(Circulation. 2000;101:2053.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Reducing Cardiac Filling Pressure Lowers Norepinephrine Spillover in Patients With Chronic Heart Failure
From the Division of Cardiology, Department of Medicine, Mount Sinai Hospital, University of Toronto.
Correspondence to John D. Parker, MD, Mount Sinai Hospital, 600 University Ave, Suite 1609, Toronto, Ontario M5G-1X5. E-mail jdp{at}inforamp.net
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Abstract |
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Background—We studied the cardiac sympathetic response to selective unloading of cardiopulmonary baroreceptors in subjects with normal left ventricular (LV) function and congestive heart failure (CHF).
Methods and Results—Eight patients with normal LV function (age 57±5 years, ejection fraction 58±2%) and 8 patients with CHF (age 60±2 years; ejection fraction 19±2%) were studied. Instrumentation consisted of an arterial line, a pulmonary artery catheter, and a coronary sinus thermodilution catheter. The radiotracer technique was used for measurement of cardiac norepinephrine spillover (CANESP) and total-body norepinephrine spillover. Lower-body negative pressure (LBNP) was applied at 2 levels: nonhypotensive and hypotensive LBNP. Nonhypotensive LBNP reduced filling pressures significantly in both groups. Arterial pressure did not change. This reduction in filling pressures caused a significant reduction in CANESP in the CHF group (from 167±53 to 125±37 pmol/min, P<0.05) but no change in the normal LV function group. Hypotensive LBNP caused a significant increase in CANESP in the normal group (73±13 vs 122±27 pmol/min, P<0.05) but no significant change in those with CHF.
Conclusions—We conclude that selective reduction in filling pressures lowers cardiac norepinephrine spillover in patients with CHF. These findings suggest that a goal of CHF management should be to reduce cardiac filling pressures while avoiding systemic hypotension.
Key Words: nervous system, autonomic • norepinephrine • nervous system, sympathetic
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Introduction |
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Cardiac norepinephrine spillover is increased in the setting of chronic congestive heart failure (CHF), and this increase has been shown to have an important impact on survival.1 The mechanisms underlying cardiac sympathetic activation remain unclear and may involve abnormalities in afferent control, local prejunctional modulation, and/or central processing. Sympathetic activation in CHF is not a generalized process and has been shown to be organ specific.2 3 Cardiac sympathetic activation occurs early during the course of CHF, and the greatest increase in sympathetic activity in this disease is directed at the heart.2 3 Importantly, recent studies have demonstrated that the response to modulation of the sympathetic nervous system is often cardiac specific.3 4 5 These findings emphasize the need to measure cardiac sympathetic activity because cardiac responses cannot be inferred from systemic or noncardiac responses. Furthermore, these observations suggest that some mechanisms involved in cardiac sympathetic activation may involve local afferent or central integrative responses that are specific to the heart and the heart failure state.
Kaye and colleagues6 have documented a positive correlation between cardiac norepinephrine spillover and pulmonary artery pressures in patients with CHF. Therefore, it has been suggested that in the setting of CHF, increased cardiac filling pressures and/or pulmonary arterial pressures may cause a direct reflex increase in sympathetic efferent outflow to the heart. This has led to the hypothesis that a reduction in cardiac filling pressure might have sympathoinhibitory effects. In a previous study, we demonstrated that generalized baroreceptor unloading caused by an infusion of nitroprusside had no effect on cardiac norepinephrine spillover in patients with CHF despite causing large increases in sympathetic outflow to the periphery.4 Although a reduction in cardiac norepinephrine spillover was not observed, this effect may have been masked by the stimulus to sympathoactivation invoked by arterial baroreceptor unloading.7 More recently, Kaye et al5 demonstrated that an infusion of nitroprusside caused a reduction in cardiac norepinephrine spillover in a selected group of patients with CHF and severe pulmonary hypertension. In the present investigation, we used a lower-body negative pressure (LBNP) chamber in an effort to unload cardiopulmonary baroreceptors in the absence of measurable changes in systemic arterial blood pressure. We hypothesized that such selective unloading of cardiac filling and pulmonary pressures would have cardiac sympathoinhibitory effects in patients with CHF.
