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(Circulation. 1995;92:1813-1818.)
© 1995 American Heart Association, Inc.

Articles

Increased Central Nervous System Monoamine Neurotransmitter Turnover and Its Association With Sympathetic Nervous Activity in Treated Heart Failure Patients

Gavin W. Lambert; David M. Kaye; Jeffrey Lefkovits; Garry L. Jennings; Andrea G. Turner; Helen S. Cox; Murray D. Esler

From the Human Autonomic Function Laboratory and Alfred Baker Medical Unit, Baker Medical Research Institute, Commercial Road, Prahran, Vic, Australia.

Correspondence to Dr Gavin W. Lambert, Human Autonomic Function Laboratory, Baker Medical Research Institute, Commercial Road, Prahran Vic 3181, Australia.

	Abstract

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Background Congestive heart failure is a debilitating disease characterized by impaired cardiac function with accompanying activation of a variety of neural and hormonal counterregulatory systems. Abnormal activity of the sympathetic nervous system and renin-angiotensin-aldosterone axis and a predisposition to the generation of fatal ventricular arrhythmias are often associated with the development of the disease. Although the underlying cause of sudden death in these patients remains to be unequivocally elucidated, abnormally increased cardiac sympathetic nervous activity may be involved.

Methods and Results Twenty-two patients with severe congestive heart failure (New York Heart Association functional class III or IV with left ventricular ejection fraction of 18±1%) and 29 healthy male volunteers participated in this study. By combining direct sampling of internal jugular venous blood via a percutaneously placed catheter with a norepinephrine and epinephrine isotope dilution method for examining neuronal transmitter release, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters and investigate their association with the increased efferent sympathetic ouflow that is variably present in treated patients with this condition. Mean cardiac norepinephrine spillover was 145% higher in treated heart failure patients than in healthy subjects (P<.05), with norepinephrine release from the heart in 6 of 22 patients being more than the highest control value. Raised internal jugular venous spillover of epinephrine (26±12 versus 2±4 pmol/min, P<.05) and of norepinephrine and its metabolites (2740±480 versus 875±338 pmol/min, P<.05), indicative of increased central nervous system turnover of both catecholamines, occurred in cardiac failure and was quantitatively linked to the degree of activation of the cardiac sympathetic nervous outflow, as was the jugular overflow of the principal serotonin metabolite, 5-hydroxyindoleacetic acid.

Conclusions An association between the degree of activation of central monoaminergic neurons and the level of sympathetic nervous tone in the heart was identified in treated patients with heart failure. Epinephrine neurons in the brain may contribute to the sympathoexcitation that is seen in this condition, with the activation of sympathoexcitatory noradrenergic neurons, most likely those of the forebrain, playing an accessory role.

Key Words: nervous system • sympathetic • heart failure • arrhythmia

	Introduction

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Congestive heart failure is characterized by diminished pumping performance of the heart, by complex neural pathophysiology, and by substantial morbidity and mortality.^{1 2 3 4} It is generally acknowledged that sympathetic nervous system stimulation is commonly present in patients with heart failure^{1 2 5} to the possible detriment of the failing myocardium,⁶ predisposing even in mild failure to lethal ventricular arrhythmias.⁷ The level of sympathetic nervous stimulation appears to be substantially greater in untreated or minimally treated heart failure patients^{2 7} than in optimally treated patients.⁴ The afferent circulatory stimulus responsible for the sympathoexcitation associated with cardiac failure and the central nervous system neuronal circuitry involved remains to be elucidated.

In the present study, our aim was to investigate the relation between central nervous system monoamine neuronal systems and the genesis of the sympathetic nervous stimulation accompanying severe congestive heart failure. Norepinephrine-, epinephrine-, and serotonin-releasing neurons in the brainstem and forebrain have an important regulatory influence over sympathetic nervous outflows to the cardiovascular system.^{8 9 10 11} To investigate central nervous system monoamine release, we measured the internal jugular venous overflow in heart failure patients and healthy volunteers of epinephrine, norepinephrine, its precursor dihydroxyphenylalanine (DOPA) and major lipophilic metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG), and 5-hydroxyindoleacetic acid (5-HIAA), the major acidic central nervous system metabolite of serotonin. We measured concurrently the rate of total body and cardiac norepinephrine spillover to plasma to investigate possible relations between cerebral neuronal systems and sympathetic outflow.

