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(Circulation. 1996;94:3161-3167.)
© 1996 American Heart Association, Inc.
Articles |
Cardiac Sympathetic Responses to Acute Vasodilation
Normal Ventricular Function Versus Congestive Heart Failure
the Division of Cardiology, Department of Medicine, Mount Sinai Hospital, University of Toronto, Ontario, Canada.
Correspondence to John D. Parker, MD, Cardiovascular Division, Mount Sinai Hospital, Suite 1609, 600 University Ave, Toronto, Ontario, Canada M5G 1X5. E-mail jdp@inforamp.com.
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Background Although there is indirect evidence of impaired baroreflex control of sympathetic outflow directed at heart muscle, the regulation of cardiac sympathetic activity in the setting of heart failure is largely unexplored. We used the norepinephrine spillover method to address the hypothesis that baroreflex control of cardiac sympathetic activity is reduced in heart failure.
Methods and Results Twenty-three patients were studied, 17 in a group with heart failure and 6 in a group with normal ventricular function. In both groups, cardiac norepinephrine spillover was assessed in response to nitroprusside infused to steady-state conditions. Nitroprusside resulted in significant reductions in mean systemic arterial pressure (normal group, -15±3% [mean±SEM]; heart failure group, -13±1%) and mean pulmonary artery pressure (normal group, -25±10%; heart failure group, -29±4%). In response to nitroprusside, there was a 98±16% increase in cardiac norepinephrine spillover in the normal group (from 81±10 to 159±25 pmol/min, P<.05). Despite similar hemodynamic responses to nitroprusside in the heart failure group, there was only a 28±14% increase in cardiac spillover (from 211±71 to 245±59 pmol/min, P=NS), a response that was significantly smaller than that seen in the normal group.
Conclusions In patients with heart failure compared with subjects with normal ventricular function, there was a significantly smaller increase in cardiac sympathetic activity in response to a steady-state infusion of nitroprusside. This result provides evidence for reduced baroreflex control of cardiac sympathetic activity in heart failure.
Key Words: norepinephrine • vasodilation • heart failure
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Introduction |
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The syndrome of congestive heart failure is characterized by increased efferent sympathetic nervous activity,1 2 with the greatest increase directed at the heart.2 Both systemic3 and cardiac sympathetic activation4 have been shown to be associated with increased mortality in this syndrome. Increased efferent sympathetic outflow directed at the heart may have several adverse effects, including desensitization and downregulation of cardiac ß-receptors,5 impairment of cardiac myocyte function and viability,6 and predisposition to ventricular arrhythmias.7 However, despite its importance, the regulation of cardiac sympathetic activity in the setting of heart failure remains largely unexplored.
Previous studies demonstrated reduced baroreflex control of generalized8 9 10 and regional sympathetic outflow10 11 12 13 14 15 in the setting of heart failure. There is much less information regarding the regulation of sympathetic outflow directed at the heart. Many studies have shown that baroreflex control of heart rate is abnormal in heart failure.8 9 12 14 15 16 17 Importantly, regulation of heart rate is specific to autonomic inputs to the sinus node, and investigations of heart rate control do not provide direct information about sympathetic outflow to heart muscle.18 Therefore, there is only indirect evidence that baroreflex control of sympathetic outflow directed at heart muscle is impaired in the setting of heart failure. Kaye et al19 showed that increases in cardiac norepinephrine spillover are directly related to increases in pulmonary arterial pressure, suggesting a failure of cardiopulmonary baroreflex inhibition of sympathetic outflow. Furthermore, our recent demonstration that digoxin reduces cardiac norepinephrine spillover in patients with decompensated heart failure20 is consistent with the presence of impaired baroreflex control of cardiac sympathetic activity. Although these studies suggest disturbed baroreflex control, the actual effect of baroreflex modulation on cardiac sympathetic activity in patients with heart failure and in subjects with normal ventricular function is unknown.
The present investigation was designed to test the hypothesis that baroreflex control of generalized and cardiac sympathetic activity is reduced in the setting of congestive heart failure. To test this hypothesis and to explore the effect of vasodilator therapy on cardiac sympathetic activity, we infused nitroprusside to unload both arterial and cardiopulmonary baroreceptors. Using the radiotracer method of Esler et al,21 we compared total body and cardiac norepinephrine spillover responses to nitroprusside in patients with heart failure and subjects with normal ventricular function.
