Clinical Science (1990)79,429-435
429
Elevated plasma noradrenaline concentrations in patients
with low-output cardiac failure: dependence on increased
noradrenaline secretion rates
WILLIAM T. ABRAHAM, JOHANNES HENSEN
AND
ROBERT W. SCHRIER
Department of Medicine, University of Colorado School of Medicine, Denver, Colorado, U.S.A.
(Received 7 March 1990; accepted 19 March 1990)
SUMMARY
1. Plasma noradrenaline concentrations are elevated
in patients with congestive heart failure; however, the
pathogenesis of these elevated noradrenaline levels is
controversial.
2. Possible mechanisms for elevated noradrenaline
concentrations in patients with congestive heart failure
include increased noradrenaline secretion, decreased
clearance of noradrenaline, and a combination of
increased secretion and decreased clearance.
3. In the present study, plasma noradrenaline clearance and apparent secretion rates were determined using
a whole-body steady-state radionuclide tracer method in
six otherwise healthy patients with moderate degrees of
low-output cardiac failure and in six normal control subjects.
4. The venous plasma noradrenaline level was elevated in the patients with congestive heart failure as compared with the control subjects (4.18k 1.34 versus
1.54 k 0.16 nmol/l, P < 0.05).There was no stimulation of
the adrenal medulla as evident by normal plasma
adrenaline levels in both groups (0.19 f0.04 versus
0.18 k 0.02 nmol/l, not significant). The apparent secretion rate of noradrenaline was elevated in the patients
with congestive heart failure (4.75 k 1.95 versus
1.78k0.18 nmol min-l m-*, P<0.05), whereas the
clearance rate of noradrenaline was similar in the two
groups (1.26k0.27 versus 1.16k0.02 1 min-l m-*, not
significant).
5. We conclude that the high peripheral venous plasma
noradrenaline concentrations in patients with mildly
decompensated low-output cardiac failure are initially
due to increased secretion, rather than to decreased metabolic clearance, perhaps in response to diminished effective arterial blood volume.
Correspondence: Dr Robert W. Schrier, University of
Colorado School of Medicine, Box C281, 4200 East Ninth
Avenue, Denver, CO 80262, U.S.A.
Key words: congestive heart failure, noradrenaline.
Abbreviations: ASR, apparent secretion rate; CHF, congestive heart failure; EABV, effective arterial blood
volume; NA, noradrenaline, NYHA, New York Heart
Association.
INTRODUCTION
Various studies have documented elevated peripheral
venous plasma noradrenaline (NA) concentration in
patients with congestive heart failure (CHF) [ l , 21. Moreover, these patients also have other hormonal indicators
of a decrease in effective arterial blood volume (EABV),
including elevated plasma concentrations of vasopressin,
renin and aldosterone [2-51. These findings support the
‘underfilling’hypothesis of sodium and water retention in
CHF [6].According to this theory, a decreased EABV, as
determined by a diminished cardiac output, causes
unloading of ventricular and arterial receptors such as the
high-pressure baroreceptors in the carotid sinus and
aortic arch. This baroreceptor inactivation results in
diminution of the tonic inhibitory effect of afferent vagal
and glossopharyngeal neural traffic to the central nervous
system and initiates the non-osmotic release of vasopressin, activation of the renin-angiotensin-aldosterone
system and stimulation of the sympathetic nervous
system. These three neurohumoral systems act in concert
in an attempt to maintain EABV. Baroreceptor-mediated
‘activation’ of the sympathetic nervous system appears to
be the primary integrator of these hormonal vasoconstrictor systems [6].
In this regard, a recent investigation has demonstrated
that alterations in baroreceptor activity are paralleled by
changes in plasma NA concentration in normal subjects
[7]. Furthermore, it has been shown that the venous
plasma NA concentration provides a reasonable estimation of average sympathetic activity in spite of regional
and organ-specific differences in sympathetic outflow [8].
W. T. Abraham et al.
430
CHF had renal insufficiency (serum creatinine concentration: range 50-110 pmolll at the time of study), hypotension (mean arterial pressure: range 8 1-1 18 mmHg at the
time of study), chronic obstructive pulmonary disease,
diabetes mellitus, liver disease, autonomic insufficiency or
thyroid disease. None of the patients was taking tricyclic
antidepressants, central a-adrenoreceptor agonists, Badrenergic blockers, monoamine oxidase inhibitors or
hydrocortisone.
