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Central and Peripheral Norepinephrine Kinetics in Heart Failure, Coronary Artery Disease, and Hypertension
M. Esler, G. Lambert, G. Jennings, A. Turner, and D. Kaye Baker Medical Research Institute Prahran 3 181 Melbourne, Australia
Central and Peripheral Norepinephrine Kinetics in Heart Failure, Coronary Artery Disease, and Hypertension Traditionally, the assessment of sympathetic nervous system function in human cardiovascular disorders has involved the measurement of plasma norepinephrine concentrations in antecubital venous plasma. This methodology has several deficiencies. One is the dependence of the plasma concentration on norepinephrine clearance, which is sometimes altered, such as in cardiac failure. The second drawback is that sympathetic nervous system responses are typically differentiated (regionalized), so that activation of one sympathetic outflow might be accompanied by no change or a reduction in sympathetic in other sites. One example of this is provided by the sympathetic nervous response to dietary sodium restriction, in which sympathetic stimulation is evident in the renal sympathetic nerves, while cardiac sympathetic tone is unchanged (1).
1. Essential Hypertension Measurement of regional sympathetic nervous system activity in patients with essential hypertension, using powerful electrophysiological methods (clinical microneurography, which measures skeletal muscle sympathetic nerve firing rates) and neurochemical techniques (radiotracer-derived measurement of norepinephrine spillover from individual organs), has indicated that activation of the sympathetic outflows to skeletal muscle, the heart, and the kidneys is commonly present, particularly in younger patients (2).No consistent increase in cardiac sympathetic activity is evident in hypertensive patients when heart rate spectral analysis methods are used, utilizing 0.1-Hz spectral power as a surrogate measure of cardiac sympathetic tone, but this is due to the welldemonstrated inability of heart rate spectral analysis to validly quantify efferent sympathetic activity in the heart. This sympathetic nervous activation no doubt contributes to the blood pressure elevation through neural influences on cardiac performance, vascular 650
Advancer in Pharmacology, Volume 42 Copyright 0 1998 by Academic Press. All rights of reproduction In any form reserved. 1054-3589/98 $25.00
NE Kinetics in Heart Failure, Coronary Artery Disease, Hypertension
65 I
resistance, and renal function (renin secretion, sodium reabsorption). In addition, it appears to have adverse consequences in hypertensive patients beyond blood pressure elevation. There is evidence that neural vasoconstriction has metabolic effects, in skeletal muscle impairing glucose delivery to muscle, causing insulin resistance and hyperinsulinemia. A trophic effect of sympathetic activation on cardiovascular growth is also probable, contributing to the development of left ventricular hypertrophy (2). An arrhythmogenic effect of the cardiac sympathetic activation is also likely, possibly accentuated by vasodilator antihypertensive drugs, which stimulate the cardiac sympathetic outflow.
II. Coronary Artery Disease Sympathetic nervous stimulation also contributes importantly to coronary artery disease syndromes. Experimental studies in nonhuman primates incriminate sympathetic nervous activation in atherogenesis, perhaps due to increased splanchnic sympathetic tone that reduces visceral blood flows and retards postprandial clearing of plasma lipids or through sympathetic nervous stimulation of the cardiovascular system that increases arterial shear stress and endothelial damage. In patients with unstable angina, the cardiac sympathetic outflow is activated at rest; this is thought to contribute both to thrombogenesis and to the development of ventricular tachyarrhythmias. In such patients, drugs that stimulate the cardiac sympathetic outflow appear to predispose to arrhythmia development. In patients with stable coronary artery disease who unexpectedly develop life-threatening ventricular arrhythmias, caridac sympathetic tone after recovery has been demonstrated to be markedly increased ( 3 ) .A behavioral trigger for such arrhythmias is often evident, as has been demonstrated frequently in studies of nontraumatic sudden death during an earthquake and in patients with panic disorder. Mental stress studied in the laboratory has been shown to cause dramatic and relatively selective stimulation of the sympathetic nerves of the heart.
