Stability of index of heart rate variability in patients with congestive heart failure

Stability of index of heart rate variability in patients with congestive heart failure Stability of indexes of heart rate variability (HRV) has not been established for patients with congestive heart failure (CHF). We therefore measured Holter-derived HRV indexes in 17 stable patients with class II or III CHF (mean age 52 +_ 9 yr; 5 men and 12 women) on two occasions 2 weeks apart. Stability was determined via paired t tests and intraclass correlation coefficients (ICCs). ICCs for time domain indexes of HRV were -->0.86 for 24 hours, -->0.73 for daytime, and ->0.72 for nighttime indexes reflecting longer-term variability. After log transformation, ICCs for the short-term 24-hour measures PNN50 (percentage of N-N intervals >50 msec different from preceding interval) and RMSSD (the root mean square of successive differences) were 0,85 and 0.67. ICCs for frequency domain indexes of HRV were 0.86 to 0.91. We compared HRV indexes, serum norepinephrine (NE) levels, and respiratory sinus arrhythmia induced by paced breathing, also considered measures of autonomic tone. NE correlated weakly with average R-R interval, and all indexes of HRV reflecting longer-term variation (r = - 0.32 to r = - 0.50). ICC was 0.78 for NE. Respiratory sinus arrhythmia was highly repeatable (ICC = 0.70) but did not correlate significantly with NE or any measure of HRV. We conclude that time and frequency domain indexes of HRV are stable over time in CHF patients without intervening events. (AM HEART J 1995;129:975-81.)

Phyllis K. Stein, PhD, Michael W. Rich, MD, Jeffrey N. Rottman, MD, and Robert E. Kleiger, MD St. Louis, Mo.

There is considerable evidence that neurohumoral balance and autonomic tone play an important role in predicting survival of congestive heart failure (CHF) patients. Serum norepinephrine level is one of the best predictors of clinical status and prognosis in patients with CHF. 1, 2 Serum norepinephrine levels have been shown to reflect activation of the sympathetic nervous system, which is evoked by the fall in cardiac output, i, 2 Indeed, "the sympathetic nervous system is activated in proportion to the severity of the disease. ''3 Thus assessment of autonomic function in CHF patients has important prognostic value. Indexes of heart rate variability (HRV) have proved to be sensitive measures of cardiac autonomic tone. 4 Moreover, indexes of H R V have shown great value as predictors of mortality after myocardial infarction. 5-7 From the Division of Cardiology, The Jewish Hospital of St. Louis, Washington University Medical Center. Partially supported by General Clinical Research Center Grant 5-M01RR0036. Received for publication Oct. 3, 1994; accepted Nov. 21, 1994. Reprint requests: Phyllis K. Stein, PhD, Division of Cardiology, Jewish Hospital of St. Louis, Washington University Medical Center, 216 S. Kingshighway, St. Louis, MO 63110. Copyright ® 1995 by Mosby-Year Book, Inc. 0002-8703/95/$3.00 + 0 4 / 1 / 6 2 9 3 0

At least one preliminary study has supported the hypothesis that indexes of H R V have prognostic value in patients with advanced CHF and may, in fact, be superior to other conventional measures of prognosis in these patients, s A variable that remains stable with repeated measurement over clinically relevant periods and is unaffected by placebos is ideal for interventional studies or for tracking changes in clinical state because smaller sample sizes and fewer independent measurements are required. On an observational level, changes observed in such variables are more likely to represent alterations in clinical status. HRV has been shown to have these qualities in normal controls, 9 in post-myocardial infarction patients, 1° patients with ventricular arrhythmias, 1° and in people with diabetes, n In patients with CHF, Van Hoogenhuyze et al. 12 found good reproducibility of indexes of HRV measured on 2 sequential days in a small group of stable class II and III patients. There are no studies reporting the stability of H R V over longer periods of time in this population. Although H R V is usually determined through analysis of ambulatory electrocardiograms, respiratory sinus arrhythmia induced by paced breathing may provide a rough measure of vagal tone. 13 This 975