	Methods

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Results for twenty-two congestive heart failure patients (age, 51±2 years) and 29 healthy volunteers (age, 48±3 years) form the basis for this report. The heart failure group were all moderately to severely symptomatic (New York Heart Association functional class III or IV) with profoundly impaired left ventricular function (left ventricular ejection fraction as assessed by radionuclide ventriculography, 18±1%) and were undergoing assessment for suitability as candidates for cardiac transplantation. Ten of the patients had angiographically demonstrated ischemic cardiomyopathy, whereas the remaining patients' failure was due to nonischemic etiologies (9 patients with idiopathic dilated cardiomyopathy, 2 patients with valvular heart disease, and 1 patient whose cardiac failure was attributable to hypertension). All patients were treated with conventional antifailure drugs that typically included a diuretic (in 95% of patients), an angiotensin-converting enzyme inhibitor (in all patients), warfarin (in 86% of patients), and digoxin (in 86% of patients). In view of the severity of heart failure, medication was continued throughout the research testing. All subjects gave written informed consent for their participation in the study, which was approved by the Alfred Hospital Ethics Review Committee.

Blood samples were obtained through central venous and arterial catheters percutaneously inserted under strict aseptic conditions in the cardiac catheterization laboratory of the Alfred Baker Medical Unit according to our established protocols.^{4 12} Subjects were studied in the supine position on a maneuverable laboratory table (model 1212, NVC Australia Pty Ltd) equipped with fixed anteroposterior fluoroscopic screening facilities (model DC 12MB-1, Toshiba Industries).

After skin preparation and adequate local anesthesia (1 to 2 mL of 2% lignocaine, Delta West Pty Ltd) a model C-PMS-301-RA 3F, 5-cm arterial catheter (Cook Australia) was inserted percutaneously into a brachial artery. The arterial catheter was used for a continuous infusion of 5% dextrose containing 4 U/mL heparin (David Bell Laboratories) via an intraflow adaptor and pressure bag, which ensured delivery of 3 mL/h at a bag pressure of 300 mm Hg, if the system was not flushed manually. Intra-arterial pressure was recorded continuously via a Spacelabs Inc model 90603 two-channel pressure monitor.

In the cardiac failure patients, a pulmonary arterial thermodilution catheter, percutaneously placed in an antecubital vein, was advanced under fluoroscopic control to the pulmonary circulation for diagnostic measurement of right-side heart pressure, pulmonary capillary wedge pressure, and cardiac output. This catheter was replaced by a 7F CCS-7U coronary sinus thermodilution catheter (Webster Laboratories), which, in 18 patients, was positioned in the coronary sinus for blood sampling and for the determination of coronary sinus blood flow. The catheter was subsequently repositioned into the right internal jugular vein beyond the mandibular angle upstream to points of entry of veins draining the face and neck to minimize any contamination of the cerebral venous effluent. The catheter was used for sampling internal jugular venous blood and for the determination of jugular blood flow. All healthy subjects underwent right internal jugular vein catheterization and, in 14 of them, the catheter was also positioned in the coronary sinus as previously described. Blood and plasma flows were interconverted using the subjects' hematocrit.