111. Cardiac Failure The demonstration that the level of sympathetic nervous drive to the failing heart inpatients with severe heart failure is a major determinant of prognosis (4). Mortality in heart failure is reduced by P-adrenergic blockade with carvedilol, indicating the clinical relevance of cardiac neuroscience research. Important initial findings were observations that the plasma concentration of sympathetic transmitter, norepinephrine, is elevated in heart failure and that clinical outcome overall is related to the plasma norepinephrine concentration (although here heart failure severity may be a confounder). Sympathetic nerve recording and radiotracer methods measuring regional sympathetic activity in the heart have now largely supplanted antecubital venous norepinephrine measurements as
652
M. Esler eta/.
research tools, with the newer methods providing information on regional sympathetic function that was previously lacking. The cardiac sympathetic nerves are preferentially stimulated in severe heart failure, with norepinephrine release from the failing heart at rest being increased as much as 50-fold, similar to the level seen in healthy people during maximum exercise (1). There is lesser stimulation of the sympathetic outflows to the kidneys and skeletal muscle. In early, mild heart failure it is only the cardiac sympathetic nerves that are activated. This preferential activation of the cardiac sympathetic outflow contributes to arrhythmogenesis and also probably to progression of the heart failure and has been linked to mortality in both mild and severe cardiac failure. An additional neurophysiological abnormality that seems to be present in heart failure patients is presynaptic augmentation of transmitter release at the existing high rates of sympathetic nerve firing. The mechanism is uncertain but may involve regional release of adrenaline from the failing heart (5) acting on presynaptic P-adrenergic receptors on sympathetic nerves. The increased cardiac norepinephrine spillover could also possibly arise in part from impaired neuronal re-uptake of the neurotransmitter.
IV. Central Nervous System Control of Human Sympathetic Nervous Outflow Although sympathetic nervous activation is present in patients with hypertension and with heart failure, the central nervous system (CNS) mechanisms involved are not entirely clear. In heart failure patients, increased intracardiac diastolic pressure seems to one peripheral reflex stimulus, and increased forebrain norepinephrine turnover an important central mechanism (6). Experiments in laboratory animals have challenged the conventional view that the dominant effects of CNS noradrenergic neurons in cardiovascular control are sympathetic nervous inhibition and blood pressure reduction, describing instead sympathetic activation. We have tested whether such a stimulant effect on sympathetic outflow is also evident in human hypertension and heart failure. CNS norepinephrine turnover was estimated from the combined overflow of norepinephrine, methoxyhydroxyphenylglycol (MHPG), and dihroxyphenylglycol into the internal jugular veins. Cerebral blood flow scans allowed differentiation between cortical and subcortical jugular venous drainage (7). In patients with pure autonomic failure, jugular overflow of norepinephrine and metabolites was not reduced, indicating brain neurons and not cerebrovascular sympathetics were the source. In healthy men, CNS norepinephrine turnover and muscle sympathetic nerve activity were directly related ( p < .02). Administration of the ganglion blocker, trimethaphan, caused a compensatory fivefold increase in jugular overflow of MHPG. Conversely, intravenous clonidine reduced CNS norepinephrine turnover by approximately 50%, this possibly representing a mechanism of drug action. In cardiac failure patients, sympathetic nervous activation was associated with a trebling of CNS norepinephrine turnover ( p < .01). In untreated patients with essential hypertension, the sympa-
NE Kinetics in Heart Failure, Coronary Artery Disease, Hypertension
653
thetic activation present was associated with 250% higher CNS norepinephrine turnover ( p < .01) but only in subcortical brain regions. A close and direct relation exists between brain norepinephrine turnover and human sympathetic nervous activity. CNS release of norepinephrine, presumably in the forebrain where noradrenergic neurons are sympathoexcitatory and pressor, appears to mediate increased sympathetic nerve firing in patients with essential hypertension and cardiac failure. Elucidation of the abnormalities in central nervous control of sympathetic outflow in heart failure in particular has become of major clinical relevance. Following the demonstration of the benefical effects of P-adrenergic blockade in heart failure, imidazoline receptor binding agents, centrally acting sympathetic nervous system suppressants similar to clonidine, are also under evaluation. Such drugs inhibit both firing of brain noradrenergic neurons and sympathetic nerve firing and are potentially cardioprotective, although this is yet to be established.