976 Stein et al. t e c h n i q u e has the p o t e n t i a l a d v a n t a g e of being easily o b t a i n e d in an office setting. However, the relation b e t w e e n r e s p i r a t o r y sinus a r r h y t h m i a a n d H R V assessed b y a m b u l a t o r y E C G m o n i t o r i n g has not b e e n established. In s u m m a r y , H R V analysis m a y be a useful tool in assessing prognosis in C H F patients, b u t t h e r e are several limitations to the existing data. T h u s the p r e s e n t s t u d y was designed to address the following questions: (1) Are t i m e a n d f r e q u e n c y dom a i n indexes of H R V reproducible over a 2-week interval in stable C H F p a t i e n t s ? (2) H o w does t h e reproducibility of indexes of H R V c o m p a r e with the reproducibility of s e r u m n o r e p i n e p h r i n e levels over a 2-week interval in stable C H F p a t i e n t s ? (3) H o w does the reproducibility of indexes of H R V c o m p a r e with the r e p r o d u c i b i l i t y of r e s p i r a t o r y sinus a r r h y t h m i a induced b y p a c e d b r e a t h i n g r e p r o d u c i b l e over a 2-week interval in stable C H F p a t i e n t s ? (4) Can ind e x e s of H R V be used as surrogates for s e r u m norepinephrine or r e s p i r a t o r y sinus a r r h y t h m i a in stable CHF patients?

METHODS Subjects. Twenty subjects gave informed consent for this study, which was approved by the Institutional Review Board. Two subjects found to have atrial fibrillation were excluded from further testing. After Holter analysis, another subject was found to have wandering atrial pacemaker and was excluded from further analysis. Thus 17 subjects formed the basis for this report. Subjects (mean age 52 + 9 years, 5 men and 12 women) were clinically stable (no hospitalizations, changes in medications, or events for 2 months) CHF patients, New York Heart Association functional class II or III, in sinus rhythm. The cause of CHF, as documented by physician reports, was cardiomyopathy in 9 (6 idiopathic, 2 hypertensive, and 1 a result of chemotherapy), and ischemic heart disease in 8. Patients with insulin-dependent diabetes, a history of alcoholism, or chronic obstructive pulmonary disease were excluded. Patients continued their regular medications during the study. Fifteen subjects were taking angiotensin-converting enzyme inhibitors, 16 diuretics, 10 cardiac glycosides, and 5 blinded medication that was either digitalis or placebo. Three patients were receiving fl-blockers. Protocol. Patients returned on an outpatient basis on two occasions, 2 weeks apart. Testing occurred at the same hour on both occasions. A Holter recorder (series 8500, Marquette Electronics, Milwaukee, Wis.) was placed on the patient, after which an indwelling catheter with a heparin lock was inserted into an antecubital vein. The patient rested comfortably for a minimum of 30 minutes in a supine position before 5 ml of blood was drawn. The blood sample was placed in a heparinized container, mixed by inversion 20 times, and immediately placed in an ice bath. Within 30 minutes the blood was centrifuged at 1000g for 20 minutes at 2 ° to 4 ° C and then stored at - 7 0 ° C. After