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Methods |
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Patient Characteristics
A total of 16 patients referred for angiography participated in this study. Eight subjects had normal LV function (ejection fraction 58±2%, mean age 57±5 years) and 8 patients had CHF (ejection fraction 19±2%, mean age 60±2 years). In the group with normal LV function, all subjects had a chest pain syndrome and some degree of coronary artery disease. Among the CHF group patients, all were in New York Heart Association class II or III, and the underlying cause of the cardiomyopathy was ischemic in 6 and idiopathic in 2. Medical therapy in the normal LV function group included ß-blockers (n=4), calcium channel blockers (n=3), ACE inhibitors (n=1), furosemide (n=1), transdermal nitroglycerin (n=1), and amiodarone (n=1). In the CHF group, medical therapy consisted of ACE inhibitors (n=6), furosemide (n=6), digoxin (n=3), ß-blockers (n=3), amiodarone (n=2), and transdermal nitroglycerin (n=1). All medical therapy was held on the morning of the study. This protocol was approved by the Ethical Review Committee for Human Experimentation of the University of Toronto. Written informed consent was obtained from all patients.
Hemodynamic and Coronary Flow
Measurements
A diagnostic right and left heart
catheterization was performed without sedation. The
pulmonary artery catheter was left in place after completion of
the diagnostic procedure. A 7F coronary sinus
thermodilution flow catheter (type CCS-7U-90B, Webster Laboratories)
was then inserted from an antecubital vein and positioned in the
coronary sinus for flow measurements and blood sampling.
Systemic arterial pressure was monitored from an 8F sidearm
sheath (Cordis Laboratories). Cardiac output was assessed by the Fick
method. The ECG, right atrial pressure, pulmonary artery
pressure, and pulmonary capillary wedge pressure were
recorded on a strip-chart recorder. For each variable, the
results were expressed as an average of measurements of 15 cardiac
cycles. Coronary sinus blood flow measurements were performed
in duplicate at each measurement point according to the method of Ganz
et al.8
Norepinephrine Spillover Measurements
Sympathetic outflow was estimated by the measurement of cardiac
and total-body norepinephrine spillover, with the use
of techniques that are well established in our
laboratory.4 9 For these measurements, tritiated
norepinephrine (1.6 µCi/min with a 16-µCi priming bolus
of L-[2,5,6-3H] norepinephrine; New
England Nuclear) was infused into the femoral vein through a Harvard
pump (model 33, Harvard Apparatus Canada) to steady-state
concentration in plasma. Norepinephrine spillover rates
were calculated as follows:
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Analysis of Plasma Catecholamines
Plasma catecholamine concentrations were measured by
high-performance liquid chromatography with
electrochemical detection. Fractions from the high-performance
liquid chromatography effluent containing
tritium-labeled norepinephrine were assayed by liquid
scintillation spectroscopy.4 9 The biochemical
analysis was performed by personnel blinded to patient
status.
Study Protocol
After the diagnostic heart
catheterization and insertion of catheters for
hemodynamic monitoring, all patients in both groups
were carefully transferred from the catheterization
table to an LBNP chamber. The LBNP chamber was specially designed for
use in patients with arterial and venous access from the
femoral site. The chamber was made of Plexiglas with a sliding top to
allow continuous observation of the groin and guarantee fast access in
case of bleeding or other complications. Once the patient was in the
LBNP chamber, a neoprene skirt was adjusted around the waist to assure
adequate air seal. The patient was left undisturbed for a minimum of 20
minutes for tritium-labeled norepinephrine to reach
steady-state concentration in plasma. Hemodynamic
measurements were then performed, and total-body and cardiac
norepinephrine spillover were assessed (control
measurements). Subsequently, negative pressure was applied and slowly
decreased to achieve a significant reduction in filling pressures
without affecting arterial pressure (nonhypotensive LBNP).
Our goal was to obtain a 30% to 40% reduction in mean
pulmonary artery pressure, as long as there were no detectable
changes in arterial pressure. None of the patients enrolled
in this study demonstrated a significant change in arterial
pressure during nonhypotensive LBNP, and the
hemodynamic end point was achieved without
difficulties. Measurements were repeated and the negative pressure was
further titrated, this time to obtain a 10% reduction in
systolic arterial pressure (hypotensive LBNP).
After hemodynamic measurements and
catecholamines were reassessed, the negative pressure was
discontinued and patients were monitored until all pressures returned
to baseline (recovery measurements).
