Effects of bisoprolol on heart rate variability in heart failure

Effects of Bisoprolol Variability

on Heart Rate in Heart Failure

Francoise Pousset, MD, Xavier Copie, MD, Philippe Lechat, MD, PhD, Patrice Jaillon, MD, PhD, Jean-Pierre Boissel, MD, PhD, Martin Hetzel, MD, F&d&k Fillette, MD, Willem Remme, MD, PhD, Louis Guize, MD, and Jean-Yves Le Heuzey, MD Analysis of heart rate variability (HRV) provides a noninvasive index of autonomic nervous system activity. HRV has been shown to be reduced in heart failure. Preliminary data indicate that j.? blockers improve clinical status in patients with heart failure, but HRV improvement remains to be demonstrated. Fifty-four patients from the randomized double-blind, placebo-controlled Cardiac Insufficiency Bisoprolol Study were included in the HRV study. The bisoprolol daily dose was 5 mg once daily. We assessed HRV during 24-hour Holter recordings before randomization and after 2 months of treatment. HRV was measured in the time domain by rootmean-square successive differences (rMSSD), the percentage of adjacent RR differences >50 ms (pNNSO), and the SD of RR intervals (SDNN), and in the frequency domain by high-frequency (0.16 to 0.40 Hz)

and low-frequency (0.04 to 0.15 Hz) power. Most patients were in New York Heart Association functional class III. The mean left ventricular ejection fraction was 27 2 7%, and heart failure was idiopathic or ischemic. After 2 months, the patients receiving bisoprolol had a reduced mean heart rate compared with that in placebo patients (p = 0.0004). Bisoprolol increased 24-hour rMSSD (p = 0.04) and 24-hour pNN50 (p = 0.04), daytime SDNN (p = 0.05), and daytime high-frequency power (p = 0.03) po wer. Bisoprolol induced a significant increase in HRV parameters related to pamsympathetic activity in heart failure. increased vagal tone may contribute to the protective effect of p blockers and may have prognostic implications. (Am J Cardiol 1996;77:6 12-6 17)

bnormal autonomic control of cardiovascular unction may contribute importantly to the Af pathophysiology of chronic congestive heart failure.

trolled, randomized European study.5 The main objective of this trial was to evaluate survival improvement on p blockade with bisoprolol in heart Analysis of heart rate variability (HRV) provides a failure. Six hundred forty-one patients with chronic noninvasive indication of autonomic nervous system heart failure of various etiologies (mainly ischemic modulation. In congestive heart failure, the attenu- and idiopathic dilated cardiomyopathy) were inated overall variability is supposed to be due to an cluded. At baseline, they were in New York Heart Association functional class III or IV with a left venautonomic imbalance caused by high sympathetic tricular ejection fraction <40%. All were receiving and concomitant low vagal activity.‘.’ In patients a baseline vasodilator and diuretic therapy. The biwho have had myocardial infarction, diminished soprolol dose was 5 mg/day, with progressive increHRV is associated with poor prognostic outcome.’ ments during 4 weeks starting at 1.25 mg once a day. In heart failure, HRV may provide unique informaOf the patients in the bisoprolol group, 59% received tion compared with other prognostic indicators. Medications may affect both autonomic balance and the target dose of 5 mg/day. The mean follow-up changes due to the disease process. Beta blockade in was 1.9 + 0.8 years, and the details of follow-up patients surviving acute myocardial infarction has have already been described.5 In the Holter ancillary study, a 2-channel24-hour proved to have a beneficial effect on morbidity and was recorded before randomizamortality.“ Recent placebo-controlled trials have electrocardiogram tion and after 2 months of treatment in 63 patients. confirmed evidence of P-blockade-induced funcSeven centers participated in the Holter study, which tional benefit in heart failure.5,6 The long-term benefit of p blockers could be partly related to res- was stratified by center. Patients with hypertension toration of a better sympathetic-parasympathetic bal- or diabetes mellitus were excluded. Nine of 63 paance. The aim of this study was to assess this hy- tients were excluded from the analysis of HRV because of inadequate Holter recordings (atria1 flutter pothesis by analyzing 24-hour HRV in a subgroup or frequent ventricular premature of patients with congestive heart failure included in or fibrillation, the Cardiac Insufficiency Bisoprolol Study (CIBIS) . complexes, or <16-hour analyzable data). Tapes were analyzed blindly. METHODS Processing of 24-hour Holter recordings: The 24Study design: We studied patients with heart failhour recordings were reprocessed for HRV using the ure from the CIBIS trial, a multicenter, placebo-conELA-Medical device (ELATEC HRV, Le PlessisRobinson, France). HRV was calculated in the folFrom the Dkpartement de Cardiologie, HBpital Broussais, Paris, lowing manner: initial QRS labeling and editing France. Manuscript received July 18, 1995; revised manuscript rewere done with the standard ELA medical algoceived October 27, 1995 and accepted October 29. rithms (version 3.OlP1.26 software). Cycles in Address for reprints: Jean-Yves Le Heuzey, MD, Dkpartement de Cardiologie, H6pital Broussais, 96 rue Didot, 75014 Paris, France. which beats had normal morphologic characteristics 612

