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JACC Vol, 19, No. 6
May 1992 :1180-4
1 18 0
Baroreflex Loading Maneuvers Do Not Suppress Increased Plasma
Arginine Vasopressin in Patients With Congestive Heart Failure
STEVEN R. GOLDSMITH, MD, FACC
Minneapolis, Minnesota
Nonspecific baroreflex loading maneuvers such as head-down tilt
readily suppress Aimulated arginine vasopressin levels in normal
tion with mannitol. Mannitol Increased osmolality from 287 ± 9 .2
humans.
8 .2 mOstWkg (p < 0.01) on two occasions. No significant suppresston of arginine vasopressin was seen during head-down tilt after
mannitol infusion compared with values in a time control period.
These results are consistent with an abnormality in baroreflex
suppression of arginine vasopressin secretion in chronic congestive
heart failure and suggest that such a defect may contribute to
long-term high levels of arginine vasopressin in this condition .
(J Am Coll Cardiol 1992 ;19:1180-4)
To
test the hypothesis that the increased arginine vaso-
pressin levels in patients with congestive heart failure would not
respond normally to harreflex loading, 12 patients with conger
live heart failure had arginine vasopressin levels and osmolality
determined in the supine position and after 15 min of 30'
head-down tilt. Arginlne vasopressin was increased to 6 .5 t
2.0 pglml at control measurement and did not decrease .
Eight patients underwent further study after osmotic stimula-
The pathophysiologic process leading to chronically elevated arginine vasopressin levels in congestive heart failure
remains poorly understood . Several reports (1-8) have confirmed that arginine vasopressin levels tend to be on average
at least twice normal in congestive heart failure, clearly in
the range where one would expect hydro-osmotic effects and
often in the range associated with vasoconstriction . Discovering the mechanism responsible for producing increased
arginine vasopressin levels in congestive heart failure may
therefore be of more than academic interest . It is clear that
although arginine vasopressin will decrease in response to
declining osmolality in congestive heart failure (4-6), plasma
levels remain high, suggesting either that there is a nonosmotic drive that "resets" the arginine vasopressin/
osmolality, relation or that there is interference with the renal
effects of arginine vasopressin, in effect a state of partial
renal diabetes insipidus.
Mast speculation to date with regard to nonosmotic drive
has focused on baroreflex mechanisms, which, if impaired in
congestive heart failure, could lead to increased arginine
vasopressin levels by a loss of tonic inhibitory input to the
responsible hypothalamic cardiovascular control centers ;
however, tonic baroreceptor-mediated restraint of arginine
From the Hennepin County Medical Center, Cardiology Division, Minneapolis, Minnesota . This research was supported by a grant-in-aid from the
American Heart Association, Dallas, Texas . Dr. Goldsmith is an Established
investigator or the American Head Association and the CIBA-Geigy Corporation, Summit, New Jersey .
Manuscript received September 4, 1991 ; revised manuscript received
Novemhr 5, 1991, accepted November 5. 1991 .
Address for repdma: Steven R . Goldsmith, MD, Hennepin County
Medical Center, Cardiology nivnioo, 701 Park Avenue, Minneapolis, Minnesole 55415 .
01992 by the
American College of Cardiology
to 294 ± 7.8 mOsmlkg (p < 0.001) and from 288
2
9 to 299 ±
vasopressin secretion is difficult to demonstrate in humans
(9-12) . Severe hypotension is required for the nonosmotic
release of arginine vasopressin in normal humans (13), and
this is not afeature of chronic stable congestive heart failure .
However, we and others (14,15) have shown that in normal
humans, increased baroreflex activity will suppress arginine
vasopressin levels that are already increased by osmotic
stimulation. It is therefore possible that impaired baroreceptor function in congestive heart failure could contribute to
the maintenance, if not the initial generation, of increased
arginine vasopressin levels . This possibility was the focus of
the current study, in which the response of plasma arginine
vasopressin to head-down tilt was assessed in a group of
patients with chronic stable congestive heart failure .
Methods
Study subjects. Twelve patients with chronic congestive
heart failure on the basis of either ischemic (n = 4) or
idiopathic (n = 8) cardiomyopathy participated in these
investigations . The protocol was reviewed and approved by
the Hennepin County Medical Center Institutional Review
Board and all patients gave informed consent . There were
nine men and three women, and their ages ranged from 43 to
78 years (mean 62) . All had confined severe reduction in
left ventricular ejection fraction by angiography . radionuelide study or echocardiographic measurement . All patients
but one were receiving therapy with digitalis, diuretic agents
and vasodilators, which were withheld at least 12 h before
the study . In all cases, vasodilator therapy included an
angiotensin-converting enzyme inhibitor.