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Methods |
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Patient Characteristics
Twenty-three patients participated in this study. They included 17 patients with congestive heart failure (heart failure group; 16 men, 1 woman; mean age, 58±2 years) and 6 patients with normal left ventricular function and normal resting hemodynamics (normal ventricular function group; 5 men, 1 woman; mean age, 59±6 years). The mean left ventricular ejection fraction in the heart failure group by radionuclide ventriculography was 22±3%. The cause of heart failure was ischemic in 15 patients and idiopathic in 2. Two heart failure patients had atrial fibrillation and were not included in the analysis of the heart rate response to nitroprusside. Medical therapy in the heart failure group included furosemide (n=16), ACE inhibitors (n=15), digoxin (n=12), isordil (n=4), hydralazine (n=2), and amiodarone (n=1). The mean left ventricular ejection fraction in the normal ventricular function group by contrast ventriculography was 75±1%. All the patients in the normal ventricular function group had coronary artery disease. Medical therapy in this group included ß-blockers (n=3), calcium channel blockers (n=2), ACE inhibitors (n=1), and digoxin (n=1). No patient in either group was studied within 3 months of a diagnosis of unstable angina or acute myocardial infarction.
The protocol was approved by the Ethical Review Committee for Human Experimentation of the University of Toronto. Written informed consent was obtained in all cases.
Hemodynamic and Coronary Flow Measurements
A diagnostic catheterization of the right and left sides of the heart, without sedation, was performed from the femoral approach. The following catheters were then inserted under fluoroscopic guidance: (1) a 7F coronary sinus thermodilution flow catheter (type CCS-7 U-90B, Webster Laboratories) from an antecubital vein, (2) a pulmonary artery catheter from a femoral vein, and (3) a left ventricular 7F micromanometer-tipped catheter (Millar Industries). Femoral artery 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, femoral artery pressure, and left ventricular pressure and its first derivative (continuous electronic differentiation) were recorded on a strip-chart recorder. For each variable, the results were expressed as an average of measurements from 15 cardiac cycles. Coronary sinus blood flow measurements were performed in triplicate at each measurement point according to the method of Ganz et al.22
Norepinephrine Spillover Measurements
Sympathetic activity was estimated by the measurement of cardiac and total body norepinephrine spillover.21 For these measurements, tritiated norepinephrine (1 to 1.2 µCi/min with a 16-µCi priming bolus of L-[2,5,6-3H]norepinephrine; New England Nuclear) was infused into a peripheral vein to steady-state concentration in plasma. Norepinephrine clearance and spillover rates were calculated as follows2 21 :
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Analysis of Plasma Catecholamines
Catecholamine concentrations were measured with the use of established methods in our laboratory.20 23 Briefly, collected samples were transferred immediately to ice-chilled tubes containing EDTA. Plasma was separated by centrifugation at 4°C and stored at -70°C until assayed. After extraction of catechols by adsorption on alumina, catecholamine concentrations were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. Fractions from the HPLC effluent containing tritium-labeled norepinephrine were assayed by liquid scintillation spectroscopy. The detection limit of the method was 
0.1 nmol/L, and peak area was linear from 0.1 to 50 nmol/L. Intra-assay (n=8) and interassay (n=14) coefficients of variation were 1.7% and 2.3%, respectively, for the determination of endogenous norepinephrine.
Study Protocol
After the diagnostic heart catheterization and insertion of catheters for hemodynamic monitoring, the patient was left undisturbed for a minimum of 20 minutes. Hemodynamic measurements were then performed, and total body spillover and cardiac norepinephrine spillover were assessed. Subsequently, an intravenous infusion of sodium nitroprusside was initiated starting at 0.2 µg·kg-1·min-1. The nitroprusside infusion was up-titrated to the hemodynamic end point of a 15% fall in mean systemic arterial blood pressure or to a minimum systolic arterial pressure of 90 mm Hg. Hemodynamic measurements and total body spillover and cardiac norepinephrine spillover were then reassessed. The nitroprusside infusion was then discontinued, and recontrol measurements were performed once systemic arterial pressure had returned to control values.
Statistical Analysis
Within-group comparisons of the effects of nitroprusside on hemodynamics and norepinephrine kinetics were made by use of the Friedman repeated measures ANOVA on ranks (SigmaStat version 1.0, Jandel Corp). The Student-Newman-Keuls test was used post hoc to identify significant pairwise differences. Between-group comparisons of baseline characteristics and effects of nitroprusside, expressed as percent change from control, were performed with a Mann-Whitney rank sum test. Nonparametric tests were used because the data were not normally distributed. A value of P<.05 was required for statistical significance. All data are presented as mean±SEM.