May 1995 American Heart Journal

the blood was drawn and the antecubital catheter removed, the output signal from the Holter recorder was routed into a standard ECG machine. As heart rates were being recorded simultaneously on the Holter monitor and the ECG machine, supine patients performed 30 seconds of continuous paced breathing at low frequency (6 complete breaths/min) to assess respiratory sinus arrhythmia. The patients' breathing was cued and observed. Patients undertook their usual daily activity and returned after 24 hours for Holter removal. Serum norepinephrine. Blood samples for one patient were lost during storage, and one sample could not be analyzed for technical reasons. Thus serum norepinephrine results were available for 31 visits. Blood samples were analyzed at the Core lab of the Clinical Research Center at Washington University Medical School by the high-performance liquid chromatography method with coulometric detection and reverse phase column chromatographyJ 4 The resulting chromatograph peaks for norepinephrine, epinephrine, and dihydroxybenzylamine (internal standard) were compared with peaks from standard known quantities. 14 Interassay and intraassay reliability of this method at the Core lab has been shown to be within 6 % to 8% for norepinephrine (S. Shah, Core Lab Director, personal communication). , Respiratory sinus arrhythmia induced by paced breathing. ECG strips obtained during paced breathing were analyzed manually by the peak-to-trough methodJ 5 Respiratory sinus arrhythmia was defined as the average of the longest interbeat interval minus the shortest interbeat interval for each breath over three respiratory cycles. The changing height of the R waves and the timing of the ECG strip were used to delineate the breathing cycles. When a ventricular premature contraction occurred during one of the respiratory cycles, the average of two cycles was used. Frequent ventricular premature contractions during paced breathing precluded determination of respiratory sinus arrhythmia in three patients. Analysis of 24-hour ECG recordings. All Holter tapes were analyzed by using a Marquette 8000 scanner and version 5.8 of the Marquette analysis program. After the scanner had automatically detected and labeled all QRS complexes, the data file was reviewed and edited by a technician who used standard Holter analysis procedures. After editing, the labeled QRS data stream was transferred to a Sun workstation for secondary editing and analysis for time and frequency domain measures of H R V J 6 A minimum of 18 hours of analyzable data was required for a tape to be accepted as valid} ~ Time domain analysis of successive N-N intervals. The following time domain measures of heart rate and heart rate variability were calculated for daytime (8 AM to 10 PM), nighttime (midnight to 6 AM) and 24-hour periods: AVGNN (average heart period in milliseconds); SDNN (the SD of heart period in milliseconds); SDANN (the SD of 5-minute mean values of N-N intervals for each 5-minute interval in milliseconds); SDNNIDX (the average of SDs of N-N intervals for each 5-minute interval in milliseconds);

Volume 129, Number 5 American Heart Journal

Table

I. Baseline and 2-week 24-hour time-domain indexes of heart rate and heart rate variability in stable patients with CHF

Average HR AVGNN (msec) Minimum HR Maximum HR SDNN (msec) SDANN (msec) SDNNIDX (msec) rMSSD (msec) In rMSSD pNN50 (%) In pNN50

977

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Baseline

2-week values

[CC

84 ± 10 723 ± 88 56 ± 10 131 ± 13 98 _+37 89 ± 35 35 ± 13 21 ± 8 3.0 ± 0.4 3.0 ± 3.2 -0.8 ± 3.6

83 ± 10 724 ± 86 56 + 9 129 _+ 14 104 _+ 37 95 ± 36 35 ± 13 20 +_ 6 2.9 _+0.3 2.5 ± 2.7 -0.6 ± 3.1

0.95 0.88 0.67 0.36 0.91 0.88 0.87 0.49 0.67 0.27 0.83

M e a s u r e m e n t s are presented as m e a n _+ SD. AVGNN, average of all normal-to-normal IN-N] intervals; rMSSD, root m e a n square of successive differences; pNNSO,percentage of N - N >50 msec different from preceding interval; SDANN, SD of 5-minute average of N - N intervals; SDNN, SD of all N - N intervals; SDNNIDX, average of 5-minute SD of N - N intervals.

rMSSD (the root mean square of successive difference of N-N intervals in milliseconds) and pNN50 (the proportion of successive N-N differences >50 msec in percentage). Power spectral analysis of N-N intervals. The following frequency domain variables were considered in this analysis: high-frequency power (0.15 to 0.40 Hz) in milliseconds 2, low-frequency power (0.04 to 0.15 Hz) in milliseconds 2, very-low-frequency power (0.00335 to 0.04Hz) in milliseconds 2, ultra-low-frequency power (1.15 × 105 to 0.0033Hz) in milliseconds 2, and total power (1.15 × 10-5 to 0.40 Hz) in milliseconds 2. Heart period power spectra were computed for each 5-minute segment of each 24-hour recording. All segments in which <80 % of R-R intervals are bounded by normal beats were excluded. The methods used for spectral analysis have been described and validated previouslyJ 61s A continuous function was constructed from the sequence of N-N intervals determined by the Marquette scanner. This function was filtered and then resampled at 252 msec to produce a time series for spectral analysis. Missing or noisy segments were replaced by linear interpolation from the surrounding signal. The average N-N interval was subtracted from the time series, a Hanning filter was applied, and fast Fourier transforms were performed to determine the frequency components underlying the cyclic activity in the time series. Measurement of ultra-low-frequency power, which reflects circadian rhythms and other longer-term rhythms, and very-lowfrequency power were based on the entire 24-hour record: ingJ 6 Frequency domain indexes of HRV have a markedly skewed distribution. 19 To permit parametric statistical comparisons, which presume a normal distribution, log transformation of frequency domain values was used. 19 Statistics. The reproducibility over time of indexes of HRV, respiratory sinus arrhythmia, and serum catecholamine levels were assessed by paired t tests. Significance value was set at p < 0.05. In addition, the strength of asso-