References 1. Esler, M., Jennings, G., Lambert, G., Meredith, I., Horne, M., and Eisenhofer, G. (1990). Overflow of catecholamine neurotransmitter to the circulation: Source, fate and functions. Physiol. Rev. 70, 963-985. 2. Esler, M., Lambert, G., and Jennings, G. (1990). Increased regional sympathetic nervous activity in human hypertension: Causes and consequences. /. Hypertens. 8, (Suppl 7), S53-SS7. 3. Meredith, I. T., Broughton, A., Jennings, G. L., and Esler, M. D. (1991). Evidence for a selective increase in resting cardiac sympathetic activity in some patients suffering sustained out of hospital ventricular arrhythmias. N. Eng. /. Med. 325, 618-624. 4. Kaye, D. M., Lefkovits, J., Jennings, G . L., Bergin, P., Broughton, A,, and Esler, M. D. (1995). Adverse consequences of high sympathetic nervous activity in the failing human heart. J. Am. Coll. Cardiol. 26, 1257-1263. 5 . Kaye, D. M., Cox, H., Lambert, G., Jennings, G . L., Turner, A., and Esler, M. D. (1995). Regional epinephrine kinetics in severe heart failure: Evidence for extra-adrenal, non-neural release. Am. J. Physiol. 269, H182-Hl88. 6. Kaye, D. M., Lambert, G. W., Lefkovits, J., Morris, M., Jennings, G. L., and Esler, M. D. (1994). Neurochemical evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in severe congestive heart failure. J. Am. Coll. Cardiol. 23, 570-578. 7. Ferrier, C., Jennings, G. L., Eisenhofer, G., Lambert, G . , Cox, H. S., Kalff, V., Kelly, M., and Esler, M. D. (1993). Evidence for increased noradrenaline release from subcortical brain regions in essential hypertension, 1. Hyperten. 11, 1217-1227.
Central and Peripheral Norepinephrine Kinetics in Heart Failure, Coronary Artery Disease, and Hypertension Traditionally, the assessment of sympathetic nervous system function in human cardiovascular disorders has involved the measurement of plasma norepinephrine concentrations in antecubital venous plasma. This methodology has several deficiencies. One is the dependence of the plasma concentration on norepinephrine clearance, which is sometimes altered, such as in cardiac failure. The second drawback is that sympathetic nervous system responses are typically differentiated (regionalized), so that activation of one sympathetic outflow might be accompanied by no change or a reduction in sympathetic in other sites. One example of this is provided by the sympathetic nervous response to dietary sodium restriction, in which sympathetic stimulation is evident in the renal sympathetic nerves, while cardiac sympathetic tone is unchanged (1).
1. Essential Hypertension Measurement of regional sympathetic nervous system activity in patients with essential hypertension, using powerful electrophysiological methods (clinical microneurography, which measures skeletal muscle sympathetic nerve firing rates) and neurochemical techniques (radiotracer-derived measurement of norepinephrine spillover from individual organs), has indicated that activation of the sympathetic outflows to skeletal muscle, the heart, and the kidneys is commonly present, particularly in younger patients (2).No consistent increase in cardiac sympathetic activity is evident in hypertensive patients when heart rate spectral analysis methods are used, utilizing 0.1-Hz spectral power as a surrogate measure of cardiac sympathetic tone, but this is due to the welldemonstrated inability of heart rate spectral analysis to validly quantify efferent sympathetic activity in the heart. This sympathetic nervous activation no doubt contributes to the blood pressure elevation through neural influences on cardiac performance, vascular 650
Advancer in Pharmacology, Volume 42 Copyright 0 1998 by Academic Press. All rights of reproduction In any form reserved. 1054-3589/98 $25.00
NE Kinetics in Heart Failure, Coronary Artery Disease, Hypertension
65 I
resistance, and renal function (renin secretion, sodium reabsorption). In addition, it appears to have adverse consequences in hypertensive patients beyond blood pressure elevation. There is evidence that neural vasoconstriction has metabolic effects, in skeletal muscle impairing glucose delivery to muscle, causing insulin resistance and hyperinsulinemia. A trophic effect of sympathetic activation on cardiovascular growth is also probable, contributing to the development of left ventricular hypertrophy (2). An arrhythmogenic effect of the cardiac sympathetic activation is also likely, possibly accentuated by vasodilator antihypertensive drugs, which stimulate the cardiac sympathetic outflow.
