Download Complex heart rate variability and serum norepinephrine levels in

JACC Vol . 23 . No . 3
March t . I994
:55-9
565
"Complex Heart iAte Nlar!A'~iE'Ay and Ser
fients With 'L___,va .-iced H&Lrt Failure
-ne Levels ha
MARY A . WOO, DISC, RN,*t WILLIAM G . STEVENSON, MD, FACC,t
DEBRA K . MOSER, DNSc, RN,* HOLLY R . MIDDLEKAUFF, MDt
Los Angeles, California
Objectives . This study was designed to examine the relation of
the Poincare plot heart rate variability pattern to sympathetic
nervous system activity as assessed by serum norepinephrine .
Background. Poincare plots demonstrate a complexity of beat
to beat behavior not readily detected by other heart rate variability measures . Previous studies have described two abnormal
Poincare patterns in patients with heart failure : a torpedo pattern
with reduced beat to beat variability and a complex pattern with
clustering of points .
Methods . To assess the relation of these plots to sympathetic
activity, plasma norepinephrine at rest and a standard deviation
measure of heart rate variability were analyzed in 21 patients with
heart failure (mean left ventricular ejection fraction [±Sln 0 .22
0.05).
Results. Eleven subjects had a torpedo-shaped and 10 subjects
had a complex Poincare plot pattern . These two groups did not
differ significantly in age, functional class, disease etiology, left
ventricular ejection fraction, heart rate, ventricular ectopic activity or in a standard deviation measure of heart rate variability .
However, patients with a complex Poincare plot pattern had
higher norepinephrine levels (722 ± 373 pg/nd) than patients with
torpedo-shaped plots (309 ± 134 pg/ml) (p = 0 .003) . Patients with
a complex pattern also had more severe hemodynamic decompensation, as evidenced by their higher levels of pulmonary capillary
wedge and mean pulmonary artery pressures and lower values for
cardiac index than those of patients with a torpedo-shaped plot .
Conclusions. Complex Poincare plots are associated with
marked sympathetic activation and may provide additional prognostic information and insight into autonomic alterations and
sudden cardiac death in patients with heart failure .
Poincare plots have been used to detect nonrandom behavior
in a variety of complex systems . Recently, they have been
used to assess heart rate variability in sudder infant death
syndrome (1), congenital central hypoventilation syndrome
(2) and heart failure (3) . Poincard plots are constructed by
graphing each sinus RR interval against the next RR interval .
The resulting graph provides a qualitative picture of both
,werail and beat to heat RR interval behavior .
In previous studies (3), we examined Poincard plots in
both healthy control subjects and patients with heart failure
(3) . All healthy control subjects had a similar Poincard plot
pattern (Fig . 1), characterized by increased symmetric RR
interval dispersion at the longer RR intervals (slower heart
rates) . In contrast, patients with heart failure had one of two
distinctive Poincare plot patterns (Fig . 2) . The first was a
"torpedo-shaped" pattern (Fig . 2, A and B), distinguished
by a decreased range of RR interval values and absence of
the increased, symmetric RR interval dispersion at longer
RR intervals seen in healthy control subjects . The second
pattern was "complex" (Fig . 2, C and D), consisting of a
thin core area of RR intervals, similar to that seen in the
torpedo-shaped patterns, and clusters of RR intervals . We
hypothesized that these two types of Poincare plot patterns
indicate different severity of sympathetic activation or autonomic dysfunction in heart failure . Thus, the purpose of this
study was to determine the relation of Poincare plot measures of heart rate variability to serum norepinephrine levels
in patients with advanced heart failure .
From the *University of California . Los Angeles School of Nursing and
tDivision of Cardiology . University of California . Los Angeles School of
Medicine, Los Angeles . California . Drs . Woo and Moser are recipients of the
1992-1993 American Association of Critical Care Nurses/Hewlett-Packard
Research Award . During the conduct of part of this study, Dr . Woo was the
recipient of the Audrienne M . Moseley Fellowship from the University of
California, Los Angeles School of Nursing, and Dr. Moser was supported by
an individual National Research Service Award (NR06507) from the National
Center for Nursing Research, Bethesda . Maryland .