Protocol. The initial investigation proceeded as follows .
On reporting to the laboratory after an overnight fast, the
0735-1097152155.00
JACC I . . Iv. No. a
May 17:2; 1 180-4
coLDSStrrn
RARUREI-LEXES AND VASOPRES5IN IN HEART FAILURE
subjects were positioned comfortably in a IO° head-up position on a tilt table . An intravenous cunnula was placed in a
vein in an arm or hand to obtain blood samples . Baseline
heart rate and arterial pressure were recorded by an automated cuff. A 30-min rest period was then observed . after
which control values for heart rate, arterial pressure, plasma
arginine vasopressin and plasma osmolality were obtained .
The subjects were then placed in a 30' head-down tilt for
15 min, and all measurements were repeated . In five subjects, plasma atrial natriuretic factor levels were also measured before and during the tilt .
Eight subjects participated in , e estensi, •r 3-dnv
investigation . On I day . subjects were simply observed for
30 min after control measurements were taken and then
placed in a 30° head-down tilt position for 15 min . On a 2nd
day, after control observations, they received a 250-m1
infusion of a 20% mannitol solution over a 30-min period,
after which all measurements were repeated. Although associated with brief intravascular volume expansion, mannitol in this amount has been previously shown to exert a net
stimulating effect on plasma arginine vasopress .a levels in
patients with congestive heart failure (16) . On this day . they
were then observed in the supine position for an additional
15 min . On a 3rd day, after control measurements . subjects
received a mannitol infusion identical to that given on the
2nd day . Measurements were repeated at 30 min, and
subjects were then placed in a 30" head-down position for
15 min . The eight subjects therefore had a 30-min control
period followed by 15 min of head-down tilt on I day, a
30-min infusion of mannitol followed by a 15-min control
period on I day, and a 30-min mannitol infusion followed by
15 min of head-down tilt on I day . The order of the 3 days
was prospectively randomized .
We therefore hoped to test I) whether any response of
arginine vasopressin to head-down ti'.*T was reproducible in
patients with congestive heart failure . and 2) whether, if a
blunted response to basal arginine vasopressin levels to
head-down tilt was found in the initial study, additional
osmotic stimulation would lead to a greater sensitivity to
nonosmotic suppression in analogous fashion to what we had
previously shown in normal subjects.
Assays. Blood samples were drawn into prechilled tubes,
kept on ice and cold centrifuged with the plasma frozen at
-4°C for later analysis for plasma arginine vasopressin .
Serum was separated for determination of osmolality, which
was performed on fresh samples by the freezing-point depression method . Plasma arginine vasopressin was analyzed
by a sensitive and specific rrtdioimmunoassay by Dr. Allan
Cowley at the Medical Colle,>,e of Wisconsin. Current interand intraassay coefficients of variation average approximately 4%, and the assay reliably detects levels of plasma
arginine vasopressin down to 0 .3 pg/ml. Plasma atrial natriuretic factor levels were measured in the Biochemical Core
Laboratory at the University of Minnesota by radioimmunoassay . The coefficient of variation is 7% and the normal
range is 7 to 40 pg/ml.
1181
Table 1 . Response of htemorfynamic and Plasma variables to
Head-Down Tilt in 12 Patients With Congestive Heart Failure
Head-Down
Coneat
HR Ibeakrmlnl
MAP no
ASP
73 0 12
85!6 .5
Hp
ImOsrvkgl
290 V 7 .8
75
-
Tia
11
88'_8.8
290 0 ' .2
ASP Ippt'mlt
6.5 *_ 2.0
6 .5
ANF :pFmll'
132_102
120 0
0 98
2 .3
'Measurements in five patients . Values are mean values ± I SD : no
changes were statistical!, ;p.ficant . ANF = plasma at dal natriuretic factor:
AV P = plasma ar&nine -p-m, HR = heart ram: MAP = mean arrerrl
pressure : 0553 = p!a>ma osmolality .
Statistics. Data were analyzed as follows . A paired I test
compared the control and head-down tilt values for heart
rate, arterial pressure, arginine vasopressin, osmolality and
atria) natriuretic factor in the subjects studied on one occasion only . For the eight subjects studied on 3 additional
days, a multiple-factor analysis of variance compared the
responses of heart rate, arterial pressure, arginine vasopressin and osmolality across time on each study day and
between study days .
Results
Initial measurements. Table I shows the responses of
heart rate, arterial pressure, arginine vasopressin and osmolality taken in the control period and after 15 min of
head-down tilt in all 12 subjects initially investigated . Baseline plasma arginine vasopressin levels were elevated in
these patients to 6.5 ± 2.0 pglml (normar 3.5 '_ I pg/mI). As
can be seen, there were no significant changes in any
variables during tilt . In the five subjects in whom atria)
natriuretic factor measurements were also made, there was
also no change from the baseline level of 132 ± 46 pg/ml
.