The overall, cardiac, and central nervous system release rates to plasma of endogenous norepinephrine were determined by the principle of isotope dilution during an infusion of tritiated norepinephrine as previously described.^{13 14} The epinephrine spillover from the brain was estimated with an analagous method using a simultaneous infusion of tritiated epinephrine.¹⁵ The central nervous system norepinephrine turnover was estimated by summing the internal jugular vein overflows of norepinephrine, DHPG, and MHPG. The internal jugular venous overflow of 5-HIAA was used as an indicator of serotonin turnover. Venoarterial plasma concentration differences combined with an appropriate internal jugular vein flow measurement were used, according to the Fick principle, to determine metabolite overflows from the brain as previously described.¹⁶ Plasma neurochemical concentrations were determined by high-performance liquid chromatography coupled with electrochemical detection according to established techniques.^{16 17 18} The interassay coefficients of variation, determined from approximately 80 consecutive assay runs, were ±11% for norepinephrine, ±8% for DHPG, ±4% for MHPG, ±3% for epinephrine, and ±5% for 5-HIAA. The intra-assay coefficients of variation, determined from five to eight repeated measurements of pooled venous plasma, were ±3% for norepinephrine, ±2% for DHPG, ±5% for MHPG, ±6% for epinephrine, and ±2% for 5-HIAA. All assays were linear within the physiological range with a sensitivity (signal-to-noise ratio of 3) of 0.1 pmol for the catechols, 1.0 pmol for MHPG, and 0.5 pmol for 5-HIAA.

All results, unless specified otherwise, are expressed as mean±SEM. Between-group comparisons were made with one-way ANOVA. Relations between continuous variables were examined by the least-squares method of linear regression. Variables that were significantly related to the rate of cardiac norepinephrine spillover to plasma in a univariate analysis were entered into a stepwise multivariate analysis. ANCOVA was used to compare the slopes and intercepts of the relation for two continuous variables between groups. The null hypothesis was rejected at P<.05.

	Results

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Rates of total body norepinephrine spillover to plasma, an index of integrated neuronal firing, and cardiac norepinephrine spillover to plasma, indicative of cardiac sympathetic neuronal activity,¹⁴ were significantly elevated overall in the heart failure patients. Total body norepinephrine spillover was increased by approximately 40% in the heart failure patients (5.25±0.55 versus 3.73±0.28 nmol/min; P<.05; normal range, 1.44 to 7.62 nmol/min; Fig 1). This elevated spillover of norepinephrine for the body as a whole was accompanied by a 145% increase in the rate of spillover of norepinephrine into the coronary sinus (383±76 versus 156±23 pmol/min; P<.05; normal range, 30 to 343 pmol/min; Fig 1). It was evident, however, that sympathetic activation was not present in all patients. Norepinephrine release from the heart in 6 of 22 heart failure patients was greater than the highest value in the healthy subjects (Fig 1).

View larger version (9K): [in this window] [in a new window]   Figure 1. Scatterplots of total body and cardiac norepinephrine (NE) spillover to plasma in healthy subjects and patients with severe congestive heart failure (CHF). Group mean values are indicated by a horizontal bar. Sympathetic nervous system activation, as evident in increased spillovers of norepinephrine to plasma, was present in some but not all patients. *P<.05, significantly greater than control subjects with one-way ANOVA.

In the heart failure patients, the pattern of release of norepinephrine, its precursor DOPA, and lipophilic metabolites from the brain into the internal jugular vein were indicative of an approximately threefold increase in mean central nervous system norepinephrine turnover (P<.01; Fig 2). The mean internal jugular venous spillover of epinephrine was increased by more than 10-fold in the heart failure group of patients (P<.05), but central nervous system epinephrine spillover values were widely dispersed, undetectable in some patients, and as high as 50 to 100 pmol/min in others. The overflow from the brain of the principal serotonin metabolite 5-HIAA also displayed a high degree of biological variability. Although the reasons for the scatter of this data remain obscure, it cannot be attributable to lack of analytical precision or reproducibility, given the small coefficients of variation for the assay. Patients with heart failure had an approximately threefold increase in the overflow from the brain of 5-HIAA (Fig 2). Although this elevated internal jugular venous 5-HIAA overflow failed to attain statistical significance, subjects with the highest cerebrovascular 5-HIAA tended to have elevated cardiac sympathetic nervous activity, as indicated by the significant relation between internal jugular venous 5-HIAA overflow and the cardiac norepinephrine spillover (Fig 3). These increases in internal jugular venous overflow in the heart failure patients were not accounted for by differences in internal jugular vein blood flow, which, if anything, tended to be reduced in the cardiac failure group (512±32 versus 449±27 mL/min).