Manuscript received July 6, 1993 ; revised manuscript received September
27, 1993, accepted September 30, 1993 .
Address for correspondence : Dr. Mary A . Woo. University of California,
Los Angeles School of Nursing, Factor Building . 10833 LeConte Avenue, Los
Angeles, California 90024-1702 .
©1994 by the American College of Cardiology
(I A no Coll Cardiol 1994,23,565-9)
Methods
ur sample consisted of 21 subjects admitted to University of California at Los Angeles (UCLA) Medical Center for
treatment of advanced heart failure . Their demographic data
are presented in Table 1 . All subjects had a thermodilution
pulmonary artery catheter inserted as part of the UCLA
standard heart failure treatment and evaluation (4) and were
on a regimen of bed rest with bedside commode privileges .
Ail participants were in sinus rhythm and none required
0735-10971941$7 .00
JACC Vol . 23, No . 3
March 1, 1994 :565-9
WOO ET AL .
HEART RATE VARIABILITY AND NOREPINEPHRINE
566
Table 1 . Characteristics of the 21 Patients With Advanced
Heart Failure
Etiology (no.)
CAD
Non-CAD
NYHAcQs
LVEF
13
8
1
0 .22
0 .6
0M
Values are reported as mean value ± SD or number of patients . CAD =
coronary artery disease ; LVEF = left ventricular ejection fraction : NYHA
class = New York Heart Association functional class .
FiWe 1 . Examples of Poincard plot patterns from two healthy
subjects : a 52-year old man (left) and a 48-year old man (right) . The
standard deviation measure of heart rate variability values was 126
and 133 ms, respectively . The X axis (RRn) indicates the value of
each RR interval, and the Y axis (RRn + 1) is the value of the
subsequent RR interval .
mechanical circulatory or ventilatory support . Exclusion
criteria were use of a pacemaker, history of cerebrovascular
accident, renal failure, diabetes mellitus, recent (within the
last 6 months) myocardial infarction, recent (within the last
2 months) change in antiarrhythmic medication and use of
calcium channel blockers or beta-adrenergic blocking
agents .
The procedure for all subjects was as follows . Patients
were fasting and had not smoked for a8 h before the study .
Two hours after insertion of a thermodilution pulmonary
artery catheter for hemodynamic assessment (usually in the
late afternoon), each subject was placed supine in their
hospital bed, with the head of the bed at a 30° angle . The
patient d, -n was left without disturbance by health care staff,
family, fhends or television for 30 min . At the end of the
30 min, 7 ml of blood was drawn painlessly through the
proximal port of the pulmonary artery catheter and inserted
immediately into a vial with ethylenediaminetetraacetic acid
2000
(EDTA) and stored in ice . The blood sample was then
centrifuged at a temperature of 5°C and the serum was
immediately frozen at -8(PC . The serum samples were later
analyzed by the UCLA clinical laboratories using liquid
chromatography with electrochemical detection (5) . Norepinephrine was drawn at the beginning of the study because
the patient's medical regimen and activity were undisturbed
at this point .
A 24-h Holter electrocardiogram (ECG) was initiated
immediately after catecholamine samples were obtained .
The ECG recordings were scanned in semiautomatic mode
(operator confirmation of all beat types) on a Del Mar 750
scanner . The time of beat, beat type and serial RR interval
values were then stored on floppy disks for later heart rate
variability analysis .
