clinical, hemodynamic and sympathetic neural correlates of heart rate variability in congestive...

CONGE6TiVE HEART FAILURE

Clinical, Hemodynamic and Sympathetic Neural Correlates Of Heart Rate Variability in

Congestive Heart Failure Michael G. Kienzle, MD, David W. Ferguson, MD, Clayton L. Birkett, MSBME,

Glenn A. Myers, PhD, W’illiam J. Berg, MD, and D. James Mariano, MD

Heart rate (HR) variabflity has long been recog- niied as a sfgn of cardiac health. In the presence of heart disease, HR variability decrea-, an ob- servation that has been associated with poor prog- nosfs in .a number of recent studies. HR variability is partkufariy altered in congestive heart faikue (CHP), a condition associated with a number of typkai functional, hemodynamic and neurohumoral alterattons. Yhe refation of meaerements of HR variabiilty to these abnormalitfes in patients with heart failure has not been carefully examined. Twenty-three patients (19 men, ‘4 Lvomen, mean age 49 years) wfth New York Heart Association cku II to IV CHF were studied prospectively with- out card&c medications; radionuciide ventriculog- raphy, right-shied heart catheterization, peroneai mf&oneurography, plasma norepinephrine and 24- to 49hour ambulatory electrocardiography were performed. Average RR interval and its standard deviation, and HR power spectrum (0 to 0.5, 0.05 to 0.15 and 0.2 to 0.5 Hz) were derived from the ambubtory electrocardiographic recordings and compared wfth left ventricubr ejection fraction, thermodilution cardiac output, pulmonary arterial wedge pressure, New York Heart Associa- tion class, age, muscfe sympathetii nerve activfty (peroneal nerve) and norepinephrine level by linear regressfon.

None of the measures of HR variability were dgnRkantfy related to age, left ventricular ejec- tfon fraction, cardiac output or functional ctassifi- catfon, whereas the 0.05 to 0.15 and 0.20 to 0.50 Hz components were weakly but significantly re- tated to cardiac output (r = 0.49 and 0.42, p = 9.02 and 0.045, respectively). in contrast, a generally .&ronger and negative relation was demonstrated between spectral and nonspectral measurements of HR variability, and indicators of sympathoexcRa&on, muscle sympathetic nerve ac-

From the Clinical Cardiovascular Physiology Laboratory, Cardiovascu- lar and Clinical Research Centers, and Cardiovascular Division, De- partments of Internal Medicine and Biomedical Engineering, Universi- ty of Iowa, Iowa City, Iowa. Dr. KienzJe is supported by grants from the General Clinical Research Center (National Institutes of Health RR 59, Bethesda, Maryland) and the Iowa Affiliate of the American Heart Association (IA 88-G-18), Des Moines, Iowa. Manuscript received August 26,199l; revised manuscript received November 13,1991, and accepted November 14.

Address for reprints: Michael G. Kienzle, MD, Department of Internal Medicine, 4426 John Colloton Pavilion, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242.

tivity and plasma norepinephrine. This relation was particularly strong with the 0.05 to 0.15 and 0.2 to 0.5 Hz spectral components, and RR standard deviation (r = -0.55 to -0.76, p = 0.04 to O.otu).

it is concluded that the decrease in spectral and nonspectral measurements of HR variabitity that accompanies CHF is not an indicator of the severity of disease, as usually measured clinically, but rather a marker of sympathoexcitation. There- fore, measurements of HR variability may provide noninvasive and unique information regarding neurohumorai maladaptation in heart failure patients.

(Am J Cardioi 1992;69:761-767)

T here are prominent neurohormonal alterations that characterize heart failure. Evidence of sympathoexcitation is readily available; circulating

!evels of norepinephrine, vasopressin and renin are substantially elevated.1-3 Recently, direct measurement of sympathetic neural activity was used in humans to ex- amine the sympathoexcitation associated with clinical heart failure.4,5 Arterial and cardiopulmonary baroreflex control of sympathetic and parasympathetic activity is impaired in both experimental and human heart failure 6-9