View larger version (19K): [in this window] [in a new window]   Figure 2. Scatterplots of unilateral internal jugular vein spillover of the catecholamine precursor dihydroxyphenylalanine (DOPA) and epinephrine (EPI) and estimated central nervous system (CNS) norepinephrine (NE) and serotonin turnover in healthy control subjects and patients with congestive heart failure (CHF). The overflow of NE and its lipophilic metabolites, dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol, was used as an index of CNS NE turnover. The internal jugular vein overflow of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin, was used as an index of brain serotonin release. Group mean values are indicated by a horizontal bar. **P<.01, *P<.05, significantly different than control subjects as indicated by one-way ANOVA.

View larger version (13K): [in this window] [in a new window]   Figure 3. Scatterplots of univariate correlations of brain epinephrine spillover (14 control subjects and 9 patients, y=7.9x+162, r=.84), 5-hydroxyindoleacetic acid (5-HIAA) overflow from the brain (9 control subjects and 18 patients, y=0.06x+244, r=.52), and estimated central nervous system norepinephrine (NE) turnover (7 control subjects and 16 patients, 7y=0.1x+170, r=.50) with cardiac NE spillover to plasma, as a measure of regional sympathetic activity, in control subjects and congestive heart failure patients. ***P<.001, **P<.01, *P<.05, significantly related variables as indicated with least-squares linear regression analysis.

The level of sympathetic activity for the body as a whole was significantly related to the internal jugular venous overflow of epinephrine (y=0.05x+3.84, r=.61, P<.01), norepinephrine, and its metabolites (y=x+3.39, r=.48, P<.01) and 5-HIAA (y=x+4.13, r=.40, P<.05). Multivariate analysis of these three variables revealed the central nervous system overflow of epinephrine to be that most strongly related to whole body norepinephrine spillover to plasma.

Least-squares linear regression demonstrated the degree of activation of the cardiac sympathetic nervous outflow, gauged from the cardiac norepinephrine spillover, to be significantly related to indicators of central nervous system noradrenergic (P<.01), adrenergic (P<.01), and serotonergic neuronal activity (P<.01, Fig 3). Multivariate analysis of internal jugular venous overflow of epinephrine, norepinephrine, and 5-HIAA identified central adrenergic activity as being most strongly related to cardiac norepinephrine spillover (P<.01).

The hemodynamic profile of the congestive heart failure patients was consistent with the severity of their cardiac failure. Pulmonary capillary wedge and mean pulmonary artery pressures were 20±2 and 26±2 mm Hg, respectively. Mean arterial blood pressure was 78±2 mm Hg, and the cardiac output was 3.88±0.24 L/min. There was a nonsignificant trend for mean pulmonary artery pressure in heart failure patients to be related to cerebral turnover of epinephrine (P=.07), serotonin (P=.08), and norepinephrine (P=.09).

	Discussion

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In the present study, we examined the cardiac and whole body sympathetic nervous system activity in patients with severe congestive heart failure and were able to demonstrate an association between the increased release of central nervous system monoamine neurotransmitters and the sympathoexcitation that is variably present in treated heart failure patients. Norepinephrine release from the heart in 6 of 22 patients was greater than the highest value in healthy subjects. Although changes in the rate of spillover of norepinephrine to plasma could derive from enhanced neuronal firing or diminished neuronal reuptake, previous experiments suggest that any impairment of uptake₁ is minimal in patients with congestive heart failure.^{2 4 19} Supportive of increased nerve firing rates in the sympathetic nerves of the heart is the observation that cardiac release of neuropeptide Y, which coexists with norepinephrine in the terminals of noradrenergic nerves and is not subject to neuronal reuptake,^{20 21} is enhanced in patients with congestive heart failure.⁴