Heart rate variability was assessed by a standard deviation measure (the standard deviation of the square root of the
mean of the squared deviations of each RR interval from the
mean RR interval over a 24-h recording period), as described
by Kleigcr et al . (6), and from Poincare plots (3) . Poincard
plots were constructed using UCLA custom-designed software (3) . Poincard plot construction consisted of plotting
each sinus RR interval against its subsequent sinus RR
interval . Poincard plots were categorized by three persons
2000
A
+1
2ffi__WnOO
2000 i
i
260
2000
RRn
2000
D
At
4F
I
1
200
RRn
2000
1
200
RRn
2000
Figure 2. Examples of Poincard plot patterns in four
patients with heart failure . A, Torpedo-shaped plot from
a 54-year old man with a norepinephrine level of
317 pg(ml and a standard deviation measure of heart rate
variability of 107 ms . 8, Torpedo-shaped plot from a
61-year old man with a norepinephrine level of 244 pg/ml
and a standard deviation measure of heart rate variability of 92 ms . C, Complex plot from a 45-year old man
who had a norepinephrine level of 1,444 pgtml and a
standard deviation measure of heart rate variability of
82 ms . D, Complex plot from a 59-year old man who had
a norepinephrine level of 750 pg/ml and a standard
deviation measure of heart rate variability of 144 ms .
Axes as in Figure 1 .
JACC Vol . 23, No . 3
March 1, 1994 :565-9
WOO ET AL .
HEART RATE VARIABILITY AND NOREPINEPHaINE
Table 2 . Clinical Characteristics of Subjects with
Age (yr)
NYHA class
Etiology
CAD
Non-CAD
PCWP (mm Hg)
LVEF
Mean heart rate (beats/min)
PVCs/24 h (no .)
RA (mm Hg)
Cardiac index (fitersimin per m2 )
Mean BP (mm Hg)
Mean PA (mm Hg)
Serum sodium (mEq/liter)
ACE inhibitor (yes)
Digoxin (yes)
Antiarrhythmic agents eyes)
Type l
Arniodarone
Different
567
Poincard Plot Patterns
Torpedo Pattern
(n = 11)
Complex Pattern
(n = 10)
55±- 8
I1 ± 0 .6
54±8
3 .1 ± 0.6
8
5
p
Value
0 .93
.89
A
0.27
3
16±7
0 .23 ± 0 .06
81 ± 13
1,051 ± 1,333
7±4
2 .28 0.3l
14
87
24 9
137 ± 4
9
8
27±5
0 .00*
0.70
0.17
0 .16
0 .09
0.04*
0A6
0.002*
0.30
0.45
0.55
0 .22 ± 0.04
89 ± 13
3,588 ± 5,557
12±8
1 .91 ± 0.44
83 ± 8
39 ± 9
135 ± 2
7
8
2
5
0
006
0.59
*Statistically significant at p < 0 .05 . Values presented are mean value ± SD or number of patients . ACE =
angiotensin-converting enzyme ; BP = blood pressure ; CAD = coronary artery disease ; LVEr = left ventricular
ejection fraction ; NYHA class = New York Heart Association functional class ; PA = pulmonary artery pressure ;
PCWP = pulmonary capillary wedge pressure ; PVCs/24 h = premature ventricular complexes on the 24-h ambulatory
electrocardiogram ; RA = right atrial pressure .
who had no knowledge of each subject's demographic and
clinical data (100% agreement) . The investigator who monitored Poincard plot construction was not involved in Poincard plot categorization . Only sinus RR intervals were used
for heart rate variability analysis and all RR intervals associated with ectopic activity and artifact were deleted from
the analysis .
The data were examined with use of the Student t test
(two-tailed) and chi-square analysis . Significance was prospectively set at p < 0 .05 . Mean values ± SD are presented .
significant differences in the standard deviation measure of
heart rate variability between the two Poincard plot configuration groups (91 ± 27 vs . 86 ± 46 ms) (p = 0 .75) (Fig . 4) .
Discussion
Patients with heart failure have autonomic nervous system abnormalities, typified by increased sympathetic activity (7), decreased vagal tone (8-10) and depressed baroreceptor responsiveness (11,12) . High sympathetic tone as
indicated by elevated norepinephrine levels at rest (13) is
Results
Eleven subjects had a torpedo-shaped and 10 had a
complex Poincard plot pattern . These two groups did not
differ significantly in age, New York Heart Association
functional classification, mean heart rate, disease etiology,
left ventricular ejection fraction, right atrial pressure, mean
blood pressure, ventricular ectopic activity or serum sodium
levels (Table 2). However, the patients with a complex
Poincard plot pattern had more severe hemodynamic decony
pensation. as indicated by their significantly higher values for
pulmonary capillary wedge and mean pulmonary artery
pressures and lower values for cardiac index than those of
patients with a torpedo-shaped plot .