II. Coronary Artery Disease Sympathetic nervous stimulation also contributes importantly to coronary artery disease syndromes. Experimental studies in nonhuman primates incriminate sympathetic nervous activation in atherogenesis, perhaps due to increased splanchnic sympathetic tone that reduces visceral blood flows and retards postprandial clearing of plasma lipids or through sympathetic nervous stimulation of the cardiovascular system that increases arterial shear stress and endothelial damage. In patients with unstable angina, the cardiac sympathetic outflow is activated at rest; this is thought to contribute both to thrombogenesis and to the development of ventricular tachyarrhythmias. In such patients, drugs that stimulate the cardiac sympathetic outflow appear to predispose to arrhythmia development. In patients with stable coronary artery disease who unexpectedly develop life-threatening ventricular arrhythmias, caridac sympathetic tone after recovery has been demonstrated to be markedly increased ( 3 ) .A behavioral trigger for such arrhythmias is often evident, as has been demonstrated frequently in studies of nontraumatic sudden death during an earthquake and in patients with panic disorder. Mental stress studied in the laboratory has been shown to cause dramatic and relatively selective stimulation of the sympathetic nerves of the heart.
111. Cardiac Failure The demonstration that the level of sympathetic nervous drive to the failing heart inpatients with severe heart failure is a major determinant of prognosis (4). Mortality in heart failure is reduced by P-adrenergic blockade with carvedilol, indicating the clinical relevance of cardiac neuroscience research. Important initial findings were observations that the plasma concentration of sympathetic transmitter, norepinephrine, is elevated in heart failure and that clinical outcome overall is related to the plasma norepinephrine concentration (although here heart failure severity may be a confounder). Sympathetic nerve recording and radiotracer methods measuring regional sympathetic activity in the heart have now largely supplanted antecubital venous norepinephrine measurements as
652
M. Esler eta/.
research tools, with the newer methods providing information on regional sympathetic function that was previously lacking. The cardiac sympathetic nerves are preferentially stimulated in severe heart failure, with norepinephrine release from the failing heart at rest being increased as much as 50-fold, similar to the level seen in healthy people during maximum exercise (1). There is lesser stimulation of the sympathetic outflows to the kidneys and skeletal muscle. In early, mild heart failure it is only the cardiac sympathetic nerves that are activated. This preferential activation of the cardiac sympathetic outflow contributes to arrhythmogenesis and also probably to progression of the heart failure and has been linked to mortality in both mild and severe cardiac failure. An additional neurophysiological abnormality that seems to be present in heart failure patients is presynaptic augmentation of transmitter release at the existing high rates of sympathetic nerve firing. The mechanism is uncertain but may involve regional release of adrenaline from the failing heart (5) acting on presynaptic P-adrenergic receptors on sympathetic nerves. The increased cardiac norepinephrine spillover could also possibly arise in part from impaired neuronal re-uptake of the neurotransmitter.