Heart rate (HR) variability has long been noted to be abnormal in the presence of heart disease or in alterations in cardiac innervation, as in diabetes melli- tus.l”-13 Recently, investigators showed that diminished HR variability is associated with poor prognostic outcome in patients with organic heart disease and may provide unique information compared with other impor- tant prognostic indicators such as left ventricular ejection fraction and ventricular ectopy.14-l6 Some investigators maintained that HR variability reflects the severity of ventricular dysfunction generally, but little information is available to substantiate this belief.12 Even less data are currently available comparing HR variability with other confirmatory measurements of the neurohormonal state in heart failure. The purpose of the present study was to prospectively compare spectral and nonspectral HR variability (derived from long-term ambulatory electrocardiographic monitoring) with selected clinical, hemodynamic and neurohumoral measurements in a group of patients with moderate to severe congestive heart failure (CHF) to better under- stand. the significance of alterations of HR variability.

HEART RATE VARIABILITY IN HEART FAILURE 761

MmHODS Study patIen& Twenty-three patients (19 men, age

range 24 to 74 years) were prospectively studied. The largest number of patients had idiopathic cardiomyopa- thy, whereas a smaller number had documented coronary artery disease. CHF was moderate to severe, as evidenced by a predominance of New York Heart Asso- ciation class III to IV and by a substantially reduced radionuclide ejection fraction in most patients (mean 0.21 f 0.07). Patients uniformly needed Ll cardiac medication for control of symptoms.

Patients were not studied within 1 month of myocardial infarction. Digitalis glycosides were discontinued 1 week before study and confirmed with a negative digox- in assay. Most oral medications were discontinued for L4 half-lives, and diuretics for 12 hours before the study. In all patients, normal electrolyte status and sinus rhythm were confu?ned before entering the protocol. In- formed written consent was obtained in all cases, and the studies were approved by the institutional review board for human studies. Patients were admitted to the clinical research center. During the first 24 to 48 hours, ambulatory electrocardiographic monitoring was performed. During this time patients were encouraged to engage in activities on the unit that simulated those during usual daily life including sleeping and waking rou- tines, and limited physical activity. Hemodynamic, microneurographic and hormonal measurements were obtained on day 2 or 3. Details of these studies are out- lined later.

vi v Patients underwent resting hemodynamic measurements at the cardiac catheterization laboratory. Hemodynamic measurements at rest included systemic arterial and right heart pressures. Thermodilution cardiac output was determined using 10 ml of iced saline solution injections (mean of 5 injections) with an SAT-l Oximeter/Car- disc Output Computer (American Edwards Laborato- ries, Santa Ana, California), and simultaneous Fick car-

diac output was determined by measuring oxygen con- sumption with a Metabolic Rate Meter (MRM, Waters Instruments, Rochester, MN) and by obtaining blood samples for arterial-mixed venous oxygen content dif- ference.

Left ventricular ejection fraction was determined during normal sinus rhythm by radionuclide ventric- ulography within 2 days of the other studies.

Mieroneurographii reeordii of muscle sympathed- ie nerve activity: In 16 of the 23 patients, we obtained multiunit recordings of postganglionic muscle nerve activity recorded from a muscle nerve fascicle in the peroneal nerve posterior to the fibular head using previously validated techniques. 4,5~17 Briefly described, recordings were obtained by percutaneous insertion of tungsten mi- croelectrodes into the peroneal nerve. The electrodes were connected to a preamplifier, and the recorded signal was directed through a bandpass filter and on through an amplitude discriminator, and visually displayed simultaneously with an audible signal. To facili- tate recording and analysis, the filtered neurogram was processed in a resistance-capacitance integrating net- work resulting in a mean voltage display of the neural activity. Resting nerve activity was recorded for up to 10 minutes to ensure that a stable and representative nerve recording had been obtained. Individual burst fre quency was expressed as bursts/min (intraobserver variability 5% and interobserver variability 10%). An exam- ple of measurements obtained in each patient is shown in Figure 1.

Plasma hormone determinathw Arterial blood samples for plasma norepinephrine were obtained from indwelling arterial catheters at the completion of the consecutive 5minute recordings of hemodynamics and sympathetic nerve activity. Norepinephrine levels were assayed by a single-isotope radioenzymatic method18 having a variability of <7%.