(normal 22 ± I t peril)
Patients studied on 3 different days (Table 2). In the eight
patients, there was no significant change in osmolality or
arginine vasopressin at any time on the day in which no
mannitol was given, confirming reproducibility of the failure
to suppress arginine vasopressin in the larger series . Arginine vasopressin and osmolality increased significantly as expected in response to the mannitol infusion, and the responses
between the 2 days on which mannitol was given were not
different . Osntolality and arginine vasopressin levels tended to
decrease slightly 15 min after mannitol infusion on both of the
additional study days ; however, the response did not differ
between these 2 days, suggesting that head-down tilt had no
suppressive effect on the further stimulated arginine vasopressin levels produced by mannitol .
Discussion
Control ofarpniaevasnprecsinsecretianinhumans. Arginine vasopressin secretion appears to be less sensitive: to
baroreflex modulation in humans than in certain experitnen-
GOLDSMITH
IAROREFLEXES AND VASOPRESSIN IN HEART FAILURE
1 182
Table 2. Results of the 3-Day Study in Eight Patients With
Congestive Hean Failure
Day I
HR (beatsimin)
MAP (mm Hg)
OSM (mOsmikgl
AVP(pgiml)
Control I
Control 2
Head-Down Till
78 ! I I
82 1 8 .4
288 1 9.3
6 .41-0.96
76 ± 12
87 1 6.3
290'_ 7 .8
6 .511 .2
791 12
91 *_ 7 .7
2901 7 .2
6 .911 .8
Control I
Mannitol
75 *- 13
90 *_ 7 .7
288 x 9
6 .5 1 1 .4
80 ± I I
91 t 9.1
299 t 8 .2'
9 1 2,6'
Control I
Mannilol
Day 2
HR (beats/min)
MAP (mm Hg)
OSM (m0sm11,g)
AVP (pg/m)
Time Control
79
90
296
7 .9
!
0
1
1
14
12
8 .4'
1 .7'
Day 3
Head-Down Tilt
HR (beatslmin)
72 1 14
79 ^- 11
82 1 II
MAP (mm Hg)
82 1 7 .5
84 1 7
90 , 6.2
OSM (m0smlkg)
2871 9.2
294'_ 7,8'
293 1 8.2'
6 .5 _ 1 .4
82 t 1 .8'
7 .31 1 .7'
AVPIpelmll
'p < 0.01 versus day I. Both osmolality and plasma arginine vasopressin
were significantly increased ip < (;.act) after mannitol infusion tMannitull
compared wirh control measurements (Control I) on days 2 and 3 and (p <
0.01) eompaed
with values on Day
I without
mannitol infusion . There was no
difference between the 2 days on which mannitol was given (days 2 and 3).
Head-down
fill
I, and
of plasma arginine vasopressin to
3) 7ompared with the time control
did not increase plasma arginine vasopressin on day
there was no difference in the response
head-down till after mannitol infusion (day
on day 2 . The order of the
3 days
was prospectively randomized. Abbrevia-
tions as in Table 1 .
tat animals (17,18) . In the dog, for example, small reductions
of central venous or arterial pressure readily increase plasma
arginine vasopressin at constant osmolality . In humans,
however, severe hypotension is required before arginine
vasopressin will be released (12,13) . This observation implies that there is less tonic baroreceptor-mediated restraint
of arginine vasopressin release in humans, since only a
relatively powerful unloading stimulus will release arginine
vasopressin nonosmotically at constant osmolality . On the
other hand, we and others (14,15,17-19) have shown that
although baroreflex loading maneuvers do not decrease basal
arginine vasopressin levels in normal humans, such maneuvers (head-down tilt, head-out immersion) do decrease arginine vasopressin levels if secretion has been stimulated by
such means as the administration of a hypertonic saline
solution, prior dehydration or the application of thermal
stress. These studies. suggest that although there is less tonic
baroreflex-related restraint of arginine vasopressin secretion
in normal humans, baroreflex loading readily modulates
increased hormone levels .
The current study was therefore designed to test the
hypothesis that baroreceptor-mediated suppression of the
increased arginine vasopressin levels in congestive heart
sACC Val. 19, No. 6
May 1992 :1180-4
failure might be abnormal. In addition, we further stimulated
arginine vasopressin levels c .tth mannitol in an attempt to
elicit the latent sensitivity of arginine vasopressin to baroreceptor suppression even if it were not evident in the basal
state . The results are consistent with a defect in the hamr .
ceptor-related mechanisms responsible for suppressing arginine vasopressin secretion in congestive heart failure, both
in the basally increased state and after additional osmotic
stimulation .