Although a diffusional barrier limits the passage of catecholamines from the circulation to the brain, movement in the reverse direction, from the brain to plasma, is less restricted.^{14 22 23} In the heart failure patients, the pattern of release of norepinephrine and its lipophilic metabolites, DHPG and MHPG, from the brain into the internal jugular vein indicated the presence of increased central nervous system norepinephrine turnover. Given the evidence that pharmacological blockade of norepinephrine reuptake results in decreased central nervous system norepinephrine turnover²⁴ and reduced neuronal firing of the locus ceruleus,^{25 26} with subsequent diminution of sympathetic nervous outflow,²⁷ it would appear that in heart failure patients increased neuronal firing rather than diminished neuronal reuptake is most likely responsible for the observed elevation in central nervous system norepinephrine turnover. Furthermore, unlike in healthy subjects in whom epinephrine spillover from the brain was minimal, brain epinephrine spillover was as high as 50 to 100 pmol/min in some heart failure patients, although it was negligible in others. The degree of activation of the cardiac sympathetic nervous outflow, as indicated by the cardiac norepinephrine spillover, was significantly related to indicators of central nervous system noradrenergic, adrenergic, and serotonergic neuronal activity, with the relation of central adrenergic activity to cardiac norepinephrine spillover being strongest.

Following von Euler's²⁸ characterization of norepinephrine as the sympathetic neurotransmitter and the subsequent demonstration of a direct relation between rates of sympathetic nerve firing and neurotransmitter release,^{29 30 31 32 33} the potential to use norepinephrine washout, or spillover to plasma, as an index of sympathetic nervous function was clear. Maas and colleagues³⁴ extended this reasoning to central nervous system neurons and demonstrated the usefulness of direct internal jugular vein blood sampling techniques in the assessment of central nervous system neuronal activity by demonstrating a reduction in MHPG jugular overflow from the brain of stump-tailed monkeys (Macaca arctoides) after clonidine administration.³⁴ Clonidine is a centrally acting suppressant of sympathetic nervous system activity known to inhibit the firing rate of locus ceruleus neurons^{35 36} and decrease the concentration of MHPG in the brain.³⁷ The observations by Maas and colleagues³⁴ on jugular venous MHPG overflow after clonidine have subsequently been reproduced in healthy human subjects.³⁸

The clinical application of such methodology is a relatively recent development. With radioenzymatic and high-performance liquid chromatography methodologies, we studied the release of norepinephrine and its metabolites into the cerebrovascular circulation in 22 patients with congestive heart failure, 35 hypertensive subjects, more than 60 healthy volunteers, and 5 patients with idiopathic peripheral autonomic insufficiency.^{16 24 39 40 41 42} The demonstration of similar cerebral norepinephrine overflows in healthy subjects and in patients with autonomic failure, in whom there was biochemical evidence of almost complete postganglionic sympathetic denervation,⁷ suggested that the norepinephrine emanated from central noradrenergic neurons and not from cerebrovascular sympathetic nerves. Supporting this view is the observation that ganglion blockade with trimethaphan does not diminish norepinephrine overflow⁴¹ and causes a compensatory increase in central nervous system norepinephrine turnover and increased overflow of lipophilic metabolites of norepinephrine.³⁸ In congestive heart failure, however, where peripheral sympathetic neuronal activation may be extreme in some patients, we cannot categorically discount regional sources as a possible minor contributor to our cerebral overflow determinations.

Central monoaminergic systems are recognized as being important in the regulation of cardiovascular reflexes.⁴³ Transneuronal labeling techniques with the retrograde transport of pseudo–rabies virus have identified the rostral ventrolateral and ventromedial medulla, serotonin-containing cells in the caudal raphe nuclei, the A5 noradrenergic group, and the hypothalamus as brain regions innervating sympathetic outflow at all thoracolumbar levels^{44 45} ; furthermore, an increased serotonergic activity has been demonstrated in brainstem and forebrain regions in the cardiomyopathic Syrian hamster, an experimental paradigm of heart failure.⁴⁶ One finding from the present study—that in some patients with heart failure (ie, the four with the highest level of cardiac sympathetic nervous activity) there was substantial spillover of epinephrine from the brain—may be in accordance with previous observations indicating that a major source of projections determining the tonic discharge of sympathetic outflow is the C1 group of epinephrine-containing neurons located in the rostral portion of the ventrolateral medulla.^{47 48} Along with the A5 group, several other central nervous system noradrenergic nuclei, including those of the locus ceruleus, lateral and paraventricular nuclei of the hypothalamus, and the amygdala are unequivocally sympathoexcitatory.^{8 10 11}