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and were within 25% of the preceding cycle length were selected for calculation of HRV. Labeled QRS complexes were converted from analog to digital on a scanner at 200 samples/s. The filter excluded the coupling time of all ectopic beats and their compensatory pause. Measures of heart period variability were calculated for the entire 24 hours as well as for daytime (9:00 A.M. to 9:00 P.M.) and nighttime ( 1 l:oo P.M. to 6:00 A.M.). Time domain measures of heart rate variability: The time domain parameters studied have already been described: the standard deviation of all normal RR intervals (SDNN, ms) ; the percentage of differences between adjacent normal RR intervals >50 ms (pNN50, %) ; and the root-mean-square of successive differences between adjacent normal RR intervals (rMSSD, ms). ‘,’ Time domain parameters are highly reproducible.‘.“,” The differences between pNN50 and rMSSD provide an assessment of parasympathetic activity, ” and the SDNN is a global index of variability.’ Frequency

domain

measures

of heart rate variability:

Spectral analysis permits the study of the beat-tobeat fluctuations of the heart rate by calculating its power spectrum and by outlining some particular frequency components reflecting autonomic control. Spectral analysis was performed using a fast-Fourier transform applied on 4 Hz time series calculated by interpolation of the RR interval. The frequency resolution was 0.004 Hz and the highest frequency evaluated was 1.00 Hz. The power spectrum was calculated as the squared magnitude of the fast-Fourier transform in 2 bands. One is called low-frequency (LF) power and corresponds to frequencies between 0.04 and 0.15 Hz. The other, called high-frequency (HF) power, corresponds to frequencies between 0.16 and 0.40 Hz. The absolute power of the spectral components was expressed in ms 2. Heart rate fluctuations in the LF band are mediated by both the sympathetic and parasympathetic systems essentially by reflex activity, whereas fluctuations in the HF band reflect modulation of vagal tone primarily by breathing.12.‘3 Total power was also calculated between 0.01 and 1.00 Hz. In addition, we determined the ratio of LF to HF power, a measure that has been used as an indicator of sympathovagal balance.14 A high value for the ratio indicates the predominance of sympathetic nervous activity. Statistical analysis: The Complete Statistical System software, version CSS/3C (delivered by Statsoft, Inc., Tulsa, Oklahoma) was used for all statistical analyses. Comparisons of continuous HRV data between groups were made using nonparametric tests for unpaired data (the Mann-Whitney U test) because of unequal variance or skewed distribution. The Student’s t test for independent samples was used to compare clinical continuous data between groups, and a chi-square test was used to compare dichotomous data between groups. Linear regression was performed by the least-squares method. Significance was set at a p value <0.05. Clinical values CONGESTIVE

are presented as mean t SD, and HRV parameters as mean (95% confidence interval of the mean).