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Results |
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Baseline Characteristics
Baseline characteristics are summarized in Table 1
. Compared with the normal ventricular function group, the heart failure group had reduced values of cardiac output and left ventricular peak positive dP/dt, as well as elevated central filling pressures. Coronary sinus plasma norepinephrine concentration was higher in the heart failure group. Arterial norepinephrine concentration and total body and cardiac spillover rates were higher in the heart failure group, although this difference did not achieve statistical significance.
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Hemodynamic Responses
The final nitroprusside infusion rate was 0.7±0.1 µg·kg-1·min-1 in the normal ventricular function group and 0.8±0.1 µg·kg-1·min-1 in the heart failure group. In both groups, nitroprusside caused a reduction in systemic arterial pressure and central filling pressures (Table 2). There were no significant differences between the two groups in the effect of nitroprusside on mean systemic arterial pressure (-15±3% versus -13±1%, normal versus heart failure group, P=NS), left ventricular end-diastolic pressure (-49±8% versus -35±6%, P=NS), mean pulmonary artery pressure (-25±10% versus -29±4%, P=NS), or right atrial pressure (-21±6% versus -29±5%, P=NS). Heart rate increased in the normal ventricular function group but not in the heart failure group (Table 2). In comparing the two groups, the difference in heart rate responses was not significant (+11±3% versus +5±3%, normal versus heart failure group, P=NS). Cardiac output increased in response to nitroprusside only in the heart failure group (Table 2). The cardiac output response in the heart failure group was significantly different from the response in the normal ventricular function group (-6±7% versus +17±6%, normal versus heart failure group, P<.01).
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Cardiac Sympathetic Responses
In the normal ventricular function group, nitroprusside resulted in a significant increase in cardiac norepinephrine spillover (from 81±10 to 159±25 pmol/min, P<.05). In contrast, in the heart failure group, there was a smaller increase in cardiac spillover that was not significant (from 211±71 to 245±59 pmol/min, P=NS; Fig 1). The increase in cardiac norepinephrine spillover in the heart failure group was significantly less than the increase seen in the normal ventricular function group (+98±16% versus +28±14%, normal versus heart failure group, P<.05). One heart failure patient with a very low cardiac norepinephrine spillover at baseline and an increase in response to nitroprusside (patient No. 22, Table 3; 1 pmol/min to 13 pmol/min, 1200% increase) was treated as an outlier and was not included in the calculation of percent change in cardiac norepinephrine spillover. However, the between-group comparison of the change in spillover remained significant even when this patient's response was included. Individual data points are provided in Table 3. The responses in the 5 heart failure patients not receiving digoxin, an agent that sensitizes baroreceptors, were similar to the spillover responses in the 12 patients receiving digoxin therapy.
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Similar to the change in cardiac norepinephrine spillover, there was a larger increase in coronary sinus norepinephrine concentration in the normal ventricular function group than in the heart failure group in response to nitroprusside (114±16% versus 34±14%, normal versus heart failure group, P<.05).
Generalized Sympathetic Responses
In the normal ventricular function group, nitroprusside resulted in an increase in total body norepinephrine spillover (from 2.57±0.34 to 3.75±0.56 nmol/min, P<.05). There was also a large increase in total body spillover in the heart failure group (from 5.38±0.93 to 7.76±1.59 nmol/min, P<.05). In comparing the groups, the total body spillover responses were similar (+45±6% versus +55±16%, normal versus heart failure group, P=NS; Fig 1
).
There was a small, nonsignificant increase in arterial plasma norepinephrine concentration in the heart failure group (Table 2). This increase was smaller than the increase observed in the normal ventricular function group (+81±17% versus +39±14%, normal versus heart failure group, P<.05; Fig 2). This blunted rise in arterial norepinephrine, despite a large increase in total body spillover, is best explained by the increase in total body norepinephrine clearance seen in the heart failure group. Although within-group changes in total body norepinephrine clearance were not significant, a comparison of the two groups revealed directionally opposite changes in clearance (-18±6% versus +16±6%, normal versus heart failure group, P<.05; Fig 2). In addition, linear regression analysis revealed a direct relation between total body clearance and the cardiac output response to nitroprusside (Fig 3). This is relevant because nitroprusside caused a significant increase in cardiac output in the heart failure group. Thus, in the heart failure group, the increase in cardiac output and the associated increase in norepinephrine clearance provide an explanation for the small increase in arterial norepinephrine concentration despite the large increase in total body norepinephrine spillover.