The normal subjects were six healthy volunteers (five
males, one female), on no medication, who ranged in age
from 32 to 60 years (mean 43.3 f 3.9 years).
Thus, the elevated plasma NA concentration seen in
patients with CHF may be solely reflective of activation of
the sympathetic nervous system, i.e. increased NA secretion. However, decreased NA clearance may account for,
or substantially contribute to, the elevated plasma NA
concentrations seen in patients with CHF. By infusing
unlabelled NA and evaluating the time course of the
return to baseline plasma NA levels, one group of investigators found NA clearance to be normal in ten clinically
stable patients with CHF [9]. However, recent studies
using steady-state radionuclide tracer methods to
examine NA kinetics suggested that both increased NA
secretion and decreased NA clearance contribute to the
high venous plasma NA levels seen in patients with CHF
[ lo , 111.
Using 'H-labelled NA, the present investigation was
undertaken to further examine the NA clearance rate and
apparent secretion rate (ASR) in patients with CHF, in
order to define the determinant(s)of the elevated venous
plasma NA concentration in this patient population.
Study protocol
Informed consent was obtained from all subjects, and
the research protocol was approved by the Human
Research Committee of our institution. Eight days before
the study, digoxin, angiotensin-converting enzyme inhibitors and diuretics were discontinued. Four days
before the study, all subjects were placed on a diet supplying 100 mmol sodium/day and 60 mmol of potassium/
day. Fluid intake was unrestricted. The NA kinetic study
was performed in the supine position after an overnight
fast and a light breakfast (toast, butter, marmalade and
one cup of decaffeinated tea or coffee). On the day before
the study, a short plastic 18-gauge intravenous catheter
was introduced into each antecubital vein. One arm was
designated for obtaining venous blood samples; the other
arm was reserved for the NA infusion.
NA kinetics were determined by a method slightly
modified from that described by Esler et uf. [12]. 'Hlabelled NA, ~-[7,8(n)]NA,with a specific activity of
20-40 Ci/mmol (0.7-1.5 x l o 1 *Bq/mmol; New England
Nuclear, Boston, MA, U.S.A.) was diluted in 2 ml of 0.02
mol/l sterile acetic acid and sterilized by Millipore filtration. A 100 pCi (3.7 x 10' Bq) aliquot of this solution was
added to 150 ml of sterile 5% (w/v) D-glucose in water
and infused intravenously at a constant rate of 0.35 pCi
min-' m - 2 (1.3X l o 4 Bq min-' m - 2 ) for 90 min. This
was equal to an infusion rate of unlabelled NA of 0.002
pg/min, an amount insufficient to elevate blood pressure,
heart rate or total plasma NA level. Serial 6 ml blood
samples were drawn at 10 min intervals during the
['H]NA infusion. These were placed in chilled tubes
METHODS
Subjects
Six patients with CHF and six normal subjects were
admitted to the Clinical Research Center of the University of Colorado Health Sciences Center. The characteristics of the population with CHF are shown in Table 1.
Four patients had ischaemic heart disease, one had idiopathic dilated cardiomyopathy and one had aortic valve
disease. Their ages ranged from 40 to 60 years, with a
mean of 51.3 f 2.9 years. Three of the patients were male;
three were female. By New York Heart Association
(NYHA) criteria, the patient's functional classifications
ranged from Classes 1-11 to IV one patient was Class 1-11,
one was Class 11, two were Class 11-111, one was Class 111
and one was Class IV. All patients had documented
cardiac dysfunction with a left ventricular ejection fraction of less than 35% by gated blood pool scan. Four
patients had evidence of decompensation by physical
examination as judged by the presence of one or more of
the following findings: oedema, rales or a third heart
sound. With the exception of two patients with hypertension (patient nos. 1 and 2 ) , the patients with CHF were
free of other morbid states; specifically, no patients with
Table 1. Characteristics of the six patients with CHF
Abbreviations: IHD, ischaemic heart disease; IDCM, idiopathic dilated cardiomyopathy; AVR,
aortic valve replacement; S,, third heart sound. Ejection fraction was determined by radionuclide
ventriculography. - ,Absent; + ,mild; + + ,moderate; + + + + , severe.
Patient
no.