Statistical Analysis
All data are presented as mean±SEM. Between-group
comparisons of baseline characteristics were performed with an unpaired
t test. Within-group comparisons of the effects of
nonhypotensive and hypotensive LBNP on hemodynamics,
catecholamine concentrations, and
norepinephrine kinetics were made by 1-way repeated
measures ANOVA with the use of the Student-Newman-Keuls test for post
hoc comparisons. Between-group comparisons of the effects of LBNP were
performed with the use of ANCOVA. A value of P<0.05 was
required for statistical significance.
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Results |
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Baseline Characteristics
In the normal left ventricular (LV) function group, cardiac filling pressures were significantly lower than in the CHF group. Despite the severity of the LV dysfunction in the CHF group, they were fairly compensated, with a wedge pressure of only 15±3 mm Hg. Total-body and cardiac norepinephrine spillover were increased in the CHF group when compared with the normal LV function group (Table 1
).
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Hemodynamic Responses
Nonhypotensive LBNP
In the group with normal LV function, there was a highly
significant reduction in right atrial, pulmonary
arterial, and capillary wedge pressures but no change in
systemic arterial blood pressure. Nonhypotensive LBNP
caused very similar hemodynamic responses in the CHF
group characterized by consistent reductions in filling
pressures and no significant change in arterial blood
pressure. A significant reduction in cardiac index was seen in the
normal LV function and CHF groups. The analysis of
covariance revealed that the hemodynamic
effects of nonhypotensive LBNP were similar in the 2 groups (Tables 2 and 3).
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Hypotensive LBNP
With the application of hypotensive LBNP, the group with normal LV
function demonstrated further reduction in filling pressures and
cardiac index. Similar responses were observed in the CHF group for all
the hemodynamic parameters mentioned above.
In the normal LV function group, there was a significant reduction in
systolic arterial pressure, but the changes in
diastolic and mean arterial pressures were not
significant. In the CHF group, despite similar levels of negative
pressure, we were able to cause a significant reduction in
systolic, diastolic, and mean arterial
pressures.
Cardiac Sympathetic Responses
Nonhypotensive LBNP
Nonhypotensive LBNP caused no change in cardiac
norepinephrine spillover in the group with normal LV
function (73±13 vs 71±14 pmol/min, P=NS). However, in the
CHF group, there was a significant reduction in cardiac
norepinephrine spillover with the application of
nonhypotensive LBNP (167±53 vs 125±37 pmol/min, P<0.05).
ANCOVA revealed that the decrease in cardiac norepinephrine
spillover observed in the CHF group was significantly different
from the change observed in the normal LV function group (Tables 2
and 3 and Figure 1).
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indicates
normal LV function group; •, CHF group; C, control; and RC, recovery.
*P<0.05 vs control, 
P<0.05 vs normal
LV function group at control.
Hypotensive LBNP
In the group with normal LV function, there was a significant
increase in cardiac norepinephrine spillover with
hypotensive levels of LBNP. This effect was not seen in the CHF group,
in which cardiac norepinephrine spillover only
increased back to baseline levels.
Generalized Sympathetic Responses
Nonhypotensive LBNP
Nonhypotensive LBNP was associated with a significant
increase in total-body norepinephrine spillover in the
group with normal LV function (from 1.8±0.2 to 2.7±0.3 nmol/min,
P<0.05). In the CHF group, similar levels of nonhypotensive
LBNP did not significantly alter total-body norepinephrine
spillover (3.4±0.6 vs 3.9±0.6 nmol/min, P=NS) (Tables 2 and 3 and Figure 2).
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Hypotensive LBNP
With the application of hypotensive levels of LBNP, there was a
significant increase in whole-body sympathetic neuronal activity as
measured by total-body norepinephrine spillover in both
the normal LV function and CHF groups.
