Abstract
Recent demonstration that the level of sympathetic nervous drive to the failing heart in patients with severe heart failure is a major determinant of prognosis, and that mortality in heart failure is reduced by beta-adrenergic blockade, indicate the clinical relevance of heart failure neuroscience research.
The cardiac sympathetic nerves are preferentially stimulated in severe heart failure, with the application of isotope dilution methods for measuring cardiac norepinephrine release to plasma indicating that in untreated patients cardiac norepinephrine spillover is increased as much as 50-fold, similar to levels of release seen in the healthy heart during near maximal exercise. This preferential activation of the cardiac sympathetic outflow contributes to arrhythmia development and to progressive deterioration of the myocardium, and has been linked to mortality in both mild and severe cardiac failure. Although the central nervous system mechanisms involved in the sympathetic nervous activation at present remain uncertain, increased intracardiac diastolic pressure seems to be one peripheral reflex stimulus, and increased forebrain norepinephrine turnover an important central mechanism.
Additional neurophysiological abnormalities present in the failing human heart include release of the sympathetic cotransmitters, epinephrine and neuropeptide Y, at high levels more typical of their release during exercise in healthy subjects, and the possible presynaptic augmentation of norepinephrine release from the cardiac sympathetic nerves by the regionally released epinephrine. Following on the demonstrable benefit of beta-adrenergic blockade in heart failure, additional antiadrenergic measures (central suppression of sympathetic outflow with imidazoline binding agents such as clonidine, blocking of norepinephrine synthesis by dopamine-β-hydroxylase inhibition, antagonism of neuropeptide Y) are now under active investigation.
Similar content being viewed by others
References
Chidsey CA, Braunwald E, Morrow AG, Mason DT. Myocardial norepinephrine concentration in man: Effects of reserpine and of congestive heart failure. N Engl J Med 1963;269:653–658.
Casolo GC, Stroder P, Sulla A, Cheucci A, Freni A, Zerauschek M. Heart rate variability and functional severity of congestive heart failure secondary to coronary artery disease. Eur Heart J 1995;16:360–367.
Kingwell BA, Thompsom 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.
Allman KC, Wieland DM, Muzik O, Degrado TR, Wolfe ER, Schwaiger M. Carbon-11 hydroxyephedine with positron emission tomography for serial assessment of cardiac adrenergic neuronal function after acute myocardial infarction in humans. J Am Coll Cardiol 1993;22:368–375.
Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993;342:1441–1446.
Hasking G, Esler M, Jennings G, Burton D, Johns J, Korner P. Norepinephrine spillover to plasma in congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 1986;73:615–621.
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.
Packer M, Bristow MR, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349–1355.
CIBIS II Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBIS II). Lancet 1999;353:9–13.
MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001–2007.
Esler M, Jennings G, Lambert G, Meredith I, Horne M, Eisenhofer G. Overflow of catecholamine neurotransmitters to the circulation: Source, fate and functions. Physiol Rev 1990;70:963–985.
Davis D, Baily R, Zelis GJ. Abnormalities in systemic norepinephrine kinetics in human congestive heart failure. Am J Physiol 1988;254:760–766.
Sundlof G, Wallin BG. The variability of muscle nerve sympathetic activity in resting recumbent man. J Physiol (London) 1977;272:383–397.
Vallbo AB, Hagbarth K-E, Torebjork HE, Wallin BG. Somatosensory, proprioceptive and sympathetic activity in human peripheral nerves. tiPhysiol Rev 1979;59:919–957.
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 (Endocrinol Metab 10): E21–E28.
Macefield V, Wallin BG, Vallbo AB. The discharge behaviour of single vasoconstrictor motoneurones in human muscle nerves. J Physiol (Lond) 1994;481:799–809.
Esler M, Jackman G, Bobik A, Kelleher D, Jennings G, Leonard P, Skews H, Korner P. Determination of norepinephrine apparent release rate and clearance in humans. Life Sci 1979;25:1461–1470.
Akselrod S, Gordon D, Madwed JB, Snidman NC, Shannon DC, Cohen RJ. Hemodynamic regulation: investigation by spectral analysis. Am J Physiol 1985;249:H867–H875.
Guzzetti S, Piccaluga E, Casati R, Cerutti S, Lombardi F, Pagani M, Malliani A. Sympathetic predominance in essential hypertension: a study employing spectral analysis of heart rate variability. J Hyperten 1988;6:711–717.
Eckberg DL. Spectral balance: a critical appraisal. Circulation 1997;96:3224–3232.
Eisenhofer G, Friberg P, Rundqvist B, Quyyumi AA, Lambert G, Kaye DM, Kopin IJ, Goldstein DS, Esler MD. Cardiac sympathetic nerve function in congestive heart failure. Circulation 1996;93:1667–1676.
Eisenhofer G, Esler MD, Goldstein DS, Kopin IJ. Neuronal uptake, metabolism, and release of tritium-labeled norepinephrine during assessment of its plasma kinetics. Am J of Physiol 1991;261(Endocrinology and Metabolism 24): E505–E515.