Patients with heart failure with a torpedo-shaped Poincare plot had significantly lower norepinephrine levels (309
t 134 pg1ml) than did patients with a complex Poincard plot
(mean 722 ± 373 pgtml) (p = 0 .003) (Fig . 3) . There were no
Figure 3. Serum norepinephrine values for subjects with torpedoshaped (309 ± 134 pg1ml) and complex (722 ± 373 pglml) Poincart
plot patterns (p = 0 .003) are shown . Mean serum norepinephrine
values ± I SD are indicated for each group .
A
CR 1,200
200
n = 0 .003
.9
•
•
1 ,000
600
•
600
CL
6,
400
E
0
Z
200
Torpedo
Polnce4 Plot
ccmprr-
568
WOO ET AL .
HEART RATE VARIABILITY AND NOREPINEPHRINE
= 0 .75
a
~100
cc
Ic
a
0 so
A
A
A&
Ih
Torpedo Poincare Plot
Complex
Figure 4. The standard deviation measure of heart rate variability
(SDRR) values for subjects with torpedo-shaped (81 ± 27) and
complex (86 ± 46) Poincar4 plot patterns (p = 0 .75). Mean SDRR
values ± I SD are indicated for each group .
predictive of poxor survival in patients with heart failure
(11,14-16) . The low standard deviation measure of heart rate
variability in this study is consistent with high sympathetic
and low parasympathetic tone in our sample of patients with
advanced heart failure .
Nonliew analysis of heart rate variability. Heart rate
variability is determined by a complex interaction of sympathetic and parasympathetic influences, which are modulated
by central and peripheral nervous system influences on sinus
node automaticity . This may behave as a nonlinear system
and give rise to complex phenomena that superficially appear to be random and may elute detection by linear analytic
techniques (17-22) . The nonlinear technique of Poincard plot
analysis can indicate levels of organization not readily
apparent from standard deviation or spectral methods of
heart rate variability analysis .
In a previous study (3) we defined normal and two
qualitatively different abnormal (torpedo and complex) Poincard plot patterns in healthy subjects and patients with
advanced heart failure . As in the present study, both abnormal Poincard plot patterns were associated with decreased
standard deviation measure of heart rate variability . However, this standard deviation measure of heart rate variability did not distinguish between the two groups . This study
demonstrates that the complex Poincard plot patterns are
associated with higher norepinephrine levels, consistent
with greater sympathetic activation . These patients also had
more severe hemodynamic abnormalities, consistent with
more severe heart failure .
Complex Pdncm* plots. Inspection of the Poincart plots
reveals that the torpedo-shaped pattern is due to reduced RR
interval range and beat to beat variability . The beat to beat
RR interval is relatively fixed, but over time the RR intervals
can move slowly up and down over a limited range . Hence,
the standard deviation measure of heart rate variability is
reduced . Complex patterns also have a reduced overall
range and high heart rate, with RR intervals tending to
converge at the lower left corner (smaller RR intervals) of
JACC Vol. 23, No . 3
March 1, 1994 :565-9
the graph . However, in contrast to the torpedo-shaped plots,
the beat to beat variability in complex patterns is increased
with the formation of unusual clusters of RR intervals .
The mechanisms generating complex RR interval plots
are unclear . The multiple asymmetric clusters of points
suggest an intricate nonlinear system of interaction between
the sympathetic and parasympathetic systems in these patients with heart failure . The large beat to beat variations can
vary greatly and could possibly indicate parasympathetic
fluctuations . It is unlikely that the profound RR interval
variations seen in complex plots are due to sympathetic
activity, as it reacts less quickly titan the parasympathetic
nervous system (8,23,24) . These marked beat to beat RR
interval changes are surprising in patients with sympathetic
hyperactivity and low parasympathetic tone . However, this
may be consistent with the exaggerated effect of vagal
stimulation in the presence of high sympathetic tone known
as "accentuated antagonism" (25) . Accentuated antagonism
has been reported in normal human subjects (26), patients
undergoing clinically indicated electrophysiologic testing
(27) and animal models (28,29), but to our knowledge it has
not been described in patients with heart failure .