Heart rate variability rn- Twenty-four to 48 hours of continuous ambulatory electrocardio-

w2o PulmE;G&tery

PAP q 44i22 RAP I 7.4

(O-50arW

Rbht Atrial lhxnIre

(g-20 mmHg) 0 I

Electrocardiogram

MSNA (bursts/mln)

FlGUREl.Exwpleof~and mMW--dbshWd withhedfaihre.!ihartsegmentofdeta fromsubjactwithheartfakehshown. --Jmi=m=-mm findtwefheartfakeareevident. lfR=hedr*MAP=menarted prtrua;MSNA=lltUSCk~ mwe~PAP=pdnawyrtery presaqRAP=lfghtatrwpreuure; SAP=systemkmtetialpremre.

762 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69 MARCH 15, 1992

graphic recordings were obtained from each patient, using Marquette 8500 recorders. The tape recording con- sisted of 2 channels of electrocardiographic data, and a timing channel used to correct for wow and flutter of the tape transport mechanism. Tapes were subsequently analyzed on a Marquette 8000 computer-based scanner that generated a file containing the RR intervals and QRS complex classification. This file was then trans- ferred to an IBM PC-AT class computer for HR variability analysis.

An RR interval signal was generated by taking a 2- minute segment of data, and sampling it to fill a 512- point array. Complexes classified as noise or ectopic were rejected. For this study group, the percentage of complexes classified as ectopic averaged 3.6 f 5.2% (range 0 to 17.1). A cubic spline interpolation was used to estimate the RR interval at each point. Segments with >40% of complexes classified as ectopic or noise were not used. Mean RR was subtracted from each segment, and a Hanning window was applied.

The power spectrum of the RR interval signal was calculated using Welch’si variant of the Bartlett proce- dure (overlapping segments of windowed intervals are used to reduce the variance of the power spectral estimate). The power spectrum was calculated as the squared magnitude of the fast Fourier transform for each segment. Segments were overlapped by 50% and averaged for each hour. Amplitude measurements of the power spectrum were multiplied by a factor of 4, and area measurements by 2.66 to correct for the Han- ning window .20

In this study, we determined the spectral power over 3 frequency regions of interest: 0.05 to 0.15, 0.2 to 0.5 and over the entire 0 to 0.5 Hz band. We also determined hourly mean and standard deviations of the RR interval from the same RR files as a more general nonspectral indicator of HR variability.

Stati- analysis: Data are expressed as mean f standard deviation. Variables were compared statistical- ly using a linear regression analysis. Power spectral measurements underwent common log transformation before application of linear regression.

RESULTS Group data: Group data for the study cohort is tabu-

lated in Table I. Substantial evidence is apparent sup porting the presence and severity of CHF in these patients. As mentioned previously, the left ventricular ejection fraction is markedly reduced for the entire group. Left ventricular filling pressure (indicated by pulmonary capillary wedge pressure) was elevated in the vast majority of patients, and cardiac output ranged from 1.6 to 9.3 liters/mm (mean 4.3). Muscle sympathetic nerve activity was clearly elevated compared with that of a group of normal subjects studied previously in our laboratories (16.7 f 2.2 bursts/min).5~21 Heart period averaged 736 f 124 ms (range 523 to 944). Stan- dard deviation of the RR interval averaged 60 f 23 ms, the average hourly spectral power in the 0.2 to 0.5 Hz frequency range was 7.8 f 8.2 ms2/Hz (range 0.45 to 28.0), and the midfrequency component (0.05 to 0.15 Hz) was 44.7 f 62.7 ms2/Hz. Total spectral power (ex-

TABLE I Group Results

n Mean + SD Minimum Maximum

Power 0.05-O. 15 23 44.7 2 62.7 1.2 290 (ms2/Hz)

Power 0.20-0.50 23 7.8 t a.2 0.45 28 (ms2/Hz)

Power O-0.50 (ms2) 23 la.6 + 15.5 0.6 62.7 RR interval (ms) 23 736 r 124 523 944 RR SD (ms) 23 60.0? 23 14 104 LVEF 23 0.21 r 0.07 0.08 0.34 TDCO (Iltersimin) 23 4.3 * 1.7 1.6 9.3 LVFP (mm Hg) 14 242 12 6 46 MSNA (bursts/mid 16 62.3 + 23.1 la.8 99.4 Norepi (picogram/ml) 14 745 2 390 128 1,530

LVEF = left ventricular ejectlon fraction; LVFP = left ventricular filling pressure; MSNA = muscle sympathetic nerve activity: Norep] = norepinephrine level; Power = spectral power; TDCO = thermal dilution cardlacoutput.

pressed as average area) was 18.6 f 15.5 ms2 (range 0.6 to 62.7).