1000950 WUJ 9 0 0 850800750-

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Fig. 1. Stability over time of time-domain measures of heart rate and heart rate variability in 17 stable patients with CHF. T I M E 1, Initial visit; T I M E 2, second visit. Error bars show mean ___SD.

ciation between baseline and 2-week values was measured by calculation of the ICC. This statistic is a measure of intrasubject reproducibility. 2° To assess the relation among serum catecholamines, respiratory sinus arrhythmia, and indexes of HRV, values for both recordings were combined into a single data set and correlational analyses were performed.

RESULTS Table I and Fig. 1 show the stability of 24-hour t i m e - d o m a i n indexes of h e a r t rate and HRV. All H R V p a r a m e t e r s reflecting longer-term variability, t h a t is, minutes to hours, remained virtually identical, with no significant test-retest differences over the 2-week period. Intraclass correlation coefficients (ICCs) for S D N N , S D A N N , and S D N N I D X were all ~ 0 . 8 7 (p <0.001). On the other hand, ICCs for p N N 5 0 and r M S S D , both measures of s h o r t - t e r m variability, were m u c h lower. However, values of p N N 5 0 and r M S S D for this p a t i e n t p o p u l a t i o n are m u c h lower t h a n values for normals 4 and, as such, fall at the extreme end of a censored distribution, p N N 5 0 and r M S S D were log transformed, providing a more normal distribution, and ICCs improved to 0.83 for n a t u r a l logarithm (ln)(pNN50) and 0.67 for ln(rMSSD). T h u s p N N 5 0 and r M S S D are also repeatable measures of H R V in studies of patients with CHF. Table II shows the stability of d a y t i m e and night-

978

May 1995 American Heart Journal

Stein et al. 10.5109.598.5-

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Fig. 2. Stability over time of frequency-domain measures of heart rate variability in 17 stable patients with CHF. Error bars show mean + SD. ULF, Ultra low frequency; VLF, very low frequency; LF, low frequency; HF, high frequency; TIME 1, initial visit; TIME 2, second visit.

Table II. Baseline and 2-week daytime and nighttime indexes of heart rate and heart rate variability in stable patients with CHF Daytime (8 AM-IO PM) Baseline AVG N N (msec) S D N N (msec) S D A N N (msec) S D N N I D X (msec) r M S S D (msec) In r M S S D p N N 5 0 (%) In p N N 5 0

687 84 74 36 21 2.9 3.0 -1.7

± ± ± ± ± ± ± ±

81 27 24* 14 11 0.4 4.4 4.0

2-Week values 684 91 84 34 19 2.9 2.0 -0.7

± + + ± ± + ± ±

77 29 28* 12 5 .3 1.8 3.0

Nighttime (Midnight-6 AM) ICC 0.92 0.77 0.73 0.78 0.20 0.51 0.37 0.64

Baseline 798 64 49 36 22 3.0 3.8 -0.62

± ± ± ± ± ± ± ±

132 28 24 14 7 0.4 3.6 3.7

2-Week values 812 66 50 38 23 3.0 4.3 -0.8

± 139 ± 27 ± 23 ± 16 ± 10 _+ 0.4 _+ 6.4 ± 3.6

ICC 0.97 0.83 0.72 0.95 0.70 0.81 0.43 0.75

Abbreviations as in Table I. *Significantly different, p = 0.05.