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Discussion |
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This is the first human study to measure cardiac norepinephrine spillover in response to LBNP. Data obtained from both the normal LV function and CHF groups are novel, providing new insights into the control of the sympathetic nervous system. The LBNP chamber has important advantages over other methods that have been used to explore the effect of changes in cardiac filling pressure on sympathetic activity. First, predictable and relatively selective cardiopulmonary baroreceptor unloading can be achieved, something that is not possible with other approaches. Second, since no pharmacological intervention is involved, we were able to avoid potential confounding effects such as might be observed when a nitric oxide donor (eg, nitroprusside) is used.10 It is recognized that nonhypotensive LBNP, although not causing a measurable decrease in systemic arterial blood pressure, may well have some impact on arterial baroreceptors.11 Nevertheless, the use of nonhypotensive LBNP does provide an opportunity to decrease cardiopulmonary filling pressures without fully engaging reflex sympathetic responses to systemic hypotension.
It is recognized that patients with chronic CHF have abnormal autonomic neuronal reflex responses to changes in cardiopulmonary loading conditions. In 1950, Brigden and Sharpey-Schafer12 demonstrated that upright tilt was associated with forearm vasodilation in patients with CHF. More than 30 years later, in a better-characterized population of patients with CHF, Ferguson et al13 reported that some patients with severe CHF develop forearm vasodilation in response to LBNP. These responses are abnormal because reductions in cardiopulmonary filling pressures should cause sympathoexcitation.13 14 It is also clear that patients with CHF have abnormal responses to increases in cardiac filling pressures. Positive correlation between measures of sympathetic activity and increased cardiac filling pressures have been recognized for several years.15 16 In 1994, Kaye and colleagues6 demonstrated that mean pulmonary artery pressure was an independent predictor of cardiac sympathetic activity in patients with chronic CHF. This relation is paradoxical, since in the setting of normal physiology, increases in cardiopulmonary pressures have sympathoinhibitory effects reflected by peripheral vascular resistance responses.17
This series of observations led to the hypothesis that reductions in cardiopulmonary pressures would lead to reductions in cardiac sympathetic activity. Subsequently, our laboratory reported that nitroprusside, given to patients with moderately severe CHF, caused increases in total-body norepinephrine spillover but had no significant effects on cardiac norepinephrine spillover.4 As expected, in patients with normal ventricular function, an infusion of nitroprusside that had similar hemodynamic effects caused marked increases in both systemic and cardiac sympathetic activity. These results demonstrate that cardiac sympathetic responses to generalized arterial and cardiopulmonary baroreceptor unloading are abnormal in chronic CHF. A cardiac sympathoinhibitory effect of preload reduction was not observed, presumably because of the simultaneous decrease in systemic arterial pressure with subsequent arterial baroreceptor–mediated increases in sympathetic outflow, some of which may be directed to the heart.7 More recently, Kaye et al5 have reported that the acute administration of nitroprusside was associated with decreases in cardiac sympathetic activity in patients with CHF and severe pulmonary hypertension. This sympathoinhibitory cardiac response occurred despite significant increases in total-body norepinephrine spillover. On the basis of these findings, the authors concluded that increased cardiopulmonary filling pressure in patients with CHF evokes an increase in cardiac sympathetic activity by a direct reflex mechanism. Although these findings are important, the administration of nitroprusside to these patients with CHF and pulmonary hypertension was associated with significant increases in cardiac output, and it is not possible to conclude that the observed cardiac sympathoinhibition occurred only as a result of a reduction in filling pressures.
In the present study, patients were well compensated despite having severe ventricular dysfunction. In this regard, they are representative of a broad range of patients with LV dysfunction and symptomatic CHF. The application of nonhypotensive LBNP in these patients caused significant reductions in cardiopulmonary filling pressure but had no effect on systemic arterial pressure. Despite the associated reduction in cardiac output, a significant decrease in cardiac norepinephrine spillover was observed. On the basis of these responses, we conclude that a selective reduction in cardiac filling and pulmonary artery pressure in patients with chronic CHF leads to a decrease in efferent cardiac sympathetic outflow. It is important to emphasize that this decrease in cardiac sympathetic activity occurred despite a tendency for total-body norepinephrine spillover to increase, a finding indicative of increased sympathetic activity in other, noncardiac, vascular beds.2 In the CHF group, there was no change in heart rate with nonhypotensive LBNP despite a significant reduction in cardiac norepinephrine spillover. Previous studies have shown a poor correlation between heart rate responses and adrenergic markers such as plasma norepinephrine or muscle sympathetic nervous activity.18 Potential mechanisms for this discrepancy include (1) sinus node dysfunction in the setting of CHF,19 (2) parasympathetic modulation of sinus node responses, (3) sympathetic drive to the heart muscle may be different from central outflow to the sinus node, and (4) concomitant use of chronotropically active drugs.
