assessment of sympathetic cardiovascular influences in man: haemodynamic and humoral markers versus...

Sympathetic activity in man

Review Paper Clinical Autonomic Research 1, 245-249 (1991)

EVALUATION of sympathetic cardiovascular influences has important physiological, pathophysiological and clinical implications. This paper reviews some of the methods employed to measure these influences in man, along with their advantages and disadvantages. The most useful methods appear to be the measurement of plasma noradrenaline (particularly when modified to calculate spillover rate of noradrenaline) and direct recording of sympathetic nerve traffic. With the former, despite the technological advances in measurement, certain methodo- logical problems remain, such as the separation of noradrenaline secretion from clearance. With the latter technique peripheral muscle and skin sympathetic activity can be measured separately but the question of regional vascular variability has still to be resolved. A combination of these two methods may represent the ideal approach. This review considers the complex problems associated with attempts to precisely quantify sympathetic cardiovascular influences in man.

Key words: Plasma catecholamines, Blood pressure variability, Microneurography, Sympathetic nervous system

Assessment of s y m p a t h e t i c card iovascular inf luences in man" h a e m o d y n a m i c and humora l markers versus m i c r o n e u r o g r a p h y

Giuseppe Mancia , M D CA and Guido Grassi, MD

Cattedra di Semeiotica Medica and Istituto di Clinica Medica Generale e Terapia Medica, Universit~ di Milano; Centro di Fisiologia Clinica e Ipertensione, Ospedale Maggiore, Via F. Sforza 35, 20122 Milano, and Centro Auxologico Italiano, Milano, Italy.

CACorresponding Author

I n t r o d u c t i o n

The sympathetic nervous system has a major influence over cardiac and vascular function. Alterations in sympathetic neural activity therefore have important physiological, pathophysiological and clinical implications. These influences for example are fundamental for short-term and probably for long-term blood pressure homeo- stasis. I Furthermore, sympathetic modulation of the cardiovascular system undergoes major changes in a variety O f diseases and may be involved in the genesis of essential hypertension. 2 Assessment of sympathetic activity also has obvious diagnostic relevance for primary and secondary dysautonomias. Plasma noradrenaline, a biochemical marker of sympathetic neural activity is inversely related to survival in congestive heart failure 3 and is of prognostic value in patients with an acute myocardial infarction. 4

This paper will briefly review some of the techniques by which sympathetic activity is measured in man, focusing on their advantages and disadvantages with particular comparison with one of the latest approaches, direct sympathetic nerve recording by microneurography. 5

Measurements Based on Haemodynamic Data

An increase in sympathetic cardiovascular drive has been inferred in the past from the occurrence of tachycardia, visceral vasoconstriction and skeletal muscle vasodilatation; this has been derived from cardiovascular patterns generated both in

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animals and man by exposure to stress and sympathetic stimulation. 6'7 Stress, however, does not produce univocal cardiovascular responses 6 emphasizing the need to determine responses in regional vascular beds, which is difficult to precisely and simultaneously assess in humans. For these reasons this approach has been largely replaced by the evaluation of the blood pressure and heart rate effects of standardized stressful stimuli elicited in the laboratory, the assumption being that whenever their effects are greater than normal the sympathetic nervous system is likely to be hyperactive. However, we have shown that the rise in blood pressure and heart rate in response to laboratory stress has a limited within-subject reproducibility, 8 that responses to one stressful stimulus shows a limited correlation with the responses to other stimuli, 9 and that cardiovascular hyperresponsiveness within the laboratory may not reflect a hyperresponsiveness to stressful stimuli occurring in normal environmental circumstances. 9 Further- more vascular hypertrophy amplifies the effects of smooth muscle constriction and an enhanced pressor response may be secondary to structural factors rather than abnormalities in sympathetic activity. 1° Recognition of limitation is also of importance in relation to an alternative approach, where evaluation of sympathetic tone is indirectly determined from the magnitude of the blood pressure fall elicited by a sympatholytic agent.

In recent years, 24-h blood pressure variabili ty (such as by blood pressure standard deviation), has been considered as a possible index of sympathetic cardiovascular control based on the evidence that sleep and other behavioural influences are respons-

Ciinical Autonomic .Research" vol 1 • 1991 245

G. Mancia and G. Grassi

ible for marked blood pressure changes through- out day and night, n However, the pronounced blood pressure variability that characterizes a 24-h period is a complex phenomenon and many other mmHg

factors which include mechanical effects of 1401 ventilation, humoral influences, vagally induced / changes in heart rate and cardiac output and 1301 fluctuations in vascular smooth muscle tone ! probably participate, thus limiting the value of this 12o1 measure as a specific index of overall sympathetic 11oJ | cardiovascular drive. According to some invest- igators 12'13 this limitation may not exist for s o m e pg/ml components of blood pressure variability, such as 290 1 the rhythmic blood pressure fluctuations that occur in the low- or mid-frequency band (0.025-0.14 Hz) 25°1 /

for all or most of the 24 h. These components have t been shown to increase and decrease under 210J

conditions which increase and reduce sympathetic t activity, 1>15 but the specificity and sensitivity of this 17o~