Diagnosis
Age
(years)
Sex
1
2
3
4
5
1HD
IHD
57
IDCM
AVR
53
IHD
48
IHD
40
M
M
F
M
F
F
6
50
60
NYHA
class
Ejection
fraction (%)
Oedema
s, or
+ +-+ +
++++
+
rales
1v
31
11-111
22
I1
30
-
1-11
11-111
111
34
-
-
25
26
++
++
++
+
-
Noradrenaline kinetics in congestive heart failure
containing ethylene glycol bis(aminoethy1 ether)tetraacetate and reduced glutathione, and then centrifuged.
The plasma was separated, stored in aliquots and frozen
at - 70°C for subsequent analysis.
43 1
ance rate. The results are expressed as means k SEM. The
null hypothesis was rejected if the P value was less than
0.05.
RESULTS
Measurement of calculations
The concentration of ['HINA in plasma was measured
after alumina extraction followed by elution with perchloric acid of the plasma obtained. ['HINA activity was
determined by liquid scintillation counting of the perchloric acid extract, and the mean concentration of the
70, 80 and 90 min (steady-state) determinations was used
for calculations. The counting efficiency of the Packard
liquid scintillation counter was 6O%, and ['HINA concentrations (c.p.m./ml) were corrected to obtain d.p.m./
ml. The mean percentage recovery of ['HINA from the
plasma was 65.7 k 2.0%. Endogenous plasma NA and
adrenaline concentrations and the NA concentrations of
the perchloric acid extracts were measured by a modification [13] of the radioenzymatic method of Peuler &
Johnson 1141. Plasma adrenaline was measured in order
to assess stimulation of the adrenal medulla. The means of
the 10 plasma NA and adrenaline determinations were
taken as the baseline NA and adrenaline concentrations,
respectively, for each subject.
During steady-state conditions, the infusion rate of
l3H]NA equals its rate of removal from the plasma. Since
the infusion dose is assumed to be too low to affect the
endogenous clearance rate, the clearance rate of
endogenous NA equals the clearance of [3H]NA,which is
expressed by the following equation (adjusted for ml/
min):
['HINA infusion rate (d.p.m./min)
NA clearance =
steady-state plasma
[3H]NA(d.p.m./l)
The ASR of NA into the plasma is calculated as:
NA ASR =
['HH]NAinfusion rate (d.p.m./min)
specific activity of plasma
['HINA (d.p.m./nmol)
where the specific activity of plasma [3H]NA (d.p.m./
nmol) = [plasma ['HINA (d.p.m./l)]/[total plasma NA
(nmol/l)].
Plasma NA and adrenaline concentrations
As depicted in Fig. 1, the mean plasma NA concentration was significantly higher in the patients with CHF as
compared with the control subjects (4.18+ 1.34 versus
1.54-t 0.16 nmol/l, P < O . O l ) . The mean plasma adrenaline levels were normal for both groups studied (patients
with CHF, 0.19 k 0.04 nmol/l; normal subjects,
0.1 8 k 0.02 nmol/l, not significant).
Plasma NA clearance rate and ASR
During the ['H]NA infusion, a steady-state plasma
['H]NA was established by the 70, 80 and 90 min measurements in both patients with CHF and normal subjects
as shown in Fig. 2. Analysis of variance confirmed that
each subject had reached a plateau of plasma ['HINA
concentration by 60 min of infusion (individual effect,
F=80.13, P<O.OOOl; timeeffect, F=0.77, P=O.39).
The calculated plasma NA clearance rate and NA ASR
are shown in Fig. 3. There was no significant difference in
NA clearance rates between patients with CHF and control subjects (1.26 k 0.27 versus 1.16 k 0.02 I min-' m-2,
not significant). However, the NA ASR was significantly
higher in the group with CHF (4.75k 1.95 versus
1.78 f 0.18 nmol m h - ' m-2, P< 0.05).
In accordance with these findings, there was a significant correlation between plasma NA level and NA
ASR (r,=O.94, P < O . O l ) . There was no correlation
between plasma NA level and NA clearance rate
( r ,= - 0.49, not significant).