In patients with normal LV function, nonhypotensive LBNP caused a significant increase in generalized sympathetic activity as measured by an increase in total-body norepinephrine spillover but had no effect on cardiac norepinephrine spillover. Increases in sympathetic outflow to the periphery, as measured by increases in limb vascular resistance or direct microneurographic recordings, are consistently reported in response to nonhypotensive LBNP.13 20 In contrast, a number of studies performed with norepinephrine kinetics have not found the significant increase in total-body norepinephrine spillover that we report here.21 22 This difference probably is secondary to the fact that in previous studies, fixed levels of LBNP (ie, -15 mm Hg) were applied instead of being titrated until a hemodynamic goal was obtained. Furthermore, patients in the present study were considerably older (57±5 years) than the normal volunteers exposed to nonhypotensive LBNP in previous reports, and this may have contributed to differences in the observed response.
In patients with normal LV function, a number of studies,14 23 24 have reported conflicting results regarding the effects of LBNP on sympathetic outflow to the heart despite evidence of increased sympathetic outflow to the periphery. In these reports, changes in heart rate were used as a surrogate marker for cardiac sympathetic responses. The present investigation confirms that nonhypotensive LBNP does not increase sympathetic outflow to cardiac muscle despite evidence of increased sympathetic outflow to a number of organ beds. This is important because it provides another example in which observations made in the periphery cannot predict cardiac sympathetic responses.
As would be expected, hypotensive LBNP was associated with significant increases in cardiac norepinephrine spillover in patients with normal LV function. This is similar to what was observed in response to combined cardiopulmonary and arterial baroreceptor unloading with nitroprusside in patients with normal LV function.4 Patients with CHF displayed abnormal cardiac norepinephrine spillover responses to hypotensive LBNP. In this group, systemic hypotension during hypotensive LBNP did not lead to an increase in cardiac norepinephrine spillover. In response to hypotensive LBNP, cardiac sympathetic responses returned to control levels from what was observed during nonhypotensive LBNP but did not increase above baseline values. This finding is consistent with our previous report in which a nitroprusside infusion caused no change in cardiac norepinephrine spillover despite causing systemic hypotension and increases in total-body norepinephrine spillover.4
The mechanism of the specific reduction in cardiac norepinephrine spillover during nonhypotensive LBNP in patients with CHF remains uncertain. The findings suggest that a reduction in cardiopulmonary filling pressures, in the absence of reductions in systemic blood pressure, has a specific effect on afferent signaling pathway(s) that leads to a reduction in cardiac sympathetic efferent neuronal activity. This, in turn, would imply that increases in cardiopulmonary filling pressures engage afferent signals that lead to cardiac sympathoexcitatory effects. This possibility is consistent with a number of animal studies in which distension of the left atrium or pulmonary veins was associated with a sympathetically mediated increase in heart rate or increased LV contractility.25 26 It is important to recognize that this explanation rests on the assumption that LBNP caused a reduction in the dimensions of right and left heart chamber pressures and/or volume.27 This assumption may not be true, since a recent report by Atherton et al28 demonstrated that in some patients with CHF, the application of LBNP was associated with paradoxical increases in LV end-diastolic volume. This effect was observed in a subset of patients with severe CHF that had marked increases in right-sided filling pressures, and the authors conclude that the increase in LV diastolic volumes during LBNP was attributable to relief of pericardial constraint and a favorable affect on ventricular interaction. In a subsequent report, they demonstrate that in patients in whom ventricular interaction was present, LBNP was not associated with reflex increases in forearm vascular resistance.29 In the present study, it seems unlikely that a favorable effect on ventricular interaction provides an explanation for the observed cardiac sympathoinhibitory effect in the CHF group. These patients had only modest increases in right and left heart filling pressures, and nonhypotensive LBNP led to a fall in cardiac index in 7 of 8 patients, a finding that would seem inconsistent with an LBNP-induced increase in LV end-diastolic volume and improved cardiac performance.