time time-domain indexes of HRV. Daytime and nighttime indexes of H R V were virtually unchanged between determinations. Consisteat with 24-hour results, ICCs for longer-term indexes of H R V were high (ICC >_0.73 for daytime and ICC ~0.72 for nighttime). Nighttime ICCs for rMSSD (ICC = 0.70) and pNN50 (ICC = 0.43) were higher than for 24hour measures. Log transformation resulted in ICCs of 0.81 for nighttime rMSSD and 0.75 for nighttime pNN50. Table III and Fig. 2 show the stability of 24-hour log-transformed frequency domain indexes of HRV. All frequency-domain measures showed good repeat-

ability with no significant test-retest differences. Moreover, ICCs for frequency domain indexes of H R V were uniformly high, ranging from 0.86 for In high frequency to 0.91 for In total power, In ultra low frequency, and In very low frequency. H R V reflects autonomic tone. 4 Measurement of serum norepinephrine provides an alternative method of assessing sympathetic activation. Respiratory sinus arrhythmia has been suggested as a measure of parasympathetic tone. We therefore investigated the reproducibility of these measures and their relation to indexes of HRV. Table IV shows baseline and 2-week values for respiratory sinus ar-

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Table III. Baseline and 2-week values for 24-hour frequen-

Table IV. Baseline and 2-week values for non-HRV vari-

cy-domain indexes of HRV on stable patients with CHF

ables in CHF patients*

Baseline in In In In In

TP ULF VLF LF HF

8.7 8.5 6.4 5.1 4.3

+_ + + + _+

0.9 0.9 0.8 1.0 1.0

2-Weeks values 8.8 8.6 6.4 5.2 4.3

+ _ _+ _ +

0.9 0.9 0.8 0.9 1.0

ICC

Measurement

Baseline

2-Week value

ICC

0.91 0.90 0.91 0.88 0.86

No. of VE No. of SVE Respiratory sinus a r r h y t h m i a (msec)t P l a s m a norepinephrine (pg/ml)$

1175 _+ 2347 300 -+ 851 149 _+ 102

1583 -+ 2508 176 -+ 249 149 _ 149

0.98 0.29 0.70

339 _+ 143

342 - 134

0.78

I-IF, High-frequency power: 0.15-0.040 Hz; LF, low-frequency power: 0.040.15 Hz; TP, total power: 1.15 x 10-5-0.0033-0.40 Hz; ULF, ultra-lowfrequency power: 1.15 x 10-5-0.0033 Hz; VLF, very-low-frequency power: 0.00335-0.04 Hz.

rhythmia, serum norepinephrine, and ventricular and supraventricular ectopic activity. ICCs were 0.78 for serum norepinephrine and 0.70 for respiratory sinus arrhythmia. Table V shows the relation between serum norepinephrine, respiratory sinus arrhythmia, and indexes of HRV. These data are based on all recordings for which serum norepinephrine values are available (n = 31 because most patients had two independent determinations of HRV and serum norepinephrine). Serum norepinephrine correlated significantly with In low frequency (r = - 0.50), in total power (r = - 0.46), In ultra low frequency (r = - 0.45), SDNN (r = - 0.44), In very low frequency (r = - 0.44), SDANN (r = - 0.41) and AVGNN (r = - 0.32). In addition, although not shown in the table, serum norepinephrine correlated significantly with daytime SDNN and SDANN (r = - 0.64). Respiratory sinus arrhythmia induced by paced breathing did not correlate significantly with serum norepinephrine or with any index of HRV.

Values are presented as mean _+ SD. SVE, Supraventricular beats; VE, ventricular ectopic beats. *Unless otherwise noted, n = 17. tn = 14. Sn = 15.

Table V. Corrections of serum norepinephrine and respi-

ratory sinus arrhythmia with heart rate and time- and frequency-Domain indexes of HRV

AVGNN SDNN SDANN SDNNIDX rMSSD pNN50 In T P In U L F In VLF In LF in H F S e r u m norepinephrine

Serum norepinephrine (n = 31)

Respiratory sinus arrhythmia (n = 30)

-0.32* -0.44t -0.41" -0.41" -0.12 -0.13 -0.46t -0.45t -0.44t -0.50t -0.24 1.00

0.02 0.01 0.00 0.07 0.12 0.25 -0.06 -0.07 -0.04 0.18 0.16 -0.21

Abbreviations as in Tables I and IV. *Correlation statistically significant, p < 0.05. tCorrelation statistically significant, p < 0.01.