RESULTS Baseline clinical data: The clinical characteristics of the patients and the associated treatments are listed in Table I. The studied population was similar to the total CIBIS population. No difference in baseline clinical data was observed between the bisopro101 and placebo groups. The other concomitant treatments were not significantly different between these 2 groups. No discontinuation of CIBIS treatment or critical event was observed during the Holter study. The second Holter study was performed for all patients after 70 + 14 days of drug treatment. The mean duration of tapes was 22.7 ? 1.5 hours for the first recording and 22.7 + 1.1 hours for the second. Baseline heart rate variability: No difference in baseline HRV parameters in time and frequency domains was observed between the placebo and the bisoprolol groups. In the studied population (n = 54), ejection fraction at baseline was significantly correlated with the SDNN over 24 hours (r = 0.45, p = 0.0006), and more poorly with the mean RR over 24 hours (r = 0.28, p = 0.04). With respect to spectral analysis, only total power over 24 hours was correlated to ejection fraction (r = 0.32, p = 0.02). No significant correlation was found between HRV and New York Heart Association functional class or

TABLE

I Baseline

Characteristics

Clinical

and

Hemodynamic

of Patients Placebo (n = 24)

Men/women

17/7 60 t

Age (yd New York Heart Association functional class Class III Class IV Etiology of heart failure Idiopathic dilated cardiomyopathy Coronary artery disease Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) left ventricular ejection fraction (%) Echocardiographic Left ventricular (mm) Left ventricular

parameters enddiastolic end-systolic

diometer (%)

Results are expressed 0s mean + SD. No significant differences were found between

HEART

FAILURE/BlSOPROLOl

AND

HEART

24/6 582

10

22 2

29

10

18

1

14 128 + 14 80+ 10 76+ 13

diameter

(mm1 Left ventricular fractional shortening Treatment Diuretic Angiotensinconverting enzyme inhibitor Other vosodilators Digitalis Antiorrhythmic drugs: omiodarone/ other Anticoagulant Antiplatelet agent

9

Bisoprolol (n = 30)

127 81 81

29

+ 9

26

63

+ 1

672

51

2 1

55

19 + 6

12 i 16 +8 k 12 f

7 1

k

1

1826

24 21

30 29

11 8

9 14

5/O

3/l

5 10

10 11

groups.

RATE

VARIABILITY

613

TABLE II Time Domain

Analysis

of Heart

Rate Variability

After Two Months

of Treatment

Placebo (n = 24) Over 24 h RR (ms) SDNN (ms) pNN50 (%) rMSSD (ms) Daytime (9:00

A.M.-9:OO

(ms)

pNN50

927 119 6.7 33

(863, 991) (105, 132) (4.1, 9.3) (27, 39)

0.0004* 0.79 0.039* 0.039*

723 82

886 95 5.2 31

(821, 952) (86, 105) (2.8, 7.6) (24, 38)

0.0002 0.05 1 0.053 0.035*

(942,

0.007* 0.36 0.08 0.07

(681, 765) (70, 93)

3.1

(1.2,

24 P.M.-6:00

5.0)

(18, 30)

879 (826, 932) 83 (70, 96) 4.6 (1.4, 7.8) 28 (20, 36)

SDNN (ms) pNN50 p) rMSSD (ms) * Significantly different from placebo at p < 0.05. Results ore expressed os meon (95% confidence interval). pNN50 = the percentage of difference between odiacent RR intervals;

SDNN

TABLE Ill Spectral

= the standard

Analysis

deviation

of Heart

normal

RR intervals

of all normal

Rate Variability

1010

> 50 tns; rMSSD

= square

(80,981

10.2

(5.6,

35

(28, 43)

After Two Months

830 232 72 4.1

(541, 1120) (135, 330) (31, 113) (2.9, 5.2)

725 209 60 4.8

(471, (127, (28, (3.2,

HF (ms*)

104

(ms’)

* Significantly different from placebo at p < 0.05. Results ore expressed q s meon (95% confidence interval). HF = high-frequency power (0.16-0.40 Hz); LF = low-frequency (0.01-l

Bisoprolol (n = 30)

THE AMERICAN

p Value

(842, 1378) 299 (212, 387) 107 (63, 152) 3.6 (2.8, 4.3)

0.07 0.25 0.07 0.60

904 231 94 3.6

(72 1, 1087) (174, 288) (48, 140) (2.8, 4.4)

0.06 0.26 0.03* 0.38

(1000,231O) (262, 671)

0.26 0.30

1110

979) 290) 91) 6.4)

(637, 1561) (125, 498) (32,

1654 466 166

177)

power

(0.04-o.