In summary, these results demonstrate that a reduction in cardiopulmonary filling pressures, in the absence of a decrease in systemic arterial pressure, is associated with a reduction in cardiac norepinephrine spillover in patients with chronic CHF. These findings have clinical implications and suggest that a goal of CHF management should be to reduce cardiac filling pressures toward normal while avoiding systemic hypotension. Although this may be stating the obvious, it is still very common to see patients with treated CHF who have poorly controlled pulmonary pressures. Since cardiac sympathetic activity has been shown to be an independent predictor of death in CHF,1 our findings suggest that therapy aimed at normalizing filling pressures may have a beneficial effect on this important risk factor.
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Acknowledgments |
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This study was funded by an operating grant from the Heart and Stroke Foundation of Ontario (grant No. T-3696) and from Bayer Inc. Dr Azevedo holds a research fellowship from the Heart and Stroke Scientific Research Corporation of Canada. We also wish to thank the staff of the Bayer Cardiovascular Clinical Research Laboratory of the Mount Sinai Hospital for their help in the completion of these studies.
Received September 22, 1999; revision received November 5, 1999; accepted December 2, 1999.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Kaye DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD. Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol. 1995;26:1257–1263.[Abstract]
2.
Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA,
Korner PI. Norepinephrine spillover to plasma in
patients with congestive heart failure: evidence of increased overall
and cardiorenal sympathetic nervous activity. Circulation. 1986;73:615–621.
3.
Rundqvist B, Elam M, Bergmann SY, Eisenhofer G,
Friberg P. Increased cardiac adrenergic drive precedes generalized
sympathetic activation in human heart failure. Circulation. 1997;95:169–175.
4.
Newton GE, Parker JD. Cardiac sympathetic responses to
acute vasodilation: normal ventricular function versus
congestive heart failure. Circulation. 1996;94:3161–3167.
5.
Kaye DM, Jennings GL, Dart AM, Esler MD. Differential
effect of acute baroreceptor unloading on cardiac and systemic
sympathetic tone in congestive heart failure. J Am Coll
Cardiol. 1998;31:583–587.
6. Kaye DM, Lambert GW, Lefkovits J, Morris M, Jennings G, Esler MD. Neurochemical evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in severe congestive heart failure. J Am Coll Cardiol. 1994;23:570–578.[Abstract]
7.
Ando S, Dajani HR, Senn BL, Newton GE, Floras JS.
Sympathetic alternans: evidence for arterial baroreflex
control of muscle sympathetic nerve activity in congestive heart
failure. Circulation. 1997;95:316–319.
8.
Ganz W, Tamura K, Marcus HS, Donoso R, Yoshida S, Swan
HJ. Measurement of coronary sinus blood flow by continuous
thermodilution in man. Circulation. 1971;44:181–195.
9.
Azevedo ER, Newton GE, Parker JD. Cardiac and systemic
sympathetic activity in response to clonidine in human heart failure.
J Am Coll Cardiol. 1999;33:186–191.
10.
Schwarz P, Diem R, Dun NJ, Förstermann U.
Endogenous and exogenous nitric oxide inhibits
norepinephrine release from rat heart sympathetic nerves.
Circ Res. 1995;77:841–848.
11. Eckberg DL. Baroreflexes and the failing human heart. Circulation. 1997;96:4133–4137.
12. Brigden W, Sharpey-Schafer E. Postural changes in peripheral blood flow in cases with left heart failure. Clin Sci. 1950;9:93–98.
13.
Ferguson DW, Thames MD, Mark AL. Effects of
propranolol on reflex vascular responses to
orthostatic stress in humans: role of
ventricular baroreceptors. Circulation. 1983;67:802–807.
14.
Scherrer U, Vissing SF, Victor RG. Effects of
lower-body negative pressure on sympathetic nerve responses to static
exercise in humans: microneurographic evidence against cardiac
baroreflex modulation of the exercise pressor reflex.
Circulation. 1988;78:49–59.
15.
Leimbach WNJ, Wallin BG, Victor RG, Aylward PE,
Sundlöf G, Mark AL. Direct evidence from intraneural
recordings for increased central sympathetic outflow in
patients with heart failure. Circulation. 1986;73:913–919.
16. 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;16:1125–1134.[Abstract]
17.
Shi X, Potts JT, Foresman BH, Raven PB. Carotid
baroreflex responsiveness to lower body positive pressure-induced
increases in central venous pressure. Am J Physiol. 1993;265:H918–H922.