Age
The mean age of the patients with CHF was 8 years
greater than that of the normal subjects (51.3k 2.9 versus
0.31 ("
Statistical analysis
The Wilcoxon rank-sum test was used to compare age,
baseline NA concentration, adrenaline level, NA clearance rate and NA ASR in CHF patients with those of
normal subjects. Analysis of variance for repeated measures was used to determine when [3H]NAconcentration
had achieved a steady state. Spearman's rank correlation
was used to determine the degree of relationship between
plasma NA and NA ASR, as well as that between plasma
NA and NA clearance rate. Correlation analysis was also
used to examine the relationship between age and plasma
NA concentration, and age and NA ASR and NA clear-
Fig. 1. Plasma NA ( a )and adrenaline ( b )concentrations
in patients with CHF ( m ) and control subjects ( 0 ) .Mean
values ( ~ S E M are
)
shown for each group. Statistical significance: * P < 0.005 compared with control subjects.
Abbreviation: NS, not significant.
W. T. Abraham et al.
432
43.3 f 3.9 years); however, this difference was not statistically significant ( P = 0.07). Moreover, age was not related
to the NA kinetic results obtained. Specifically, age was
not related to baseline plasma NA level in either patients
with CHF ( r ,= - 0.07, not significant) or control subjects
( r ,= 0.07, not significant), nor was age related to the NA
ASR or to NA clearance rate in either group.
DISCUSSION
The present study confirms previous reports of elevated
peripheral venous plasma NA concentrations in patients
with C H F [l, 21. The elevated peripheral venous plasma
NA levels seen in our patients with CHF were singularly
dependent on increased ASR of NA into the plasma. The
NA clearance rates were comparable between patients
with CHF and normal subjects, and these clearance rates
for NA are in close agreement with previously published
data for normal subjects [12, 151.
Our results differ from previous studies of NA kinetics,
using the same whole-body steady-state radionuclide
tracer method, in patients with CHF which suggested that
decreased NA clearance contributed significantly to the
increased circulating NA levels [lo, 111. Since the
methodology used was the same and our control data
agrees with other published reports, it is reasonable to
assume that these different results may relate to the stage
of the CHF. Only one of our patients was in NYHA Class
l 800
ooo1
N CHF, and one was in NYHA Class 111. This is in
contrast to the investigations by Hasking et af. [lo] and
Davis et af. [l11, which focused primarily on patients in
NYHA Classes 111 and IV. All of the patients in the study
by Davis et al. [l11 were decompensated, as evident by
pulmonary and/or systemic venous congestion; data on
the degree of clinical decompensation was not given for
the study population of Hasking et al. [lo].Both studies
included patients with impaired renal function as
measured by either an elevated serum creatinine concentration or a decreased renal blood flow index [ 10, 111.
Thus, our study population tended to be less decompensated and with less evidence of either significant
venous congestion or renal vasoconstriction than the
populations studied by Hasking et af. [ 101 and Davis et af.
[Ill.
The implications of these differences in C H F population may be best appreciated with an understanding of
organ-specific NA kinetics. Esler et af. [ 161 have
examined whole-body and organ-specific NA kinetics in
27 unmedicated subjects without renal or liver disease or
cardiac failure. Organ-specific fractional extraction of NA
was determined by using a constant-rate infusion of isotope-labelled NA, and the arterio-venous plasma NA difference (corrected for fractional extraction) and organ
blood flow measurements were used to determine organspecific NA secretion rates. The major contributors to the
release of NA into plasma were the lungs, the kidneys and
skeletal muscle. All organs studied extracted significant
amounts of labelled NA; however, given their relatively
high blood flows, the lungs, the kidneys, skeletal muscle
and the hepatomesenteric bed make the most significant
contributions to NA clearance.
The general lack of significant renal insufficiency and/
or severe pulmonary or systemic venous congestion in our
patients with CHF most probably explains the normal NA
I T*
7.0 ( a )
2.0 ( b )
1
m
z
*0°
0
I
0
0
30
60
90
Ti m e (min)
Fig. 2. Plasma concentration of ["H]NA constant rate
infusion (0.35 pCi min-' m-*). Mean values ( ~ S E M for
)
patients with C H F ( o - . - 0 ) and normal subjects
(0-0)
are shown. A plateau for plasma radioactivity
was established in all subjects by the 70, 80 and 90 min
measurements.