approach as a marker of sympathetic drive in man needs further evaluation, ts

Humoral Indices of Sympathetic Activity

Sympathetic activity has been inferred from 24-5 urinary excretion of catecholamines and their precursors or metabolites. This has been largely replaced, however, by measurement of plasma noradrenaline which is the most commonly used index of sympathetic tone in man. Because physiological and pathophysiological conditions characterized by an increase (tilting, exercise, stress, congestive heart failure), or a reduced (sleep, primary and secondary dysautonomias), sympathetic drive are reflected by changes in plasma noradrenaline concentration 16-2° there is no doubt that this index is valid. However, several technical and biological limitations should also be considered. Although new assay techniques are better than previous ones 21 the sensitivity and reproducibility of plasma noradrenaline measurements are not yet optimal. Circulating noradrenaline also represents only a small fraction (5-10%) of the noradrenaline secreted from the sympathetic nerve terminals. Alterations of plasma noradrenaline levels may depend both on changes in its secretion and on changes in its tissue clearance. Some vascular beds may contribute to plasma noradrenaline less than others, making its circulating level an unbalanced and sometimes insensitive index of overall sympathetic activity. 22 This we had previously noted in subjects in whom sympathetic activity was either reduced or increased by stimulating and deactivating respectively the carotid baroreceptors using the neck chamber technique. As shown in Figs 1 and 2, the increase in sympathetic activity resulted in a small but

246 Clinical Autonomic Research. vol 1.1991

R E D U C T I O N IN B A R O R E C E P T O R A C T I V I T Y

(n = 9)

MAP b/min HR

8o t r oo, 70

N A pg/ml A

4 0 i 4'min C; i imin

c = control 2-4min increased neck tissue pressure (27±2mmHg)

FIG. 1. Increase in mean arterial pressure (MAP), heart rate (HR), plasma noradrenaline (NA) and adrenaline (A) induced by carotid baroreceptor deactivation before (C: control values); and after 2 and 4 min of increase in neck tissue pressure obtained by the neck chamber technique. The values are means -t- SEM from nine subjects (modified from ref. 23).

I N C R E A S E IN B A R O R E C E P T O R A C T I V I T Y

( n = 7 )

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100 j 70 ,

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NA A

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50

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FIG. 2. Reduction in MAP, HR, NA and A induced by carotid baroreceptor stimulation. The values are from seven of the nine subjects in Fig. 1. Symbols and explanations as in Fig. 1 (modified from ref. 23).

consistent blood pressure rise while the reduction in sympathetic activity resulted in a small but consistent blood pressure fall. Neither the increase nor the reduction in blood pressure, however, were accompanied by a consistent alteration in plasma noradrenaline, which was modified only by tilting


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FIG. 3. Changes in MAP, HR, NE and E induced by a 10-min head-up tilting. Data from the same subjects of Fig. 1. Symbols and explanations as in Fig. 1, noradrenaline (NE) and adrenaline (E) (modified from r#f. 23, by permission).

which may have been a more intense sympathetic cardiovascular stimulus 23 (Fig. 3).

Esler 24'25 has modified the traditional plasma noradrenaline approach by infusing small amounts of tritiated noradrenaline and thus enabling measurement of the clearance of this substance from plasma. This represents an important advantage because the derivation of plasma noradrenaline minus the clearance reflects the noradrenaline 'spill-over' from sympathetic effector-junctions into the systemic circulation. 24 It does not overcome all the problems posed by the traditional approach, however, as within the sympathetic-effector junctions noradrenaline is affected by a variety of factors by Esler and others 26'27 as emphasized. The amount of spill-over onto plasma may reflect, only to a limited extent, secretion of noradrenaline from sympathetic nerves.

D i r e c t R e c o r d i n g o f S y m p a t h e t i c N e r v e A c t i v i t y

In 1968 Hagbarth and Vallbo 28 developed a method for directly recording efferent post- ganglionic sympathetic nerve activity from human peroneal or brachial nerves. This has since been used in many laboratories. The method basically consists of an insertion of a tungsten microelectrode. There is also a reference microelectrode in nerve fascicles, after mapping the subcutaneous course of the nerve. The electrodes are connected

to a preamplifier and the recorded signal is routed via an amplitude discriminator to a storage oscilloscope, a polygraph and a loud-speaker. This allows both visual and acoustic identification of spontaneous sympathetic bursts and their quantification as number over time, if necessary after normalization for heart rate values under certain circumstances. Total burst amplitude (mean amplitude per number of bursts) can also be calculated, thus providing a further quantification of sympathetic neural activity.