(84,

247)

0.19

0.94

3.4 (2.7, 4.1)

15 Hz); LF/HF

= ratio of low-frequency

power

to high-frequency

power;

Total

.OO Hz).

dilation of the left ventricle. HRV assessed by time domain analysis was not statistically different according to the etiology of heart failure. In the frequency domain analysis, patients with heart failure secondary to coronary artery disease tended to have a higher LF/HF ratio over 24 hours (4.5 vs 3.2, p = 0.06), during daytime (4.9 vs 3.4, p = 0.09), and during nighttime (4.3 vs 3.1, p = 0.07). At baseline, there was a moderate but significant correlation between the mean 24-hour RR interval and the 24-hour SDNN value (r = 0.45, p = 0.0006). There was no correlation between the mean 24-hour RR interval and pNN50 (r = 0.20, p = 0.15) or rMSSD (r = 0.22, p = 0.22). Effects of P-adrenergic receptor blockade: The effects of 2-month treatment on mean RR interval and on time domain measures of HRV are listed in Table II. The 2 time domain measures of parasympathetic 614

adjacent

of Treatment

3.7 (2.6, 4.7)

LF/HF

= totol power

between

A.M.)

1098 31 1

power

differences

P.M.]

LF (ms2)

power

14.8)

root of the meon of squared

Placebo (n = 24)

Total

1079)

89

intervals.

I Over 24 h Total power (ms’) LF (ms2) HF (ms’) LF/HF Daytime (9:00 A.M.-9:OO Total power (ms’) LF (ms2) HF (ms?) LF/HF Nighttime (1 1:OO P.M.-6:OO

l

A.M.)

RR (ms)

normal

775 (729, 82 1) 114 (99, 129) 3.7 (1.4, 5.9) 26 (20, 40)

(“A)

rMSSD (ms) Nighttime (1l:OO

p Value

P.M.)

RR (ms)

SDNN

Bisoprolol (n = 30)

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cardiac activity, pNN50 and rMSSD, increased substantially over 24 hours. The effects of bisoprolol on spectral analysis are presented in Table III. We observed an increase in all frequency domain variables during bisoprolol treatment, but only HF power during daytime was statistically increased with bisopro101 compared with placebo. Figure 1 shows an example of the increase in I-IF power in a patient after 2 months of therapy with bisoproJo1. The action of bisoprolol on HRV was not influenced by gender. The effects of 2 months of bisoprolol on HRV were not significantly different in patients with ischemic heart failure or idiopathic dilated cardiomyopathy. Heart rate variability as a predictive risk factor: Five patients from the Holter study died during the follow-up of CIBIS (mean follow-up, 1.9 year) : 4 in the bisoprolol group and 1 in the placebo group (p = 0.49). The mode of death was end-stage heart MARCH

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CONTROL

BISOPROLOL

l.P : UP:

3s *

m

ma 4JI

NIGHT

FIGURE 1. Example of the increase in high-frequency /top), day and night power s tra (bottoms at contr high frequency prolol. Note the increase in Jr* yhme quency power; lF/HF = ratio of low- to high-hequency

wer in a patient in the bisoprolol group. L&pane/, 2Ghour or (baseline before treatment). Right pane/, same spectm after spectrum [arrow). T = total power LF = low-frequency power; power; FFT = fast-Fourier transform.