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Discussion |
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Previous studies that explored the regulation of efferent sympathetic activity in the setting of heart failure measured accessible sympathetic outflow to skeletal muscle14 15 17 or end-organ responses such as forearm vascular resistance10 11 12 and heart rate.8 9 12 14 15 16 17 With exception,13 the effect of baroreflex perturbations on efferent sympathetic outflow to less accessible internal organs has not been well characterized in patients with heart failure. The important new feature of the present investigation was that it was designed to evaluate efferent sympathetic outflow directed at heart muscle in response to an intervention that results in generalized baroreceptor unloading. This was accomplished by the measurement of cardiac norepinephrine spillover in response to an infusion of nitroprusside. The results of the present study demonstrate that steady-state vasodilation produced by nitroprusside is associated with a large reflex increase in cardiac norepinephrine spillover in a group of subjects with normal ventricular function. In contrast, in patients with heart failure, the same stimulus does not increase cardiac sympathetic activity. This finding demonstrates that the cardiac sympathetic response to baroreceptor unloading is abnormal in the setting of heart failure.
The observed increase in cardiac norepinephrine spillover in the normal ventricular function group in response to a reduction in systemic arterial and central filling pressures provides, to the best of our knowledge, the first demonstration in humans that sympathetic outflow to heart muscle is responsive to baroreceptor unloading. This observation is consistent with studies in humans24 25 that have shown that unloading arterial baroreceptors causes a reflex increase in heart rate. Similarly, studies in cats26 27 have demonstrated that hypotension causes a large increase in directly measured cardiac sympathetic nerve activity. Studies in dogs28 29 have shown that baroreceptor unloading results in increased left ventricular contractility, presumably as a result of increased cardiac sympathetic activity. In the present study, there was no increase in left ventricular positive dP/dt despite a large increase in cardiac norepinephrine spillover. This finding is consistent with previous studies that also found no change in this index of contractility during a steady-state infusion of nitroprusside.30 Although the mechanism remains speculative, it is likely that the lack of a positive dP/dt response represents the net result of factors that tend to increase contractility (increased cardiac sympathetic tone) and those that would tend to reduce it (decreases in preload and afterload) when this steady-state intervention is applied. This concept is supported by the observation that short-term reductions in preload and afterload induced by inferior vena cava occlusion are clearly associated with a decrease in positive dP/dt in the normal human left ventricle.31
The attenuation of the cardiac norepinephrine spillover response in the heart failure group provides the first experimental evidence for an abnormality in the reflex control of sympathetic outflow directed at heart muscle in the setting of heart failure. Several possible mechanisms may account for this observation. First, it might be suggested that cardiac sympathetic nerves are maximally stimulated in patients with heart failure and that their activity cannot increase further in response to baroreceptor unloading. This does not appear to be the case, because previous studies have demonstrated increases in cardiac norepinephrine spillover in response to short-term ß-blockade23 and exercise32 in the setting of heart failure. Reduced baroreceptor sensitivity, which has also been demonstrated in the setting of heart failure,33 34 could account for impaired cardiac sympathetic responses to baroreceptor deactivation. Attenuated cardiac sympathetic responses to baroreceptor unloading could also be explained by a change in the operational point of the baroreflex stimulus–cardiac response relation toward the threshold for baroreceptor firing in the setting of heart failure.12 16
Importantly, impaired afferents alone do not explain the discordance between the blunted cardiac and the intact total body norepinephrine spillover responses in the heart failure group. Total body spillover is a generalized index of sympathetic activity from multiple vascular beds.21 Although the source(s) of the increase in total body spillover cannot be determined, an intact response suggests that some noncardiac regional sympathetic outflow(s) increased in response to nitroprusside. For example, the total body response may have resulted in part from a reflex increase in renal sympathetic outflow.13 34 35 The observation that total body spillover but not cardiac spillover increased in response to nitroprusside is therefore consistent with the recently demonstrated organ-specific nature of impaired reflex sympathetic responses in the setting of heart failure.13 A possible mechanism to explain the reflex increase in total body spillover in the present study and in renal sympathetic outflow in other heart failure studies13 34 35 is that central gain preserves some regional sympathetic responses, despite presumed disturbances in afferent pathways. However, in the present study, central processing apparently did not preserve reflex cardiac sympathetic responses to baroreceptor unloading. This observation underscores the regional nature of the regulation of sympathetic outflow in the setting of heart failure and demonstrates that generalized sympathetic responses cannot be used as a surrogate end point for the evaluation of sympathetic outflow to the heart.