The experience derived from a 20-year long use has enabled assessment of the main advantages and disadvantages of microneurography. An important feature is that the recorded bursts can be split into a larger component to skeletal muscle resistance vessels and a smaller component to skin blood vessels and sudomotor glands. There is now unequivocal evidence that the muscle component is abolished by pharmacological blockade of sympathetic ganglia and local anaesthesia of the nerve proximal but not distal to the recording site. Furthermore, simultaneous nerve recording at two different sites indicates that the conduction velocity of the bursts for this component is about ] m/s, which is the velocity described in experimental animals for unmyelinated nerve fibres. Finally, in subjects with hypertension or congestive heart failure a close positive relationship has been found between the number of muscle sympathetic bursts recorded by microneurography and plasma noradrenaline (Fig. 4). 29,30 The overall evidence therefore indicates that microneurographic recordings accurately reflect post-ganglionic sympathetic nerve activity. This is currently the only method that can provide a direct rather than an indirect assessment of sympatho-neural activity in man.

Other important features need mention. Recording from both the peroneal and the brachial nerves can be safely performed, the only in- convenience reported being a mild and short lasting paraesthesia in less than 10% of the subjects. 31 The

Plasma Norepi Levels pg/ml

1500 N.E. = -219 + 14.4 x SNA • n = 10. r = 0.726 p = .02

1000

5O0 - • ~ , / , , 1 - A • •

0 I I I I I I 20 30 40 50 60 70 80 90

Muscle SNA (bursts/min)

FIG. 4. Correlation between plasma noradrenaline levels (NE) and resting muscle sympathetic nerve activity (SNA) in ten patients with heart failure (reproduced from ref. 30, by permission).

Clinical Autonomic Research. vol 1 • 1991 247

G. Mancia and G. Grassi

recording can be prolonged for several hours allowing rapid but transient changes in sympathetic nerve traffic to a variety of laboratory manoeuvres to be repeatedly assessed. The burst pattern and the calculated resting sympathetic activity simultaneously recorded from two different nerves are remarkably similar, s'32 Moreover they are highly reproducible within healthy subjects when re- studied at intervals of weeks or months, suggesting that the measurements reflect individual character- istics of sympathetic activity, s

This should be balanced against the disadvantages listed below. Firstly, sympathetic nerve traffic to the skin is exquisitely dependent on thermal and alerting stimuli, which makes it less reproducible than muscle sympathetic nerve traffic and therefore more difficult to interpret in relation to sympathetic cardiovascular control in health and disease. Secondly, muscle and skin regional vascular beds, although important, make up only a fraction of the peripheral circulation and this raises the problem of whether the data are representative of overall cardiovascular sympathetic drive. This is a major issue as animal studies indicate marked regional differences in both sympathetic tone and sympathetic adjustment to a variety of stimuli. 33 Furthermore in man, muscle sympathetic nerve traffic increases when blood pressure spontaneously fails and is influenced by a variety of reflexes; 34 however, this is not so for skin sympathetic nerve traffic (Fig. 5). These studies emphasize that differences in sympathetic drive and modulation are likely to occur in regional vascular beds in man and that these responses may vary depending upon the stimulus. Thirdly because of its dependence on the position of the recording electrode in relation to the active nerve fibres, burst amplitude cannot be used for comparing nerve traffic in different subjects or recording sessions. This can only make use of

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FIG. 5. Simultaneous recordings of skin sympathetic (left peroneal nerve) and muscle sympathetic nerve activity (right peroneal nerve) in a normotensive subject, in resting conditions. Only muscle sympathetic nerve activity was closely correlated with spontaneous blood pressure oscillations. From top to bottom: respiratory measurements, skin sympathetic nerve traffic, muscle sympathetic nerve traffic, blood pressure in mmHg, heart rate in beats/rain (reproduced from ref. 32, by permission).

the number of bursts, i.e. a finite-step scale limiting the sensitivity of the approach. We feel that small quantitative differences in nerve traffic should be always interpreted with caution especially if, as in the skin, the signal-to-noise ratio of the recording is not optimal.

A fourth disadvantage applied to both microneurography and plasma noradrenaline measurements. This is because both sympathetic nerve traffic and noradrenaline secretion represent an intermediate step in the sequence of events that leads to cardiac and vascular activation. End organ function is dependent on a variety of factors such as adrenergic receptor sensitivity and receptor density, which determine local events and also infuence negative feed-back relationships. Thus an elevation in sympathetic nerve traffic and plasma noradrenaline may not necessarily imply an increase in sympathetically modulated cardiovascular responses.

Conclusions

This review emphasizes in man the difficulties quantifying sympathetic cardiovascular influences and identifying their derangement in disease. A number of methods employed in the past, and still widely used today, are technically and biologically questionable. Other methods, such as power spectral analysis, are promising but need further validation. The best methods presently available are measurements of plasma noradrenaline (particularly when modified to calculate noradrenaline spillover rate) and direct recording of sympathetic nerve traffic. Both methods have disadvantages which can be reduced if they are used in combination, possibly also with the evaluation of the cardiac and vascular responses to manipulation of sympathetic drive. The determination of neural, synaptic and effector events, should also allow us to address further the precise mechanisms accounting for alterations in sympathetic function in both normal and diseased man.

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2 4 8 Clinical Autonomic Research-vol 1 " 1 9 9 1


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Received 3 April 1991 ; accepted 11 July 1991.

Clinical Au tonomic Research .vol 1 • 1991 249

assessment of sympathetic cardiovascular influences in man: haemodynamic and humoral markers versus...

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