failure (n = 3 ) and sudden cardiac death (n = 2). At baseline these 5 patients had lower HRV: Mean SDNN value during the daytime was 57 ms (95% confidence interval, 26 to 87) versus 82 ms (95% confidence interval, 74 to 89) in living patients ( p = 0.047). Other HRV components were not significantly different between these 2 groups, especially the mean RR interval during daytime (p = 0.36). When we considered patients with death or cardiac decompensation (n = 12, 8 in the bisoprolol group and 4 in the placebo group), they tended to have at CONGESTIVE

baseline reduced SDNN ms (p = 0.07).

power spectrum 2 months of bisoI-IF = high-fre-

during daytime:

53 vs 69

DISCUSSION These results indicate that in heart failure, ,&blocker therapy is associated with both RR interval changes ( 19.6% heart rate reduction) and partial restoration of HRV. This is the first placebo-controlled study on the effects of p blockade on HRV in heart failure. Patients with heart failure have faster heart rates, which partly account for the depression of HRV.1,2*15 HEART FAILURE/BISOPROlOl

AND

HEART RATE VARIABILITY

615

The autonomic imbalance, consisting of an attenuation of parasympathetic activity and a predominance of sym athetic drive, also accounts for this depression.16TR We observed a large intersubject range in HRV parameters due to different levels of the sympathetic compensatory tone which depends on severity of the disease, drugs, extent of P-adrenoceptor down-regulation, or age of the patient, and so forth. Clinical stability, a prerequisite for inclusion in CIBIS study, could partly explain the relatively high values of HRV parameters in some patients. We did not find any correlation of HRV with the clinical characteristics of heart failure, such as functional class. Although global indexes of HRV, SDNN, and total power were correlated with ejection fraction, HRV seems to be a marker of sympathovagal balance rather than of severity of left ventricular dysfunction. The effects of @blockers on HRV parameters depend on ( 1) their influence on the sympathovagal balance and (2) on the importance of bradycardia. It is almost impossible to distinguish any part of each effect. It is especially important for the SDNN. In accordance with other investigators, we found a slight correlation between mean RR interval and SDNN.3,9*18 However, it has been reported that for a similar heart rate, normal young subjects have higher SDNN than patients with congestive heart failure.’ In our study, bisoprolol increased SDNN during daytime. The 24-hour SDNN did not increase significantly, mainly because of a decrease in day-night differences in the average RR interval in the bisopro101 group. In this study, the influence of heart rate seems to be less important on pNN50 and on rMSSD. With bisoprolol, we observed an increase in these 2 measures of tonic vagal activity. Cook et al, I9 giving atenolol to healthy subjects, and Molgaard et al, ‘O giving metoprolol to survivors of myocardial infarction, reported similar changes. HF power in the power spectrum also reflects parasympathetic modulation, In our study, bisoprolol increased HF power, especially during daytime. Such an increase has been reported with p blockers in normal young subjects and after myocardial infarction.19*21 Changes in respiratory rate must also be taken into account in the interpretation of the increase in HF power with bisoprolol. It has been demonstrated that HF power decreases with the increase in respiratory rate.22 After 2 months of treatment, no significant change in New York Heart Association functional class was observed in the 2 groups. Thus, we can suggest that no significant change in respiratory rate occurred during this time period. In a preliminary result of a controlled study with carvedilol in heart failure, Schramm et a123 observed an increase in all components of the power spectrum. The lack of significant change in LF spectral domain does not suggest that bisoprolol leaves intact cardiac sympathetic activity in the heart; rather, these results may indicate that in LF power, the decrease in the sympathetic component was blunted by the increase in parasympathetic component. Indeed, LF power reflects both 616