Rehtions among measumd vahabkm The overall relation between the clinical, hemodynamic and neurohormonal variables, and HR variability is illustrated by the 2 patient examples shown in Figure 2. These 2 patients resemble each other clinically in regard to age, functional class and left ventricular ejection fraction. The patient on the left had a lower filling pressure and higher cardiac output than the one on the right. How- ever, they differ the greatest relative to the measurements of muscle sympathetic nerve activity and plasma norepinephrine. The patient on the left (with the least evidence for sympathoexcitation) also had greater power apparent over the entire power spectrum. In contrast, the patient on the right had markedly elevated levels of both norepinephrine and sympathetic nerve traffic, no visible peak in the high- and midfrequency ranges, and decreased power in the lowest frequencies.

The relation between the power spectral measurements and the other measured variables are tabulated in Table II and shown for selected comparisons in Figure 3. As is apparent, RR interval variability was not significantly related to age, functional class, left ventricular filling pressure or ejection fraction. In contrast, the amount of RR standard deviation and both high- and midfrequency spectral power had a positive and significant relation to cardiac output. Both RR standard deviation and the 3 spectral power measurements (especial- ly the midfrequencies) generally displayed a negative and significant relation to 1 or both indicators of sym- pathcexcitation, plasma norepinephrine and muscle sympathetic nerve activity. As one may expect, spectral power, RR interval and its standard deviation were significantly related, as were muscle sympathetic nerve activity and plasma norepinephrine (r = 0.79, p <0.003).

DISCUSSION The major findings in this study are in 2 general

areas. First, we demonstrated that the observed alterations of HR variability noted in advanced heart failure are not tightly linked to many of the clinical character- istics frequently used to describe its severity, such as functional class, and measurements of systolic function


Power spectral measurements underwent log transformation before statistical analysis. Each spectral region of interest (listed at top of table) was compared with variables (listed along left margin of table) using linear regression analysis, resultin in r and p values for each comparison.

NYHA = New York Heart Association; other abbreviations as in B able I.

TABLE II Regression Analysis of Measured Variables

0.2 to 0.5 Hz vs 0.05 to 0.15 Hz vs Oto0.5Hzvs RRSDvs

Age (yr) NYHA LVEF TDCO (L/min) LVFP (mm Hg) RR (ms) RR SD (ms)

0.2-0.5 (msg/Hz) 0.05-0.15 fmsg/Hz) O-O.5 (ms2) Norepi (picogram/ml) MSNA fburstslmin)

r Value

0.04 -0.02

0.18 0.42

-0.28 0.50 0.67

- 0.77 0.69

-0.55 -0.47

p Value

0.860 0.910 0.420 0.045 0.330 0.015 0.001 -

<O.OOl <O.OOl

0.043 0.065

r Value

0.07 -0.34

0.30 0.49

-0.33 0.70 0.92 0.77 - 0.83

-0.72 -0.75

p Value

0.750 0.110 0.180 0.020 0.250

10.001 <O.OOl <O.OOl

<O.OOl 0.004 0.001

r Value p Value

0.28 0.190 -0.02 0.920

0.32 0.140 0.26 0.240

-0.06 0.820 0.55 0.006 0.76 <O.OOl 0.69 <O.OOl 0.83 <O.OOl - -

-0.43 0.120 -0.56 0.024

r Value p Value

0.21 0.330 -0.24 0.270

0.31 0.150 0.37 0.080

-0.38 0.190 0.78 <O.OOl - -

0.67 <O.OOl 0.92 <O.OOl 0.76 < 0.001

-0.68 0.008 -0.76 0.001

and vascular congestion. Second, we showed that the amount of HR variability (expressed as the power spectrum of normal RR intervals or by nonspectral methods such as RR standard deviation) is closely and negatively linked to the degree of sympathoexcitation, the impor- tance of which is discussed later.