Fig. 3. Plasma NA ASR ( a )and NA clearance rate ( b )in
patients with CHF ( a ) and normal subjects ( 0 ) determined during steady-state radionuclide infusion. Mean
values ( f SEM) for each group are shown. Calculated NA
clearance rate and NA ASR are derived from data averaged from the 70, 80 and 90 min (steady-state) [WH]NA
determinations. Statistical significance: * P < 0.05 compared with normal subjects. Abbreviation: NS, not significant.
Noradrenaline kinetics in congestive heart failure
clearance results. In this regard, our patients with CHF
were on average similar to those studied by Goldsmith et
al. [9], who likewise found NA clearance to be normal in
their CHF study population. The notion that milder
forms of CHF are associated with normal NA clearance is
supported further by recent NA kinetics data obtained
from patients with CHF during steady-state exercise [17].
It is thus likely that decreased NA clearance becomes
important primarily in patients with more severely
decompensated CHF, as suggested by the work of
Hasking et al. [ 101 and Davis et al. [ 111.
Other significant differences between our study and
previous studies may include the concomitant use of
medications that affect NA kinetics. We took care not to
include subjects taking such medications as clonidine, tricyclic antidepressants and, of course /3-adrenergic
blockers (all known to affect NA kinetics [18, 19]),and we
discontinued all diuretics, angiotensin-converting enzyme
inhibitors and digoxin well in advance of the study. Additionally, in order to evaluate stimulation of the adrenal
medulla, we concomitantly measured plasma adrenaline
concentrations in our subjects and found these to be
normal for both patients with CHF and normal control
subjects.
Hoeldtke & Cilmi [20] have shown that there is an
increase in plasma NA concentration, related to an
increase in the NA ASR, in elderly subjects. These data
were obtained from elderly subjects who were 63-85
years of age and compared with that from young subjects
of 30-40 years of age. Our patients with CHF were, on
average, 8 years older than the control subjects. However,
this age difference appeared to have no impact on the NA
kinetic results obtained in the present study. There was no
relationship between age and any of the NA kinetic parameters studied in either patients with CHF or normal subjects. The difference between our results and those of
Hoeldtke & Cilmi [20] may relate to the fact that none of
our subjects was either particularly young or old.
Recently, the validity of using a continuous infusion of
tracer NA to determine NA kinetics has been questioned.
Henriksen et al. [21] have suggested two potential problems pertaining to the use of [3H]NA in such studies:
delayed distribution of ["H]NA to slowly equilibrating tissues, and neuronal re-release of [3H]NA. In the former
case, the failure to achieve steady-state conditions during
[3H]NAinfusion, due to delayed distribution of tracer NA
to some tissue spaces, might result in an overestimation of
NA clearance. In the latter instance, re-use of [3H]NA,i.e.
re-release of tracer NA to plasma, might lead to underestimation of NA clearance from plasma. The half-time of
NA in plasma has been estimated at 5-7 min [21]. Thus,
our steady-state measurements taken at 70, 80 and 90
min correspond to greater than ten half-times or nearly
100% of the steady-state concentration in a well-mixed
system. However, it appears that tracer NA kinetics do
not strictly conform to a simple well-mixed model [21].In
spite of the complexities of NA kinetics, statistical
analysis confirmed that steady-state was achieved by 60
min in all subjects during the present study. This time
course to steady-state plasma [3H]NA concentration
433
agrees well with previously published data in normal subjects, patients with autonomic insufficiency, cirrhotic
patients and patients with CHF [11,12, 15,221.
Animal studies have shown that re-use of [3H]NAby
neuronal uptake and release is evident when high doses,
i.e. doses that are 100 times that used in human studies, of
tracer NA are used [23]. However, Esler et al. [24] have
concluded that such re-release of [3H]NAis unlikely to be
of a rate sufficient to affect the results of human studies
when low-dose [3H]NAinfusions are used. Their conclusion is based on the fact that studies employing manoeuvres to increase or to decrease endogenous NA release
in humans do not demonstrate the corresponding changes
in plasma ['HINA concentration that would be expected if
['HINA was re-released in any significant quantity [ 18,
25,261.