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parasympathetic and sympathetic activity.24 Moreover, the algorithm applied in spectral analysis probably caused an overestimation of LF power because very LF and LF bands were not separated. The mechanism for the increase in vagal activity is not clear. Perhaps bisoprolol increased HRV by a central parasympathomimetic effect. The confounding influence of the other treatments should be considered in the interpretation of the data. In our study, most patients received angiotensin-converting enzyme inhibitors which increase vagal activity in heart failure.25 Digitalis has been demonstrated to produce marked and sustained reduction in sympathetic nerve activity in heart failure.26 Moreover, digitalis is known to have a vagotonic effect, and a recent study indicates that long-term therapy with digoxin substantially increases parasympathetic activity.27,28 Although there is no significant difference between the 2 groups, digitalis, widely prescribed in the study, could have potentiated the bisoprolol-induced parasympathetic tone. The association between abnormalities of HRV and cardiac death could be of particular interest in heart failure. In the Framingham study, SDNN was a significant predictor of all-cause mortality after adjusting for other risk factors.18 After myocardial infarction, HRV has been shown to have an independent and predictive value for survival.3 Patients who died during the follow-up of the CIBIS trial had lower SDNN at baseline, especially during daytime. The estimation of HRV may offer another prognostic marker in heart failure. Further larger studies are necessary to confirm the validity of risk stratification by HRV in heart failure. The mechanism responsible for the prevention of sudden cardiac death by /? blockade is thought to be caused by a reduction in excess sympathetic activity to the heart. Our study suggests that P-blocker therapy may additionally increase vagal activity in heart failure. Part of the beneficial effect can be related to increased vagal activity, per se. A link between P-blockade intervention associated with an increase in HRV and possible beneficial effects on prognosis must be confirmed. Acknowledgment: We thank Yves Faisandier, MD, for his technical assistance.

APPENDIX Investigators: Paul (Rotterdam, Holland); (Freyming Merlebach, trice Morelon (Dijon, cardo Seabra Games United Kingdom).

Bernadet (Toulouse, France); Robert Campricotti Ariel Cohen (Paris, France); Pierre Dambrine France); Vinzenz Hombach (Ulm, Germany); PaFrance); Jean-Claude Quiret (Amiens, France); Ri(Linda-A-Velha, Portugal); Bernard Silke (Belfast,

1. Saul JP, Arai Y, Berger RD. Lilly LS, Colucci WS, Cohen RJ. Assessment of autonomic regulation in chronic congestive heart failure by heart rate spectral analysis. Am J Car&l 1988;61:12921299. 2. Casolo G, Balli E, Taddei T, Amumasi J, Gori C. Decreased spontaneous heart rate variability in congestive heart failure. Am .I Cat-did 1989$X: 1162- 1167. 3. Kleiger RE, Miller JP, Bigger IT, Moss AJ, and the multicenter post-infarction beart rate variability and its aswciadon with increased research group. Deaemed mortality after myocardial infarction. Am J Cm-did 1987;59:256-262. 4. Olsson G, Wikstraad J, Warnold I, Manger-Cats V, McBoyle D, Herlitz I, Hjalmarson A, Sonnenblick EH. Metoprolol induced reduction in postinfarction

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mortality: pooled results from five double-blind randomized trials. Eur Heart J 1992;13:28-32. 5. CIBIS Investigators and Committees. A randomized trial of P-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circularion 1994:90:1765-1773. 6. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver NA, Gilbert EN, Johnson NR, Goss FG, Hjalmarson A, for the Metoprolol in Dilated Cardiomyopathy (MDC) trial study group. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993;342: 1441- 1446. 7. Bigger JT, Fleiss JL, Steimnan RC, Roltitzky LM, Kleiger RE, Romnan JN. Correlations among time and frequency domain measures of heart period variability hvo weeks after acute myocardial infarction. Am J Car&l 1992;69:891-899. 8. Stein PK, Bosner MS, Kleiger RE, Conger BM. Heart rate variability: a measure of cardiac autonomic tone. Am Heart J 1994;127:1376-1381. 9. Van Hoogenhuyze D, Weinstein N, Martin GJ, Weiss JS, Schaad IW, Sahyouni XN, Fintel D. Remme WJ, Singer DH. Reproducibility and relation to mean heart rate of heart rate variability in normal subjects and in patients with congestive heart failure secondary to coronary artery disease. Am J Cardiol 1991;68:1668-1676. 10. Kleiger RE, Bigger JT, Bosner MS, Chung MK, Cook JR, Rolnitzky LM, Steinman R. Fleiss JL. Stability over time of variables measuring heart rate variability in normal subjects. Am J Cardiol 1991;8:626-630. 11. Ewing DJ, Neilson JMM. Travis P. New method for assessing cardiac parasympathetic activity using 24 hour electrocardiograms. Br Heart J 1984;52:396-402. 12. Akselrod S, Gordon D, Ubel FA, Barger AC, Cohen RJ. Power spectrum analysis of heart rate fluctuations: a quantitative probe of beat-to-beat cardiovascular control. Science 1981;213:220-222. 13. Pomeranz B, Macaulay RJB, Caudil MA, Kutz I, Adam D, Gordon D, Kilbom KM, Barger AC, Shannon DC, Cohen RJ, Benson H. Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol 1985;248(H):l51-153. 14. Pagani M, Lombardi F, Guzzetti S, Rimoldi 0, Furlan R, Pizzinelli P, Sandrone G, Malfatto G, Dell’Orto S, Piccaluga E, Turiel M, Baselli G, Cermti S, Malliam A. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res 1986:59:178-193. 15. Kienzle MG, Ferguson DW, Birkett CL, Myers GA, Berg WJ, Mariano DJ. Clinical, hemodynamic and sympathetic neural correlates of heart rate variability in congestive heart failure. Am J Cardiol 1992;69:761-767.