The discordance between symptomatology and clinical findings in patients with heart failure has long been appreciated. This discrepancy is best illustrated by the inability of resting indexes of left ventricular perfor-

mance to accurately predict exercise capacity.21-2s Rel- atively few studies carefully addressed the relation between cardiac performance and specific alterations in neural control in heart failure, although recent studies demonstrated a relation between selected measurements of left and right ventricular function, and resting levels of directly measured muscle sympathetic nerve activity and plasma norepinephrine.5*21*26

If HR variability is not an indicator of the severity of cardiac dysfunction, what is its significance? Our

LVEF: .19 .22

LVFP (mmHg): 7 17

CARDIAC OUTPUT: 6.5 4.9 (literdmin)

MSNA (burstcdmin): 18.8 67.4

NoREPNEPWNE: 143 685 (Wml)


study indicates that reduction of HR variability is sig- sympathoinhibition (phenylephrine infusion) do not ap nificantly related to sympathoexcitation, which is relat- pear to correlate well with HR variability. However, a ed to other measures of autonomic dysfunction in heart significant inverse relation appears during interventions failure. Recently, studies examining the relation be- (such as nitroprusside) that elicit reflex sympathoexcita- tween HR variability and measurements of sympathetic tion.27 Additional studies in subjects with heart failure nerve activity (nerve activity and norepinephrine) were demonstrated a reciprocal relation between cardiac va- reported.27*28 In normal subjects, measurements of sym- gal nerve traffic (as indicated by RR interval and stan- pathetic and vagal influence at rest or during reflex dard deviation) and peroneal muscle sympathetic nerve

0.1 1 10 100 1000 0.1 1 10 100 1000

Mid Freq Mid Freq

4 0.1 1 10 100 1000

Mid Freq

10

8

0 0.1 1 10 100 1000

Mid Freq

120 r I 2000 , I

c

l-=0.55

0 0 I a.--

80 0” 2

60 m E

1000

40 00

: z 500

20 0 0 r 01 01 I 0 0 0.1 1 10 100 0.1 1 10 100

High Freq High Freq

40 I I 10, I

35 /- r=O. 18 0

30 0

0

r=0.42 8

t

0 0

25 0 ,-. _

:I

15

o&

00 0 0 0 2

i

0 00 10 0 0

0

B 0.1 1 10 100 0.1 1 10 100

High Freq High Freq


activity.28 These studies (performed in a smaller group of patients) differed significantly in terms of methodolo- gy. These subjects with CHF were studied at rest for brief periods in a setting in which factors such as respi- ratory rate were controlled; hemodynamic and clinical variables were not correlated to the study findings. It is of interest that we noted a similar inverse relation when using long periods of HR data in ambulatory patients.

How might the reduction of HR variability and sympathoexcitation be linked pathophysiologically? PO- tential mechanisms for the observed sympathoexcitation in CHF include an increase in excitatory influences to central sympathetic outflow, a decrease in inhibitory influences at the brainstem level or an alteration at the central level (or any combination). Experimental evidence supports the concept that impaired inhibitory af- ferent baroreflex influences on central sympathetic outflow at the brainstem level have a role in sympathoexcitation.5-9*28 If this is true, and if baroreflex ab normalities responsible for altered HR variability and sympathoexcitation are linked, an inverse relation between measurements of sympathetic (nerve activity, norepinephrine) and parasympathetic influence (power spectrum and standard deviation of HR) would be pre- dicted; our data are consistent with this notion.

Clinical impkatiaw Measurement of HR variability has been applied to studies of normal physiology and to a variety of clinical disorders involving the heart or its neural control systems, including coronary artery disease and myocardial infarction, cardiac transplantation, diabetic and other neuropathic conditions, obesity and hypertension.10-16,28-31 The association noted between abnormalities of HR variability and cardiac death (sudden and nonsudden) has been of particular interest.14-I6 Survivors of an aborted sudden cardiac death episode have particularly reduced HR variability. Some studies that compared measures of HR variability to other known predictors of cardiac death after myocardial infarction (including left ventricular ejection fraction and ambient ventricular ectopy) suggested that HR variability has independent and additive predictive value for survival.i4 Experimental studies demonstrated a survival benefit in animals, with evidence for more persistent parasympathetic influence after infarction when rechal- lenged with stimuli such as exercise and ischemia.32,33 Parasympathetic influence is thought to confer a “pro- tective” electrophysiologic effect on a variety of ar- rhythmia models, largely by opposing sympathetic ef- fects34; demonstrating such effects in studies of humans is more problematic.