Limitations. Our sample size was small and may not have
detected other clinical associations with the Poincard plot
patterns . There was only one measure of norepinephrine in
each subject because repeated measures were not possible in
this study . We applied only one method of standard deviation of heart rate variability in this study, and the relation of
other standard deviation measures to Poincare plots is
unknown . We did not utilize spectral analysis measures of
heart rate variability because of the frequent ventricular
ectopic activity in our subjects . Ventricular ectopic activity
was probably not responsible for the unusual RR interval
behavior in the complex plots because the RR intervals
containing ventricular or atrial ectopic activity were excluded from our Poincard plot and standard deviation measure of heart rate variability analysis . Moreover, in a previous study, we demonstrated that ventricular ectopic activity
did not affect subsequent sinus to sinus RR intervals in
patients with advanced heart failure (30) .
We cannot exclude the possibility that sinus node abnormalities are more frequent in patients with a complex PoincarE plot pattern . Sinus node dysfunction or sinoatrial node
exit block could contribute to the unusual RR interval
clustering behavior seen in complex plot patterns . However,
our patients did not have bradyarrhythmias or other evidence of sinus node dysfunction on their ECG .
Conclusions. Patients with advanced heart failure with
similar functional class, ejection fraction and disease etiology can have marked differences in beat to beat heart rate
variability that can be detected in Poincare plots but not
necessarily in standard deviation measures of heart rate
variability . Complex Poincare plots are associated with
higher norepinephrine levels, suggesting more severe heart
failure, than are torpedo-shaped patterns . Further investigation is warranted to determine if Poincare plots may provide
JACC Vo1 . 23, No. 3
March 1 . 1994 :56,5-9
WOO ET AL .
HEART RATE VARIABILITY AND NOREPINEPHRINE
additional prognostic information and insight into autonomic
alterations and sudden cardiac death in patients with heart
failure .
We thank L'.nne W . Stevenson, MD, Director of the Ahmanson-UCLA
Cardiomyopathy Clinic and Connie Wright, RN of the UCLA Holtee Laboratory for their assistance in this study .
569
failure on baroreflex control of sympathetic neural activity . Am i Cardiol
1992 :69 :523-31 .
13 . Ferguson DW, Berg WJ, Sanders JS . Clinical and hemodynamic correlates of sympathetic nerve activity in normal humans and patients with
heart failure : evidence from direct microneurographic recordings . J Am
Coll Cardiol 1990 ;16 :1125-34 .
14 . Cohn JN, Levine TB, Olivari MT, et al . Plasma norepinephrine as a guide
to prognosis in patients with chronic congestive heart failure . N Engl J
Med 1984 -,311 :819-23 .
15 . Porter TR, Eckberg DL, Fritsch JM, et al . Autonomic pathophysiology in
heart failure patients . J Clin Invest 1990 ;85 :1362-71 .
References
Schechiman VL, Raetz SL, Harper R K . e t al . Dynamic analysis of
cardiac R-R intervals in normal infants and in infants who subsequently
succumbed to sudden infant death syndrome . Pediatr Res 1992,31 :60612.
2 . Woo MS, Woo MA, Gozal D . Keens T, Harper RM . Heart rate variability
in children with congenital central hypoventilation syndrome . Pediatr Res
1992 ;31 :291-6 .
3 . Woo MA, Stevenson WG, Moser DK, Harper RM, Trelcase R . Patterns
of beat-to-beat heart rate variability in advanced heart failure . Am Heart
I 102 :121704A0 .
4 . Stevenson LW . Dracup KA, TTlhch JR Eicacy of medical therapy
tailored for severe congestive heart failure in patients transferred for
urgent cardiac transplantation . Am J Cardiol 1989 ;63:461-4 .
S . 11jemdahl P. Inter-laboratory comparison of plasma catecholamine determinations using several different assays . Acta Physiol Scand 1984 ;527 :
4454 .