The basis of the differing degree of sympathetic nervous activation found among heart failure patients is not clear. It appears not to be due to the etiology of the heart failure as cardiac norepinephrine spillover is identical in patients with idiopathic congestive cardiomyopathy and those whose failure is attributable to ischemia and myocardial infarction⁴ or to its therapy. Although the level of sympathetic nervous stimulation appears to be substantially greater in untreated or minimally treated heart failure patients^{2 7} than in optimally treated patients,⁴ Kaye and colleagues⁴ demonstrated that individual antifailure drugs do not differentially influence the cardiac and total body kinetics of norepinephrine. Among patients with heart failure encompassing a broad spectrum from mild to very severe, the extent of sympathetic stimulation is related to heart failure severity,⁷ but in the present study all patients had profoundly impaired left ventricular function and were undergoing assessment for suitability as candidates for cardiac transplantation. In the recent report by Kaye and colleagues,⁴ a strong relation between biochemical measures of cardiac sympathetic activity and pulmonary artery pressures was demonstrated in patients with severe heart failure, raising the possibility of reflex linkage of cardiopulmonary baroreceptors, and pressures in the right side of the heart, with efferent cardiac sympathetic activity.⁴ In the present study, there was a trend for mean pulmonary artery pressure to be related to cerebral monoamine turnovers and for peripheral sympathetic activity to be increased most in those patients with highest intracardiac pressures.

This finding of intracardiac pressures being a determinant of the degree of sympathetic activation in patients with cardiac failure is contrary to an alternative explanation of the sympathetic nervous stimulation present, which emphasizes a desensitization of low-pressure baroreflexes as a basis for withdrawal of tonic inhibition of peripheral sympathetic activity.³ Whether elevated pulmonary pressures provide the hemodynamic signal for increased sympathetic outflow to the myocardium remains to be established. Cardiopulmonary volume receptor afferents do project to the noradrenergic nuclei of the locus ceruleus, and the firing rate of locus ceruleus neurons is changed by alterations in cardiopulmonary pressures.^{49 50} Functionally, the locus ceruleus and its hypothalamic and amygdala projections are also closely linked with behavioral responses involving autonomic activation.³⁶ This convergence of inputs to the locus ceruleus may be pertinent in the context of reports indicating that experimental hypothalamic stimulation can induce cardiac arrhythmias^{51 52} and that psychological stress is a common antecedent of potentially fatal ventricular fibrillation in those with underlying heart disease.^{53 54}

Although sympathetic nervous system activation in heart failure may have adverse consequences,^{6 55 56} the reflex mechanisms of sympathetic nervous stimulation in heart failure and its central nervous system integration remain uncertain. We provide evidence here that release of central nervous system monoaminergic neuronal transmitters is increased in human heart failure and that the apparent degree of activation of aminergic brain neurons is linked to the magnitude of peripheral sympathetic nervous stimulation present in treated heart failure patients. Although these findings are not immediately clinically applicable, they do suggest that forms of sympathetic suppressant therapy in heart failure in addition to peripheral blockade of ß-adrenoceptors, specifically the use of centrally acting inhibitors of sympathetic nervous outflow, such as clonidine, might be beneficial. Clonidine inhibits noradrenergic neurons of the forebrain,⁵⁷ where released norepinephrine stimulates sympathetic outflow^{8 10 11} and lowers sympathetic nervous tone in the periphery.

	Acknowledgments

 
This work was supported by a National Health and Medical Research Council Grant to the Baker Medical Research Institute. Dr Gavin Lambert is supported by a Dora Lush National Health and Medical Research Postgraduate Scholarship. The authors wish to thank Elizabeth Dewar, Sister Leonie Johnston, and Kaye Varcoe for their expert assistance in the research catheter laboratory. The photographic expertise of Neil Potter is gratefully acknowledged.

Received January 23, 1995; revision received March 29, 1995; accepted April 16, 1995.

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