Head-down tilt as a stimulus . Head-down tilt is a nonspecific baroreceptor loading maneuver . We have documented
(15,19) that this maneuver is associated with a sustained
increase is central venous pressure in normal humans . In
addition, although there are usually no direct effects on
arterial pressure, the head-down tilt maneuver results in
hydrostatic stress on the carotid sinus and therefore must be
considered to deliver at least a mild stimulus to the sinoaortic baroreceptor as well. The maneuver readily suppresses
sympathetic activity in normal humans (20,21), and we have
previously confirmed that although it does not decrease
basal arginine vasopressin levels in normal humans (19),
head-down tilt readily suppresses arginine vasopressin levels
if they are subjected to prior osmotic stimulation (15). These
results are analogous to those of von Ameln et al. (14), who
resolved the long-standing controversy concerning the response of arginine vasopressin to head-out immersion in
normal humans. Head-out immersion, like head-down tilt, is
a maneuver that results in an increase in central blood
volume and central venous pressures . Von Ameln et al. (14)
clearly showed that the application of head-out immersion
did not alter basal arginine vasopressin levels in normal
humans, but that if levels were stimulated by a combination
of dehydration and increased osmolality, immediate suppression of arginine vasopressin during immersion was seen .
Taken together, these studies in normal humans suggest that
the application of nonspecific baroreceptor loading maneuvers does suppress arginine vasopressin in normal humans if
levels are high before the stimulus is applied .
We did not measure central hemodynamics in this study .
However, it was recently reported (22) that a virtually
identical head-down tilt did, as expected, result in an increase in central venous pressures in patients with congeslive heart failure . This increase is not surprising, because
patients with congestive heart failure, with abnormal preload
reserve, would be expected to have, if anything, a larger
response in central venous and pulmonary capillary wedge
pressure than normal subjects when placed into a head-down
position . Although both pressure and volume measurements
would be needed to fully explore the degree of signal given to
the cardiac baroreceptors, since they respond
ID
stretch, it
therefore seems that head-down tilt is a stimulus that is
capable of "loading" cardiopulmonary and sinoaortic
baroreceptors in patients with congestive heart failure as
well as in normal persons at least as reflected by pressure
and gravitational considerations. We (20) have previously
shown that plasma norepinephrine does not respond nor-
Vut. 19. Nd. 6
May 1992:11g0-4
JACC
G01-11SAHTH
BAROREFLEXES AND vasopnESSIN IN HEART FAILURE
really to head-down tilt in congestive heart failure . suggesting that
there is
abnormal baroreflex regulation of the
sympathetic nervous system in response to this maneuver .
The current results are analogous to those with plasma
norepinephrine and suggest that there is also an abnormality
in baroreflex suppression of the increased arginine vasopressin levels of congestive heart failure .
Possible explanations for the results. It is not possible
from these studies to identify the mechanism responsible for
the absence of baroreflex suppression of arginine vasopressin in congestive heart failure . Possible explanations for
baroreflex failure during head-down tilt include I I less afferent signal from either less relative stretch on the baroreceptors or diminished responsiveness of the baroreceptors
themselves, either in the heart or in the sinoaortic area :
2) abnormal central processing of a normal afferent signal : or
1 18 3
Conclusions. We have demonstrated that increased arginine vasopressin levels are not responsive to a baroreflex
loading stimulus in congestive heart failure . even after
additional osmotic stimulation with mannitol . These data,
along with observations on the sympathetic nervous system
and atrial natriuretic factor, suggest that abnormal baroreceptor function in congestive heart failure may contribute
significantly to the overall imbalance in neuroenducrine
activation. In turn, such an imbalance may contribute to the
excessive vasoconstriction and salt and water retention
characteristic of tuffs disease, although a causal link between
abnormalities in these systems and the pathophysiologic
processes in congestive heart failure has yet to be firmly
established . As with the renin-angiotensin system. long-term
pharmacologic manipulation of these systems would be
required to provide such proof.
3) deficient efferent response to normal central output . Most
experimental data suggest that the abnormality is probably at
the level of the haroreceptors themselves . because, at least
with regard to sympathetic responses . baroreceptor function
W-1, Cam? Crayeu . RN for her help in cardcaheg these studies : Meredith
Skelton for the arginine mpres
«aye and Tim Ono and Becky
Wcs(ergree for preparing the manuscript
seems to be restored by heart transplantation (23) and to be
improved by pharmacologic treatment such as angiotensinconvening enzyme inhibition 1241 and digitalis (25). which
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