Chang PC, Kriek E, van der Krogt JA, van Brummelen P. Does regional norepinephrine spillover represent local sympathetic activity? Hypertension 1991;18:56–66.
Dominiak P, Schulz W, Delius W, Kober G, Grobecker H. Catecholamines in patients with coronary heart disease. In: Delius W, Gerlach E, Grobecker H, Kubler W eds. tiCatecholamines And The Heart. Recent Advances In Experimental And Clinical Research. Berlin, Springer-Verlag, pp223–235, 1981.
Kaye DM, Lambert GW, Lefkovits J, Morris M, Jennings GL, 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.
Rundqvist B, Elam M, Bergmann-Sverrirsdottir Y, Eisenhofer G, Friberg P. Increased cardiac adrenergic drive precedes generalized sympathetic activation in human heart failure. Circulation 1997;95:169–175.
Meredith IT, Broughton A, Jennings GL, Esler MD. Evidence for a selective increase in resting cardiac sympathetic activity in some patients suffering sustained out of hospital ventricular arrhythmias. New Engl J Med 1991;325:618–624.
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.
Newton GE, Parker JD. Cardiac sympathetic response to acute vasodilatation: normal ventricular function versus congestive cardiac failure. Circulation 1996;94:3161–3167.
Patel KP, Zhang PL, Krukoff TL. Alterations in brain hexokinase activity associated with heart failure in rats. Am J Physiol 1993;265:R923–R928.
Patel KP, Zhang K. Neurohumoral activation in heart failure: Role of paraventricular nucleus. Clin Exp Pharmacol Physiol 1996;23:722–726.
Elam M, Yao T, Svensson H, Thoren P. Regulation of locus coeruleus neurons and splanchnic sympathetic nerves by cardiovascular afferents. Brain Res 1984;290:281–287.
Lambert GW, Kaye DM, Lefkovits J, Jennings GL, Turner AG, Cox HS, Esler MD. Central nervous system monoamine neurotransmitter turnover and its association with sympathetic nervous activity in treated heart failure patients. Circulation 1995;92:1813–1818.
Manolis AJ, Olympios C, Sifaki M, Handanis S, Cokkinos D, Bresnahan M, Gavras I, Gavras H. Combined sympathetic suppression and angiotensin-converting enzyme inhibition in congestive heart failure. Hypertension 1997;29:525–530.
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.
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. New Engl J Med 1984;311:819–823.
Mann DL, Kent RL, Parsons B, Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992;85:790–804.
Morris MJ, Cox HS, Lambert GW, Kaye DM, Jennings GL, Meredith IT, Esler MD. Region-specific plasma NPY concentrations and overflows at rest and during sympathetic activation in man. Hypertension 1997; 29:137–143.
Potter EK, Ulman LG. Neuropeptides in sympathetic nerves affect vagal regulation of the heart. News Physiol Sci 1994;9:174–177.
Moriarty M, Potter EK, McCloskey DI. Pharmacological separation of cardioaccelerator and vagal inhibitory capacities of sympathetic nerves. J Auton Nerv Syst 1993;43:7–16.
Majewski H, McCulloch M, Rand MJ, Story DF. Adrenaline activation of prejunctional ?-adrenoceptors in guinea pig atria. Br J Pharm 1980;71:435–444.
Kaye DM, Cox H, Lambert G, Jennings GL, Turner A, Esler MD. Regional epinephrine kinetics in severe heart failure: Evidence for extra-adrenal, non-neural release. Am J Physiol 1995;269:H182–H188.
Johansson M, Rundqvist B, Eisenhofer G, Friberg P. Cardiorenal epinephrine kinetics: evidence for release in the human heart. Am J Physiol 1997;273:H2178–H2185.
Newton GE, Azevedro ER, Parker JD. Inotropic and sympathetic responses to the intracoronary infusion of a beta2-adrenoceptor agonist: a human in vivo study. Circulation 1999;99:2402–2407.
Meredith IT, Friberg P, Jennings GL, Dewar EM, Fazio VA, Lambert GW, Esler MD. Regular exercise lowers renal but not cardiac sympathetic activity in man. Hypertension 1995;18:575–582.
Haikerwal D, Du X-J, Turner A, Esler MD, Dart DM. Presynaptic antisympathetic action of amiodarone and its metabolite desethylamiodarone. J Cardio Pharmacol 1999;33:309–315.
Kaye DM, Dart AM, Jennings GL, Esler MD. Antiadrenergic effect of amiodarone therapy in human heart failure. J Am Coll Cardiol 1999;33:1553–1559.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Esler, M., Kaye, D. Measurement of Sympathetic Nervous System Activity in Heart Failure: The Role of Norepinephrine Kinetics. Heart Fail Rev 5, 17–25 (2000). https://doi.org/10.1023/A:1009889922985
Issue Date:
DOI: https://doi.org/10.1023/A:1009889922985