Reduction of baroreflex sensitivity (determined by phenylephrine infusion) in patients after myocardial infarction has been reported to be associated with increased risk of cardiac death (primarily sudden).35 When long-term ambulatory electrocardiographically derived estimates of HR variability are compared directly with baroreflex sensitivity in the same patient groups after infarction, only a modest correlation can be shown.36 Whether these 2 techniques detect a similar autonomic abnormality or whether 1 will prove superior as a predictor of outcome remains unknown.

REFERENCES 1. Cohn JN, Levine TB, Ohvari MT, Gartberg V, Lura D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Eng J Med 1984;311:819-823. 2. Goldsmith SR, Francis GS, Cowley AW, Levine B, Cohn JN. Increased plasma arginine vasopressin levels in patients with congestive heart failure. J Am Co/l Cardiof 1983;1:1385-1390, 3. Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the renin- angiotensin-aldcsterone system to clinical state in congestive heart failure. Circu- lation 1981;63:645-651. 4. Vallbo AB, Hagbarth KE, Torebjork HE, Wallin BG. Somatosensory, proprio- ceptive, and sympathetic activity in human peripheral nerves. Physiol Reu 1979;59:919-951. 5. Leimbach WN, Wallin BG, Victor RG, Aylward PE, Sundlof G, Mark AL. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 1986;73:913-919. 6. Higgins CB, Vatner SF, Eckterg DL, Braunwald E. Alterations in the barore- ceptor reflex in conscious dogs with heart failure. J Ciin Invest 1972;51:715-724. 7. Levine TB, Francis GS, Goldsmith SR, Cohn JN. The neurohumoral and hemodynamic responses to orthostatic tilt in patients with congestive heart failure. Circulation 1983;67:1070-1075. 8. Ferguson DW, Abboud FM, Mark AL. Selective impairment of baroreflex- mediated vasoconstrictor responses in patients with ventricular dysfunction. Cir- culation 1984;69:45 l-460. 9. Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac parasympathetic control in patients with heart disease. N Eng J Med 1971;285:877-883. 10. Lombardi F, Sandrone G, Pempruner S, Sala R, Garimoldi M, Cerutti S. Baselli G, Pagani M, Malliam A. Heart rate variability as an index of symptho vagal interaction after acute myocardial infarction. Am / Cardiol 1987;60: 1239-1245. 11. Hayano J, Sakakibara Y, Yamada M, Ohte N, Fujinami T, Yokoyama K, Watanabe Y, Takata K. Decreased magnitude of heart rate spectral components in coronary artery disease: its relation to angiographic severity. Circulation 1990;81:1217-1224. 12. Saul JP, Arai Y, Berger RD, Lilly IS, Colucci WS, Cohen RJ. Assessment of autonomic regulation in chronic congestive heart failure by heart rate spectral analysis. Am J Cardiol 1988;61:1292-1299. 13. Ewing DJ, Campbell JIW, Clarke BF. Assessment of cardiovascular effects in diabetic neuropathy and prognostic implications. Ann Infern Med 1980;92: 3088311. 14. Kleiaer RE. Miller JP. Biaaer JT. Moss AJ. Decreased heart rate variabilitv and its a&ciation with increased mortality after acute myccatdial infarction. Am J Cardiol 1987:59:256-262. 1s. Martin GJ, Magid NM, Myers G, Bamett PS, Schaad JW, Weiss JS, Lesch M, Singer DH. Heart rate variability and suddm death secondary to coronary artery disease during ambulatory electrocardiographic monitoring. Am J Cardiol 1987;60:86-89. 16. Myers GA, Martin GJ, Magid NM, Bamett PS, Schaad JW, Weiss JS, Leach M, Singer DH. Power spectral analysis of heart rate variability in sudden cardiac death: comparison to other methods. IEEE Trans Biomed Brig 1986;33: 1149-l 165. 17. Mark AL, Victor RG, Nerhed C, Walfm BG. Microneurographic studies of the mechanisms of sympathetic nerve responses to static exercise in humans. Circ Res 1985;57:461-469. 18. Peuler JD, Johnson GA. Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. life Sci 1977;21:625-636. 19. Welch PD. The use of fast Fourier transform for the estimation of power spectra: a method based on time averaging over short, modified periodograms. IEEE Tram Audio Electroacoust 1967;ALL15~10-73. 20. Bendat JC, Piersol AG. Random Data: Analysis and Measurement Proce- dures. New York: John Wiley, 1986395-396. 21. Ferguson DW, Berg WJ, Sanders JS, Kempf JS. Clinical and hem&namic correlates of sympathetic nerve activity in normal humans and patients with heart failure: evidence from direct microneurographic recordings. J Am Co11 Cardiol 1990;16:1125-1134. 22. Benge W, Litchtield RL, Marcus ML. Exercise capacity in patients with severe left ventricular dysfunction. Circulation 1980;61:955-959. 23. Litchtield RL, Kerber RE, Benge W, Mark AL, Sopko J, Bhatnagar RK, Marcus ML. Normal exercise capacity in patients with severe left ventricular dysfunction: compensatory mechanisms. Circulation 1982:66:129-l 34. 24. Higginbotham MB, Morris KG, Corm EH, Coleman RE, Cobb FR. Determi- nants of variable exercise performance among ptients with severe left ventricular dysfunction. Am J Cardioi 1983;51:52-60. 25. Franc&a JA, Park M, Levine TB. Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure. Am J Cardiol 1981;47:33-39. 26. Oren R, Roach PJ, Berg WJ, Schobel HP, Ferguson DW. Resting muscle sympathetic nerve activity correlates with right rather than left ventricular ejection fraction in human heart failure (at&r). J Am Coil Cardiol 1991;17:2OA. 27. Saul JP, Ree RF, Eckberg DL, Berger RD, Cohen RJ. Heart rate and muscle sympathetic nerve variability during reflex changes of autonomic activity. Am J Physiol 1990,258:H713-H721. 28. Porter TR, Eckberg DL, Fritsch JM, Rea RF, Beightol LA, Schmedtje JF,