DISCUSSION

The results of the current investigation indicate that both longer-term time-domain and frequencydomain 24-hour indexes of HRV are highly reproducible in stable patients with class II or III CHF. It should be noted that the reproducibility of HRV indexes over the 2-week period was at least as good as that for serum norepinephrine. Respiratory sinus arrhythmia induced by paced breathing also showed good reproducibility. Although it is difficult to make a priori statements comparing ICCs without large (e.g., >0.20) differences (Fleiss 2° and personal communication), the difference in repeatability between the best measures of HRV (ICC >0.90) and respiratory sinus arrhythmia and serum norepinephrine (ICC <0.78) suggests that HRV may be a more reliable measure. The poor reproducibility of pNN50 and rMSSD

can be partly explained by their highly skewed distribution (Fig. 1, pNN50). Low values for indexes of vagal tone found in our patients are consistent with other reports. 21 Thus log transformation of these variables proved to be a necessary preliminary step in this population. The relation between serum norepinephrine and HRV was statistically significant, but correlations were only moderate. This is probably because indexes of HRV reflect both sympathetic and parasympathetic influences.4 Correlations were better for serum norepinephrine and SDNN and SDANN during the daytime when sympathetic tone is higher. Not surprisingly, there was no significant correlation between serum norepinephrine and the indexes of HRV, primarily reflecting vagal tone. These results

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Stein et al.

are generally consistent with the findings of Kienzle et al. 22 In 23 patients with predominantly class III to IV CHF, who were taking no medications, correlations were r = - 0.72 for serum norepinephrine and In power in the range of 0.05 to 0.15 Hz. However, because their sampling was done on 2-minute segments of the R-R signal, longer-term components, that is, frequencies >1 cycle/min of HRV, could not be determined. Although correlations were lower in the current investigation, this difference may in part be the result of the wider range of serum norepinephrine values in-the Kienzle et al. study (128 to 1530 pg/ml) compared to the current investigation (140 to 688 pg/ml). An important finding of this study is the lack of a significant relation between respiratory sinus arrhythmia induced by paced breathing and either serum catecholamines or any Holter-derived index of HRV. Clearly, respiratory sinus arrhythmia induced by paced breathing cannot be used as a surrogate for HRV or serum norepinephrine. Although respiratory sinus arrhythmia has been clearly correlated with vagal efferent outflow in anesthetized animals, 13 the relation between respiratory sinus arrhythmia induced by slow, paced breathing and vagal tone has not been characterized. Eckberg 23 has shown that the amount of respiratory sinus arrhythmia measured by the peak-to-trough method increases with respiratory period. At the breathing frequency used in this investigation, respiratory sinus arrhythmia in Eckberg's healthy subjects was approximately 250 _+ 50 milliseconds, considerably more than the 149 milliseconds recorded in our CHF patients. Respiratory sinus arrhythmia induced by paced breathing appears to have both an autonomic and nonautonomic component. Hrushesky 24 has shown that respiratory sinus arrhythmia induced by paced breathing is reduced but does not disappear under conditions of autonomic blockade and in autonomic neuropathy. Using transmitral Doppler flow measurements, Hrushesky showed that "basal" respiratory sinus arrhythmia appears to reflect myocardial distensibility. Thus in the current study, in CHF patients with decreased vagal tone, the relative contribution of the nonautonomic component of respiratory sinus arrhythmia may be exaggerated by the deep, slow breathing. Also, although none of the correlations is statistically significant, an examination of Table V shows the highest correlations between respiratory sinus arrhythmia and indexes reflecting vagal tone. We suspect that respiratory sinus arrhythmia may be most comparable to baroreceptor sensitivity, another index of autonomic function that has been shown to be poorly correlated with HRV. is