18. Grassi G, Esler M. How to assess sympathetic activity in humans. J Hypertens. 1999;17:719–734.[Medline] [Order article via Infotrieve]
19.
Colucci WS, Ribeiro JP, Rocco MB, Quigg RJ, Creager MA,
Marsh JD, Gauthier DF, Hartley LH. Impaired chronotropic response to
exercise in patients with congestive heart failure: role of
postsynaptic ß-adrenergic desensitization.
Circulation. 1989;80:314–323.
20. Floras JS, Aylward PE, Victor RG, Mark AL, Abboud FM. Epinephrine facilitates neurogenic vasoconstriction in humans. J Clin Invest. 1988;81:1265–1274.
21.
Baily RG, Prophet SA, Shenberger JS, Zelis R, Sinoway
LI. Direct neurohumoral evidence for isolated sympathetic nervous
system activation to skeletal muscle in response to
cardiopulmonary baroreceptor unloading. Circ Res. 1990;66:1720–1728.
22.
Goldsmith SR, Rector TS, Bank AJ, Garr M, Kubo SH.
Effect of angiotensin II on noradrenaline
release in the human forearm. Cardiovasc Res. 1994;28:663–666.
23.
Joyner MJ, Shepherd JT, Seals DR. Sustained increases
in sympathetic outflow during prolonged lower body negative pressure in
humans. J Appl Physiol. 1990;68:1004–1009.
24.
Abboud FM, Eckberg DL, Johannsen UJ, Mark AL.
Carotid and cardiopulmonary baroreceptor control of splanchnic
and forearm vascular resistance during venous pooling in man.
J Physiol (Lond). 1979;286:173–184.
25. Kollai M, Koizumi K, Yamashita H, Brooks CM. Study of cardiac sympathetic and vagal efferent activity during reflex responses produced by stretch of the atria. Brain Res. 1978;150:519–532.[Medline] [Order article via Infotrieve]
26.
Kurz MA, Wead WB, Roberts AM. Reflex inotropic
responses to distension of left atrium or pulmonary veins.
Am J Physiol. 1990;258:H121–H126.
27.
Oren RM, Schobel HP, Weiss RM, Stanford W, Ferguson DW.
Importance of left atrial baroreceptors in the cardiopulmonary
baroreflex of normal humans. J Appl Physiol. 1993;74:2672–2680.
28. Atherton JJ, Moore TD, Lele SS, Thomson HL, Galbraith AJ, Belenkie I, Tyberg JV, Frenneaux MP. Diastolic ventricular interaction in chronic heart failure. Lancet. 1997;349:1720–1724.[Medline] [Order article via Infotrieve]
29.
Atherton JJ, Thomson HL, Moore TD, Wright KN,
Muehle GW, Fitzpatrick LE, Frenneaux MP. Diastolic
ventricular interaction: a possible mechanism for abnormal
vascular responses during volume unloading in heart failure.
Circulation. 1997;96:4273–4279.
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M. Petersson, P. Friberg, G. Lambert, and B. Rundqvist Decreased renal sympathetic activity in response to cardiac unloading with nitroglycerin in patients with heart failure Eur J Heart Fail, October 1, 2005; 7(6): 1003 - 1010. [Abstract] [Full Text] [PDF]
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 D. Kaye and M. Esler Sympathetic neuronal regulation of the heart in aging and heart failure Cardiovasc Res, May 1, 2005; 66(2): 256 - 264. [Abstract] [Full Text] [PDF]
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 A. Al-Hesayen and J. D. Parker Impaired Baroreceptor Control of Renal Sympathetic Activity in Human Chronic Heart Failure Circulation, June 15, 2004; 109(23): 2862 - 2865. [Abstract] [Full Text] [PDF]
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 J. A L Calbet Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans J. Physiol., August 15, 2003; 551(1): 379 - 386. [Abstract] [Full Text] [PDF]
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M. P. Schlaich, D. M. Kaye, E. Lambert, M. Sommerville, F. Socratous, and M. D. Esler Relation Between Cardiac Sympathetic Activity and Hypertensive Left Ventricular Hypertrophy Circulation, August 5, 2003; 108(5): 560 - 565. [Abstract] [Full Text] [PDF]
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 R. S. T. Leung, M. E. Bowman, J. D. Parker, G. E. Newton, and T. D. Bradley Avoidance of the left lateral decubitus position during sleep in patients with heart failure: relationship to cardiac size and function J. Am. Coll. Cardiol., January 15, 2003; 41(2): 227 - 230. [Abstract] [Full Text] [PDF]