6 . Klelger RE, Miller JP, Bigger JT, Moss AJ, Multicenter Post-Infarction
Research Group . Decreased heart rate variability and its association with
increased mortality after acute myocardial infarction . Am ) Cardiol
1987 :59 :256-62.
7 . Francis GS, Benedict C, Johnstone DE, et al . Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and
without congestive heart failure . Circulation 1990 ;82 :1724-9 .
8 . 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 . J Am Coll Cardiol 1991 .18 :46472 .
9. Flapan AD, Nolan J, Neilson JMM, Ewing D) . Effect of captopril on
cardiac parsympathetic activity in chronic cardiac failure secondary to
coronary artery disease . Ain J Cardiol 1992 :69 :532-5 .
10. Packer M . The neurohormonal hypothesis : a theory to explain the
mechanism of disease progression in heart failure . J Am Coll Cardiol
1992 :20 :248-54 .
IL Cohn JN . Abnormalities of peripheral sympathetic nervous system control in congestive heart failure . Circulation 1990 .82 Suppl 1 :1-59-67 .
12 . Ferguson DW, Berg WJ . Roach PJ, Oren RM, Mark AL . Effects of heart
16. Singer DH, Martin GJ, Magid N, et al . Low heart rate variability and
sudden cardiac death . J Electro(wdiol 1988,21 Suppl :S46-55 .
17 . Denton TA, Diamond GA, Helfant RH, Khan S, Karagueuzian H .
Fascinating rhythm: a primer on chaos theory and its application to
cardiology . Am He., rt 1 1990 :120:1419-40 .
18 . Glass L, Hunter P . There is a theory of heart . Physica 1990 ;43 :1-16 .
19 . Goldberger AL . Nonlinear dynamics, fractals, and chaos : applications to
cardiac elect rophysiology . Ann Biomed Engin 1990 ;18 :195-8 .
20. Glass I . . Zeng W . Complex bifurcations and chaos in simple theoretical
models of cardiac oscillations . Ann N Y Acad Sci 1989 :316-27 .
21 . Chialvo DR . Toward very simple generic models of excitable cells . Order
and chaos in cardiac tissues : facts and conjectures . Ann N Y Acad Sci
N9
22 . Goldberger AL . Findley LJ, Blackburn MR, Mandell AJ . Nonlinear
dynamics in heart failure : implications of long-wavelength cardiopulmonary oscillations . Am Heart J 1984 :107 :612-5 .
23 . Katona PG, Jih F . Respiratory sinus arrhythmia : noninvasive measure of
parasympathetic cardiac control . J Appl Physiol l91_- 1 9 :801-5 .
24. Akselrod S, Gordon D, Shannon DC, Barger AC, Ube[ FA . Power
spectrum analysis of heart rate fluctuation : a quantitative probe of
beat-to-beat cardiovascular control . Science 1981 :213 :220-2 .
25 . Levy MN . Sympathetic-parasympathetic interactions in the heart . Circ
Res 1971 ;29 :437-45 .
26. Fukudo S, Lane JD, Anderson N B . et al . Accentuated vagal antagonism
of beta-adrenergic effects on ventricular repolarization : evidence of
weaker antagonism in hostile type A men . Circulation 1992 :85 :2045-53 .
27 . Sousa J, Calkins H, Rosenheck S . Kadish A . Morady F . Effect of
epinephrine on the efficacy of the internal cardioverter-defibrillator . Am J
Cardiol 19920 :509-12 .
28 . Levy MN, Blattberg B . Effect of vagal stimulation on the overflow of
norepinephrine into the coronary sinus during cardiac sympathetic nerve
stimulation in the dog. Circ Res 1976 :38 :81-5 .
29 . Morady F, Kou WH, Nelson SD, et al . Accentuated antagonism between
beta-adrenergic and vagal effects on ventricular refra - toriness in humans.
Circulation 1988 :77 :289-97 .
30 . Woo MA, Stevenson WG . Moser DK. Effects of ventricular ectopy on
sinus R-R intervals in patients with advanced heart failure . Heart Lung
1992 ;21 :515-22 .