Because nitroprusside causes generalized baroreceptor unloading, the specific afferent pathways involved in the regulation or dysregulation of cardiac sympathetic outflow cannot be understood from the present study. However, if impaired cardiac sympathetic responses result from an abnormality in cardiopulmonary afferents, this could explain the paradoxical association between increased filling pressures and increased cardiac sympathetic activity in patients with heart failure.19 If cardiopulmonary afferent control of sympathetic outflow to the heart is completely lost in the setting of heart failure, and if the increases in filling pressures have a causal relation to cardiac sympathetic activation, nitroprusside might have been expected to reduce sympathetic outflow to the heart. This did not occur; however, it should be noted that nitroprusside also unloaded arterial receptors. Therefore, a potentially beneficial sympathoinhibitory response to the lowering of central filling pressures may have been obscured by a parallel sympathoexcitatory reflex arising from deactivation of arterial baroreceptors.
The total body spillover response in the heart failure group should be compared with previous studies8 9 10 that demonstrated blunted plasma norepinephrine responses to baroreceptor unloading. Plasma norepinephrine concentration is a poor index for short-term changes in efferent sympathetic outflow. As occurred in the present study and other studies,36 37 plasma norepinephrine concentration does not reflect changes in norepinephrine spillover when hemodynamic interventions also alter norepinephrine clearance. The total body response can also be compared with studies14 15 that performed microneurography in response to baroreceptor unloading. Total body spillover measured from an arterial sample has been shown not to reflect changes in muscle sympathetic nerve activity.37 Therefore, the results of the present study are not inconsistent with observations of impaired reflex control of sympathetic outflow to skeletal muscle.14 15
Limitations to the present study should be considered. Medical therapy was not discontinued before this investigation. In the majority of heart failure patients, this included digoxin and ACE inhibitors, agents that improve baroreflex function.17 33 Nevertheless, treatment with these agents did not prevent the observed abnormal cardiac sympathetic response to nitroprusside. In fact, the disturbance in reflex control of cardiac sympathetic activity may have been underestimated by continuing medical management. As discussed previously, the use of nitroprusside did not allow the isolation of arterial versus cardiopulmonary afferent responses. Nitroprusside was chosen to address the clinical question of the effect of vasodilator therapy on cardiac sympathetic activity in the setting of heart failure. The present investigation also did not examine the effects of baroreceptor loading, an approach that would be difficult and potentially dangerous in the setting of heart failure. Norepinephrine spillover may reflect changes in efferent sympathetic nerve activity, changes in norepinephrine release due to prejunctional modulation, and changes in norepinephrine reuptake.23 38 39 Nitroprusside could theoretically obscure an increase in cardiac sympathetic activity as a result of prejunctional inhibition of norepinephrine release or central sympathoinhibition.40 However, this is unlikely, because cardiac spillover increased in the normal ventricular function group and total body spillover increased in both groups in response to nitroprusside. Finally, coronary sinus blood flow was assessed by use of a thermodilution method22 that has several limitations. These include insensitivity to small changes in flow41 and error introduced by reflux of right atrial blood into the coronary sinus.42 To minimize the effect of right atrial reflux, the catheter was always positioned with the distal thermistor 
2 cm from the os of the coronary sinus. In addition, to improve accuracy, flow measurements were performed in triplicate at steady-state hemodynamic conditions. Despite the limitations of the thermodilution method, coronary flow measurements are unlikely to have biased the between-group comparisons of cardiac spillover responses.