Antecubital venous plasma sampling presents another
potential methodological problem when using a tracer NA
infusion to determine plasma NA turnover [27]. This
sampling site is based on the original method described by
Esler et al. [12].However, if forearm uptake of ['HINA is
unrepresentative of whole-body uptake, estimations of
NA ASR and NA clearance rate may not be reflective of
whole-body NA kinetics. Moreover, it has been shown that
the specific activity of [3H]NA in venous samples from
various sites is lower than that measured in mixed venous
and arterial plasma, due to peripheral extraction of the
tracer [24]. Consequently, the NA ASR is higher when
calculated from venous plasma than when determined
from pulmonary or systemic arterial sites. There is now
general agreement that pulmonary or systemic arterial
samples are preferable, although no site is considered
ideal [24, 271. It has been calculated that less than 22% of
NA released by sympathetic nerves reaches the circulation [28].Thus, no matter what sampling site is chosen for
total NA ASR measurements, this method provides only a
crude estimation of the actual release rate of NA from
sympathetic nerves. Given these limitations, it does
appear that the NA ASR determined by this steady-state
radionuclide tracer method is better than plasma NA concentration alone as an index of sympathetic nervous
activity, as the confounding effect of NA clearance is eliminated [12]. The advantage of venous sampling in the
present study is that it permits comparison of our results
with previous studies of NA kinetics in CHF using the
same methodology [lo, 111. Moreover, since the data
obtained from our CHF patients are compared with that
from normal subjects studied under identical conditions,
valid inferences can be made about differences in sympathetic nervous system activity between the two groups.
In this regard, however, the flow dependence of NA
clearance may be of importance in the present study. Both
NA ASR and NA clearance rate are flow dependent [29].
Thus, if our patients with CHF had significantly
decreased forearm blood flow, allowing more time for
uptake of [3H]NA,NA clearance might be overestimated.
Forearm blood flow was not assessed in our subjects.
However, given the mildly decompensated state of these
patients in general, it is unlikely that alterations in forearm
blood flow contributed much to the present results.
434
W. T. Abraham e t al.
The dependence of elevated plasma N A concentration
in the present study on increased secretion, in concert
with the aforementioned elevations of plasma vasopressin, renin and aldosterone, provides support for the
‘diminished EABV’ hypothesis of sodium and water
retention in CHF. T h e results of earlier investigations
have led us t o define the ‘fullness’ of the arterial vascular
compartment by the interrelationship between cardiac
output and peripheral vascular resistance [4, 15, 30, 311.
A diminished cardiac output is suggested t o decrease
E A B V and initiate sodium and water retention in lowoutput cardiac failure, whereas arterial vasodilatation is
the proposed mechanism of decreased E A B V in highoutput cardiac failure [6]. Thus, diminished circulatory
perfusion of ventricular and arterial baroreceptors
appears to simultaneously activate the three major neurohumoral vasoconstrictor systems, namely the sympathetic
nervous system, the renin-angiotensin system and the
non-osmotic release of vasopressin, in patients with CHF.
Activation of these vasoconstrictor systems occurs to protect arterial perfusion of the vital organs. Moreover, the
severity and prognosis of CHF has been shown t o correlate with the extent of activation of this integrative
system [31, 321. For example, CHF patients with the highest resting venous plasma N A concentrations are known
to have the worst prognosis [32].Thus, activation of this
vasoconstrictive system may initially be important in
maintaining arterial perfusion pressure in the setting of a
failing left ventricle; however, the effect of an increase in
cardiac afterload may be detrimental and lead t o a vicious
cycle that further impairs left ventricular performance
[331.
In summary, N A kinetics were studied in six CHF
patients without significant associated morbidity and in
six normal control subjects. We found that the elevated
peripheral venous plasma N A concentrations seen in the
patients with CHF were solely dependent o n elevated N A
secretion rates. In the absence of significant adrenal
medullary stimulation, this elevated N A secretion is
reflective of an activated sympathetic nervous system,
most likely in response t o a diminished EABV. At more
advanced stages of CHF, increased plasma N A concentrations may also be d u e t o decreased N A clearance.
T h e present results, however, indicate that the initial rise
in plasma N A concentration in patients with CHF is
primarily d u e to increased N A secretion, rather than t o
decreased N A clearance.
ACKNOWLEDGMENTS
We are indebted to the staff of the Clinical Research
Center at the University of Colorado Health Sciences
Center for their exemplary care of our patients and t o
Vicki Van Putten for her technical assistance. This investigation was supported by United States Public Health
Services Research grant MOl-RR00051 from the Division of Research Resources, National Institutes of Health.
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