IV. Central Nervous System Control of Human Sympathetic Nervous Outflow Although sympathetic nervous activation is present in patients with hypertension and with heart failure, the central nervous system (CNS) mechanisms involved are not entirely clear. In heart failure patients, increased intracardiac diastolic pressure seems to one peripheral reflex stimulus, and increased forebrain norepinephrine turnover an important central mechanism (6). Experiments in laboratory animals have challenged the conventional view that the dominant effects of CNS noradrenergic neurons in cardiovascular control are sympathetic nervous inhibition and blood pressure reduction, describing instead sympathetic activation. We have tested whether such a stimulant effect on sympathetic outflow is also evident in human hypertension and heart failure. CNS norepinephrine turnover was estimated from the combined overflow of norepinephrine, methoxyhydroxyphenylglycol (MHPG), and dihroxyphenylglycol into the internal jugular veins. Cerebral blood flow scans allowed differentiation between cortical and subcortical jugular venous drainage (7). In patients with pure autonomic failure, jugular overflow of norepinephrine and metabolites was not reduced, indicating brain neurons and not cerebrovascular sympathetics were the source. In healthy men, CNS norepinephrine turnover and muscle sympathetic nerve activity were directly related ( p < .02). Administration of the ganglion blocker, trimethaphan, caused a compensatory fivefold increase in jugular overflow of MHPG. Conversely, intravenous clonidine reduced CNS norepinephrine turnover by approximately 50%, this possibly representing a mechanism of drug action. In cardiac failure patients, sympathetic nervous activation was associated with a trebling of CNS norepinephrine turnover ( p < .01). In untreated patients with essential hypertension, the sympa-
NE Kinetics in Heart Failure, Coronary Artery Disease, Hypertension
653
thetic activation present was associated with 250% higher CNS norepinephrine turnover ( p < .01) but only in subcortical brain regions. A close and direct relation exists between brain norepinephrine turnover and human sympathetic nervous activity. CNS release of norepinephrine, presumably in the forebrain where noradrenergic neurons are sympathoexcitatory and pressor, appears to mediate increased sympathetic nerve firing in patients with essential hypertension and cardiac failure. Elucidation of the abnormalities in central nervous control of sympathetic outflow in heart failure in particular has become of major clinical relevance. Following the demonstration of the benefical effects of P-adrenergic blockade in heart failure, imidazoline receptor binding agents, centrally acting sympathetic nervous system suppressants similar to clonidine, are also under evaluation. Such drugs inhibit both firing of brain noradrenergic neurons and sympathetic nerve firing and are potentially cardioprotective, although this is yet to be established.
References 1. Esler, M., Jennings, G., Lambert, G., Meredith, I., Horne, M., and Eisenhofer, G. (1990). Overflow of catecholamine neurotransmitter to the circulation: Source, fate and functions. Physiol. Rev. 70, 963-985. 2. Esler, M., Lambert, G., and Jennings, G. (1990). Increased regional sympathetic nervous activity in human hypertension: Causes and consequences. /. Hypertens. 8, (Suppl 7), S53-SS7. 3. Meredith, I. T., Broughton, A., Jennings, G. L., and Esler, M. D. (1991). Evidence for a selective increase in resting cardiac sympathetic activity in some patients suffering sustained out of hospital ventricular arrhythmias. N. Eng. /. Med. 325, 618-624. 4. Kaye, D. M., Lefkovits, J., Jennings, G . L., Bergin, P., Broughton, A,, and Esler, M. D. (1995). Adverse consequences of high sympathetic nervous activity in the failing human heart. J. Am. Coll. Cardiol. 26, 1257-1263. 5 . Kaye, D. M., Cox, H., Lambert, G., Jennings, G . L., Turner, A., and Esler, M. D. (1995). Regional epinephrine kinetics in severe heart failure: Evidence for extra-adrenal, non-neural release. Am. J. Physiol. 269, H182-Hl88. 6. Kaye, D. M., Lambert, G. W., Lefkovits, J., Morris, M., Jennings, G. L., and Esler, M. D. (1994). Neurochemical evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in severe congestive heart failure. J. Am. Coll. Cardiol. 23, 570-578. 7. Ferrier, C., Jennings, G. L., Eisenhofer, G., Lambert, G . , Cox, H. S., Kalff, V., Kelly, M., and Esler, M. D. (1993). Evidence for increased noradrenaline release from subcortical brain regions in essential hypertension, 1. Hyperten. 11, 1217-1227.