a high degree of activation of the defense-alarm reaction. A second, less likely, possibility is that the two drugs do not differ sufficiently to cause different effects on HR variability. Next to a higher lipophilicity of metoprolol,³⁶ the actual brain concentrations of metoprolol are also 10 to 20 times higher.³⁷ Despite a difference in brain concentrations, van Zwieten et al,³⁸ found that the influence on cardiovascular parameters was equal. Although the hypotensive action of atenolol was diminishing, its concentration in cerebrospinal fluid and in the brain was still increasing.

QT Interval
QT interval prolongation independently contributes to increased cardiovascular mortality³⁹ and sudden death.^{40 41} Experimental studies have shown that the sympathetic nervous system affects the QT interval.^{21 42} Ablation of the right stellate ganglion, stimulation of the left, and physical or emotional stress increased the QT interval and the incidence of ventricular fibrillation during myocardial ischemia. Moreover, increased dispersion of ventricular recovery time may lead to serious ventricular arrhythmias.⁴³ Our data show a reduction of the QT_c interval after ß-blockade. It was an interesting finding that this effect on QT was attended by an increased QT dispersion during atenolol but not during metoprolol. It may be postulated that lipophilic ß-blockers cause a more balanced sympatholytic effect than do hydrophilic ß-blockers. The level at which this effect occurs remains to be investigated.

Study Limitations
The study was performed in a stable postinfarction patient group, which may have limited the proportion of potential effects induced by both ß-blockers. It would have been interesting to know the effects of ß-blockers on HR variability in less stable patients with angina or heart failure or during emotional stress. In clinical practice, however, patients like those in our study are generally treated with ß-blockers as secondary prevention, and therefore we believe that our data contribute to the understanding of the effects of these drugs in the postinfarction setting. A second limitation is the fact that during exercise stress testing, analysis of HR variability data was performed during fluctuating HR. Therefore, we used discrete Fourier transformation, which is most independent of HR.¹⁴

Conclusions and Implications
We conclude that ß-blockade enhances HR variability in stable postinfarction patients with a low degree of neurohumoral activation who are subjected to normal daily stress. Obviously, this effect may improve prognosis and argues in favor of more widespread use of ß-blockade in postinfarction patients (rather than, eg, antiarrhythmics, which are known to reduce HR variability in these subjects). Our data show that the two ß-blockers have equal effects on HR variability during the tests used. Therefore, our data demonstrate that lipophilicity does not distinguish among the ß-blockers regarding their salutary effects on HR variability during the specific challenges used. Regarding the above explanations, we postulate that either the low brain levels reached with hydrophilic ß-blockers are sufficient to obtain an equal effect on HR variability compared with the high levels obtained with lipophilic ß-blockers or, which is more acceptable, that different kinds of stress, eg, emotional stress, coronary artery occlusion, or low cardiac vagal tone, may better discriminate between lipophilicity and hydrophilicity of ß-blockers.

Drug-induced changes in HR variability should be interpreted with caution if major changes in HR occur due to the studied compound. The observed changes in HR variability in the present study were mainly the result of a reduction in HR as after adjustment for HR they were abolished. This fact has not received much attention. We propose that future studies of HR variability take into account appropriate adjustment for HR changes when considering the effects of drugs that directly or indirectly affect HR.

	Selected Abbreviations and Acronyms

 

AV = atrioventricular CCV = coefficient of component variance HF = high frequency HR = heart rate LF = low frequency MS = millisecond(s) NN = normal-to-normal NU = normalized units NYHA = New York Heart Association QTc = corrected QT rMSSD = root-mean-square of successive difference SDNN = SD of NN interval TF = total frequency

Received November 29, 1994; revision received June 14, 1995; accepted July 27, 1995.

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