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C.-S. Liang, Y. Himura, M. Kashiki, and S. Y. Stevens Differential pre- and postsynaptic effects of desipramine on cardiac sympathetic nerve terminals in RHF Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1863 - H1872. [Abstract] [Full Text] [PDF]
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D.M. Kaye Alterations in oxygen consumption and sympathetic nervous activity in heart failure: independent or associated mechanisms? Eur. Heart J., May 2, 2002; 23(10): 764 - 766. [Full Text] [PDF]
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C.F. Notarius, E.R. Azevedo, J.D. Parker, and J.S. Floras Peak oxygen uptake is not determined by cardiac noradrenaline spillover in heart failure Eur. Heart J., May 2, 2002; 23(10): 800 - 805. [Abstract] [Full Text] [PDF]
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A. Al-Hesayen, E. R. Azevedo, G. E. Newton, and J. D. Parker The effects of dobutamine on cardiac sympathetic activity in patients with congestive heart failure J. Am. Coll. Cardiol., April 17, 2002; 39(8): 1269 - 1274. [Abstract] [Full Text] [PDF]
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J. S. Floras The "Unsympathetic" Nervous System of Heart Failure Circulation, April 16, 2002; 105(15): 1753 - 1755. [Full Text] [PDF]
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 A. Nohria, E. Lewis, and L. W. Stevenson Medical Management of Advanced Heart Failure JAMA, February 6, 2002; 287(5): 628 - 640. [Abstract] [Full Text] [PDF]
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S. Capomolla, O. Febo, C. Opasich, G. Guazzotti, A. Caporotondi, M. T. La Rovere, M. Gnemmi, A. Mortara, M. Vona, G. D. Pinna, et al. Chronic infusion of dobutamine and nitroprusside in patients with end-stage heart failure awaiting heart transplantation: safety and clinical outcome Eur J Heart Fail, October 1, 2001; 3(5): 601 - 610. [Abstract] [Full Text] [PDF]
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 M. H. Drazner, J. E. Rame, L. W. Stevenson, and D. L. Dries Prognostic Importance of Elevated Jugular Venous Pressure and a Third Heart Sound in Patients with Heart Failure N. Engl. J. Med., August 23, 2001; 345(8): 574 - 581. [Abstract] [Full Text] [PDF]
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J. S. Floras, G. C. Butler, S.-I. Ando, S. C. Brooks, M. J. Pollard, and P. Picton Differential sympathetic nerve and heart rate spectral effects of nonhypotensive lower body negative pressure Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2001; 281(2): R468 - R475. [Abstract] [Full Text] [PDF]
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Y. Goso, H. Asanoi, H. Ishise, T. Kameyama, T. Hirai, T. Nozawa, S. Takashima, K. Umeno, and H. Inoue Respiratory Modulation of Muscle Sympathetic Nerve Activity in Patients With Chronic Heart Failure Circulation, July 24, 2001; 104(4): 418 - 423. [Abstract] [Full Text] [PDF]
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D. M. Kaye, D. Mansfield, A. Aggarwal, M. T. Naughton, and M. D. Esler Acute Effects of Continuous Positive Airway Pressure on Cardiac Sympathetic Tone in Congestive Heart Failure Circulation, May 15, 2001; 103(19): 2336 - 2338. [Abstract] [Full Text] [PDF]
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H. P. Brunner-La Rocca, D. M. Kaye, R. L. Woods, J. Hastings, and M. D. Esler Effects of intravenous brain natriuretic peptide on regional sympathetic activity in patients with chronic heart failure as compared with healthy control subjects J. Am. Coll. Cardiol., April 1, 2001; 37(5): 1221 - 1227. [Abstract] [Full Text] [PDF]
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 C. F. Notarius and J. S. Floras Limitations of the use of spectral analysis of heart rate variability for the estimation of cardiac sympathetic activity in heart failure Europace, January 1, 2001; 3(1): 29 - 38. [Abstract] [PDF]
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