In summary, this investigation has established the cardiac sympathetic response to generalized unloading of baroreceptors in patients with normal ventricular function. This study has also demonstrated that in patients with heart failure, the cardiac sympathetic response to unloading of baroreceptors is markedly attenuated. These observations are relevant because potent vasodilators like nitroprusside are commonly used in the management of heart failure. Although the infusion of nitroprusside is associated with improved hemodynamics in the setting of heart failure, it nevertheless results in reflex generalized sympathetic activation. Although this increase is not directed at the heart, sympathetic activation could have implications for sustained vasodilator therapy. Importantly, this investigation evaluated the response to a short-term intervention, and responses during long-term vasodilator therapy might well be different. Finally, in demonstrating abnormal baroreflex control of cardiac sympathetic activity, this investigation provides additional rationale for the use of agents that restore baroreflex function17 33 as a strategy to potentially reduce sympathetic outflow directed at the heart.20
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Acknowledgments |
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Dr Parker is a scholar of the Medical Research Council of Canada. Dr Newton is supported by Boeringher Ingelheim Canada. This work was supported by a grant-in-aid from the Heart and Stroke Foundation of Ontario (A2811) and Bayer Inc. The authors 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 June 27, 1996; revision received July 30, 1996; accepted August 7, 1996.
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References |
|---|
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Leimbach WN, Wallin BG, Victor RG, Aylward PE, Sundlof G, Mark AL. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation. 1986;73:913-919.
2.
Hasking GJ, Esler MD, Jennings GJ, 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. Cohn JN, Levine TB, Olivari MT, Garberg V, Tura D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819-823.[Abstract]
4. 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]
5.
Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S, Stinson EB. ß1- And ß2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective ß1-receptor down-regulation in heart failure. Circ Res. 1986;59:297-309.
6.
Mann DL, Kent RL, Parsons B, Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation. 1992;85:790-804.
7. Meredith IT, Broughton A, Jennings GL, Esler MD. Evidence of a selective increase in cardiac sympathetic activity in patients with sustained ventricular arrhythmias. N Engl J Med. 1991;325:618-624.[Abstract]
8. Olivari MT, Levine TB, Cohn JN. Abnormal neurohumoral response to nitroprusside infusion in congestive heart failure. J Am Coll Cardiol. 1983;2:411-417.[Abstract]
9.
Levine TB, Francis GS, Goldsmith SR, Cohn JN. The neurohumoral and hemodynamic response to orthostatic tilt in patients with congestive heart failure. Circulation. 1983;67:1070-1075.
10. Mohanty PK, Arrowood JA, Ellenbogen KA, Thames MD. Neurohormonal and hemodynamic effects of lower body negative pressure in patients with congestive heart failure. Am Heart J. 1989;118:78-85.[Medline] [Order article via Infotrieve]
11.
Ferguson DW, Abboud FM, Mark AL. Selective impairment of baroreflex-mediated vasoconstrictor responses in patients with ventricular dysfunction. Circulation. 1984;69:451-460.
12. Creager MA, Creager SJ. Arterial baroreflex regulation of blood pressure in patients with congestive heart failure. J Am Coll Cardiol. 1994;23:401-405.[Abstract]
13.
Middlekauff HR, Nitzsche EU, Hamilton MA, Schelbert HR, Fonarow GC, Moriguchi JD, Hage A, Saleh S, Gibbs G. Evidence for preserved cardiopulmonary baroreflex control of renal cortical blood flow in humans with advanced heart failure: a positron emission tomography study. Circulation. 1995;92:395-401.
14. Ferguson DW, Berg WJ, Roach PJ, Oren RM, Mark AL. Effects of heart failure on baroreflex control of sympathetic neural activity. Am J Cardiol. 1992;69:523-531.[Medline] [Order article via Infotrieve]
15.
Grassi G, Seravalle G, Cattaneo BM, Lanfranchi A, Vailati S, Giannattasio C, Del Bo A, Sala C, Bolla GB, Pozzi M, Mancia G. Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure. Circulation. 1995;92:3206-3211.
16.
Sopher SM, Smith ML, Eckberg DL, Fritsch JM, Dibner-Dunlap ME. Autonomic pathophysiology in heart failure: carotid baroreceptor-cardiac reflexes. Am J Physiol. 1990;259:H689-H696.
17. Dibner-Dunlap ME, Smith ML, Kinugawa T, Thames MD. Enalaprilat augments arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with heart failure. J Am Coll Cardiol. 1996;27:358-364.[Abstract]
18.
Kingwell BA, Thompson JM, Kaye DM, McPherson GA, Jennings GL, Esler MD. Heart rate spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure. Circulation. 1994;90:234-240.
19. 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]
20. Newton GE, Tong JS, Schofield AM, Baines AD, Floras JS, Parker JD. Digoxin reduces cardiac sympathetic activity in severe congestive heart failure. J Am Coll Cardiol.. 1996;28:155-161.[Abstract]
21.