Mohanty PK. Autonomic pathophysiology in heart failure: sympathetic-choliner- gic interrelations. J Chin Inuest 1990$X5:1362-1371. 3% Smith ML, Ellenbogen KA, Eckberg DL, Szentpetery S, Thames MD. Subnormal heart period variability in heart failure: effect of cardiac transplantation. J Am Coil Cardiol 1989;14:106-111. 30. Peterson HR. Rothchild M, Weinberg CR, Fell RD. McLeiih KR, Pfeifer MA. Body fat and the activity of the autonomic nervous system. N Eng J Med 1988;318:1077-1083. 31. Mancia G, Ferrari A, Gregorini L, Parati G, Pomidossi G, Bertinieri G, Grassi G, di Rienzo M, Pedotti A, Zanchetti A. Blood pressure and heart rate variabilities in normotensive and hypertensive human beings. Circ Res 1983;53: 96-104. 32. Schwartz PJ, Billman GE, Stone HL. Autonomic mechanisms in ventricular fibrillation induced by myocardial &hernia during exercise in dogs with healed

mywardial infarction: an experimental preparation for sudden cardiac death. Circula?ion 1984;69:790-800. 33. Billman GE, Hoskins RS. Time-series analysis of heart rate variability during submaximal exercise: evidence for reduced cardiac vagal tone in animals suscep tible to ventricular fibrillation. Circulation 1989;80:146-157. 34. Kolman BS, Verrier RL, Lawn B. The effect of the vagus nerve stimulation upon vulnerability of canine ventricle: role of sympathetic parasympathetic inter- actions. Circulation 1976;52:578-585. 35. La Revere MT, Specchia G, Mortara A, Schwartz PJ. Baroreflex sensitivity, clinical correlates, and cardiovascular mortality among patients with a first myocardial infarction: a prospective study. Circulation 1988;78:816-824. 36. Bigger JT, La Revere MT, S&man RC, Fleiss JL, Rottman JN, Rolnitzky LM, Schwartz PJ. Comparison of baroreflex sensitivity and heart period variability after myocardial infarction. J Am Cofl Cardiol 1989;14:1511-1518.


clinical, hemodynamic and sympathetic neural correlates of heart rate variability in congestive...

Documents