CONGESTIVE

16. Binkley PF, Nunziata E, Haas GJ, Nelson SD, Cody RJ. Parasympathetic withdrawal is an integral component of autonomic imbalance in congestive heart failure: demonstration in human subjects and verification in a paced canine model of ventricular failure. JAm Co11 Cardiol 1991;18:4.@-472. 17. Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac paraaympathetic control in patients with heart disease. N Engr J Med 1971;285:877-883. 18. Tsuji H, Venditti FJ, Manders ES, Evans JC, Larson MG, Feldman CL, Levy D. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation 1994;90:878-883. 19. Cook JR, Bigger JT, Klieger RE, Fleiss JL, Steinman RC, Rolnitsky LM. Effect of atenolol and diltiazem on heart period variability in normal persons. JAm Coil Cardiol 1991;17:160&1612. 20. Molgaard H, Mickley H, Pless P, Bjerregaard P, Moller M. Effects of metoprolol on heart rate variability in survivors of acute myocardial infarction. Am J Cardiol 1993;71:1357-1359. 21. Sandrone G, Mortara A, Torzillo D, La Revere MT, Malliani A, Lombardi F. Effects of beta blockers (atenolol or metoprolol) on heart rate variability after acute myocardial infarction. Am J Cardiol 1994;74:340-345. 22. Sanderson JE, Yeung D, Yeung L, Kay R, Tomlinson B. Bern&i L, Woo JM. Different respiratory rates affect the measurement of autonomic tone by power spectral analysis of heart rate variability in patients with heart failure (abstr). JAm Co[l Cardiol 1995;(suppl):425A. 23. Schramm MS, Marks ML, Olsen SL, Gilbert EM. Chronic o-blocker therapy with carvedilol increases parasympathetic drive in heart failure (abstr). Circulation 1993:88(no. 4, part 2):1-104. 24. Malliani A, Pagani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain. Circulation 1991;84:482-492. 25. Osterziel KJ, Rhorig N, Dietz R, Manthey J, Hech J, Khubler W. Influence of captopril on the arterial baroreceptor reflex in patients with heart failure. Eur Heart J 1988;9:1137-1145. 26. Ferguson DW, Berg WJ, Sanders JS, Roach PJ, Kempf JS, Kienzle MG. Sympathoinhibitory responses to digitalis glycosides in heart failure patients: direct evidence from sympathetic neural recordings. Circulation 1989;80:6577. 27. Partanen J. Effects of intravenous digoxin on the heart at rest and during isometric exercise: a noninvasive study in normal and autonomically blocked volunteers. J Cardiovasc Pharmacol 1988:11:158166. 28. Kmm H, Bigger T, Goldsmith R, Packer M. Effect of long-term digoxin therapy on autonomic function with chronic heart failure. J Am Coil Cardiol 1995;25:289-294.

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HEART

RATE VARIABILIW

617