Esler M, Jennings G, Korner P, Blombery P, Sacharias N, Leonard P. Measurement of total and organ-specific norepinephrine kinetics in humans. Am J Physiol. 1984;247:E21-E28.
22.
Ganz W, Tamura K, Marcus HS, Donoso R, Swan HJC. Measurement of coronary sinus blood flow by continuous thermodilution in man. Circulation. 1971;44:181-195.
23.
Newton GE, Parker JD. Acute effects of ß1-selective and nonselective ß-adrenergic receptor blockade on cardiac sympathetic activity in congestive heart failure. Circulation. 1996;94:353-358.
24.
Johnson JM, Rowell LB, Neiderberger M, Eisman MM. Human splanchnic and forearm vasoconstrictor responses to reductions of right atrial and aortic pressures. Circ Res. 1974;34:515-524.
25.
Takeshita A, Mark AL, Eckberg DL, Abboud FM. Effect of central venous pressure on arterial baroreflex control of heart rate. Am J Physiol. 1979;236:H42-H47.
26.
Honda T, Ninomiya I, Azumi T. Cardiac sympathetic nerve activity and catecholamine kinetics in cat hearts. Am J Physiol. 1987;252:H879-H885.
27. Ninomiya I, Nishimaru N, Irisawa H. Sympathetic nerve activity to the spleen, kidney, and heart in response to baroreceptor input. Am J Physiol. 1971;221:1346-1351.
28. Glick G. Importance of the carotid sinus baroreceptors in the regulation of myocardial performance. J Clin Invest. 1971;50:1116-1123.
29. Vatner SF, Pagini M, Rutherford JD, Millard RW, Manders WT. Effects of nitroglycerin on cardiac function and regional blood flow distribution in conscious dogs. Am J Physiol. 1978;234:H244-H252.
30.
Starling MR, Montgomery DG, Mancini GBJ, Walsh RA. Load independence of the rate of isovolumic relaxation in man. Circulation. 1987;76:1274-1281.
31.
Varma SK, Owen RM, Smucker ML, Feldman MD. Is t a preload-independent measure of isovolumetric relaxation? Circulation. 1989;80:1757-1765.
32.
Hasking GJ, Esler MD, Jennings GL, Dewar E, Lambert G. Norepinephrine spillover to plasma during steady-state supine bicycle exercise: comparison of patients with congestive heart failure and normal subjects. Circulation. 1988;78:516-521.
33.
Wang W, Chen JS, Zucker IH. Carotid sinus baroreceptor sensitivity in experimental heart failure. Circulation. 1990;81:1959-1966.
34.
Dibner-Dunlap ME, Thames MD. Baroreflex control of renal sympathetic nerve activity is preserved in heart failure despite reduced arterial baroreflex sensitivity. Circ Res. 1989;65:1526-1535.
35.
Wang W, Chen JS, Zucker IH. Carotid sinus baroreceptor reflex in dogs with experimental heart failure. Circ Res. 1991;68:1294-1301.
36. Davis D, Sinoway LI, Robison J, Minotti JR, Day FP, Baily R, Zelis R. Norepinephrine kinetics during orthostatic stress in congestive heart failure. Circ Res. 1987;61(suppl I):I-87-I-90.
37.
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.
38.
Yamaguchi N, De Champlain J, Nadeau R. Correlation between the response of the heart to sympathetic stimulation and the release of endogenous catecholamines into the coronary sinus of the dog. Circ Res. 1975;36:662-668.
39.
Goldstein DS, Brush JE, Eisenhofer G, Stull R, Esler M. In vivo measurement of neuronal uptake of norepinephrine in the human heart. Circulation. 1988;78:41-48.
40.
Zanzinger J, Czachurski J, Seller H. Inhibition of sympathetic vasoconstriction is a major principle of vasodilation by nitric oxide in vivo. Circ Res. 1994;75:1073-1077.
41. Rossen JD, Oskarsson H, Stenberg RG, Braun P, Talman CL, Winniford MD. Simultaneous measurement of coronary flow reserve by left anterior descending coronary artery Doppler and great cardiac vein thermodilution methods. J Am Coll Cardiol. 1992;20:402-407.[Abstract]
42.
Mathey DG, Chatterjee K, Tyberg JV, Lekven J, Brundage B, Parmeley WW. Coronary sinus reflux: a source of error in the measurement of thermodilution coronary sinus flow. Circulation. 1971;57:778-786.
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