In conclusion, the results of this study affirm that indexes of HRV determined by 24-hour Holter monitoring are stable and reproducible in patients with class II and III CHF when they take their usual medications. In addition, although some indexes of HRV correlate significantly with serum norepinephrine levels, the correlation is not sufficiently high for them to be considered surrogates. The moderate correlation of serum norepinephrine and indexes of HRV is consistent with the hypothesis that longer:term measures of HRV reflect influences other than sympathetic tone. Also, in post-myocardial infarction patients Bigger et al. 25 have reported that the strongest predictors of mortality in the frequency domain are ultra-low-frequency power and very-low-frequency power, both of which reflect longer-term and circadian rhythms rather than simply sympathetic or parasympathetic input to the heart. Moreover, analysis of HRV provides information about vagal tone that is unrelated to serum catecholamines and sympathetic tone. Although historically the emphasis in CHF research has been on elevated sympathetic tone, more recently some investigators have begun to look at concomitant withdrawal of parasympathetic tone. Nolan et al. 26 reported that indexes of parasympathetic activity are reduced in patients with CHF as a result of myocardial ischemia and reported a correlation of r = 0.49 between counts (an index similar to pNN50) and LVEF. Binkley et al. 21 reported that analysis of HRV in patients with idiopathic cardiomyopathy and in dogs measured longitudinally in a paced canine model of CHF showed evidence of enhanced sympathetic tone and reduced parasympathetic tone. Indexes of HRV can provide stable, clinically useful measures for studies of prognosis among CHF patients. We t h a n k Andrew F. Hall for assistance in the preparation of this m a n u s c r i p t .

REFERENCES

1. Cohn JN, Levine TB, Olivari MT. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819-23. 2. Massie BM, Conway M. Survival of patients with congestive heart failure: past, present, and future prospects [Abstract]. Circulation 1987; 75(suppl IV):IV-11. 3. Packer M. Modulation of functional capacity and survival in congestive heart failure: effects of activation of the sympathetic nervous system. Postgrad Med 1988;96-103. 4. Kleiger RE, Stein PK, Bosner MS, Rottman JN. Time domain measurements of heart rate variability. Cardiol Clin North Am 1992;10:48798. 5. Cripps TR, Malik M, Farrell TS, Camm AJ. Prognostic value of reduced heart rate variability after myocardial infarction: clinical evaluation of a new analysis method. Br Heart J 1991;65:14-9. 6. Kleiger RE, Miller JP, Bigger JT, Moss AJ, Multicenter Post-Infarction Research Group. Decreased heart rate variability and its association

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with increased mortality after acute myocardial infarction. Am J Cardiol 1987;59:256-62. Malik M, Cripps T, Farrell T, Carom AJ. Prognostic value of heart rate variability after myocardial infarction: a comparison of different dataprocessing methods. Med Biol Eng Comput 1989;29:603-11. Binder T, Frey B, Porenta G, Heinz G, Wutte M, Kreiner G, Gossinger H, Schmidinger H, Pacher R, Weber H. Prognostic value of heart rate variability in patients awaiting cardiac transplantation. PACE 1992; 15:2215-20. Kleiger RE, Bigger JT, Bosner MS. Stability over time of variables measuring heart rate variability in normal subjects. Am J Cardiol 1991; 68:626-30. Bigger JT, Fleiss JL, Rolnitzsky LM, Steinman RC. Stability over time of heart period variability in patients with previous myocardial infarction and ventricular arrhythmias. Am J Cardio] 1992;69:718-23. Nolan J, Flapan AD, Goodfield NE, Bloomfield P, Neilson JM, Ewing D. Reproducibility of a time domain measurement of cardiac parasympathetic activity from ambulatory electrocardiograms (ABS) [Abstract]. J Am Coll Cardiol 1993;21:158A. Van Hoogenhuyze DK, Weinstein N, Martin GJ, Weiss JS, Schaad JW, Sahyouni XN, Fintel D, Remme WJ, Singee 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;68:1668-76. Katona PG, Jih F. Respiratory sinus arrhythmia: noninvasive measure of parasympathetic cardiac control. J Appl Physio[ 1975;39:801-5. Van Der Hoorn FA, Boomsma F, Man in 't Veld AJ, Schalekamp MA. Determination of catecholamines in human plasma by high-performance liquid chromatography: comparison between a new method with fluorescence detection and an established method with electrochemical detection. J Chromatogr 1989;487:17-28. Hilsted J, Jensen SB. A simple test for autonomic neuropathy in juvenile diabetics. Acta Med Scand 1979;205:385-7. Rottman JN, Steinman RC, Albrecht P, Bigger JT, Rolnitzky LM, Fleiss J. Efficient estimation of the heart period power spectrum suit-

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