(Circulation. 1995;91:351-358.)
© 1995 American Heart Association, Inc.
Articles |
Effects of Aging on the Responsiveness of the Human Cardiac Sympathetic Nerves to Stressors
From the Baker Medical Research Institute, Melbourne, Australia (M.D.E., J.M.T., D.M.K., A.G.T., G.L.J., H.S.C., G.W.L.), and the Department of Kinesiology, University of Colorado, Boulder (D.R.S.).
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Abstract |
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Background Aging increases human sympathetic nervous activity at rest. Because of the probable importance of neural stress responses in the heart as triggers for clinical end points of coronary artery disease, it is pertinent to investigate whether sympathetic nervous responses to stresses are increased by aging.
Methods and Results We applied kinetic methods for measuring the fluxes to plasma of neurochemicals relevant to sympathetic neurotransmission in younger (aged 20 to 30 years) and older (aged 60 to 75 years) healthy men during mental stress (difficult mental arithmetic), isometric exercise (sustained handgrip), and dynamic exercise (supine cycling). The increase in total norepinephrine spillover to plasma with mental stress was unaffected by age. In contrast, the increase in cardiac norepinephrine spillover was two to three times higher in the older subjects (P<.05). The probable mechanism of this higher cardiac norepinephrine spillover was reduced neuronal reuptake of the transmitter, because age had no influence on the overflow of the norepinephrine precursor, dihydroxyphenylalanine, or intraneuronal metabolite, dihydroxyphenylglycol (levels of these two substances reflect rates of cardiac norepinephrine synthesis and intraneuronal metabolism), and the transcardiac extraction of plasma radiolabeled norepinephrine was lower in the older subjects (P<.05). An almost identical pattern of neurochemical response was seen with isometric exercise. During cycling, total norepinephrine spillover was 16% lower in the older men, but cardiac norepinephrine spillover was 53% higher.
Conclusions Reduced norepinephrine reuptake increases the overflow of the neurotransmitter to plasma from the aging heart during stimulation of the cardiac sympathetic outflow. Failure of transmitter inactivation at postjunctional receptors with aging would amplify the neural signal, and in the presence of myocardial disease could trigger adverse stress-induced cardiovascular events, particularly when accompanied by an age-dependent reduction in vagal tone. Reduction of postsynaptic adrenergic responsiveness with aging, however, might protect against this, as indicated by our finding that in no case was the heart rate increase during stress greater in older men, despite their having larger increases in cardiac norepinephrine spillover.
Key Words: norepinephrine • dihydroxyphenylalanine • dihydroxyphenylglycol
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The extent to which human sympathetic nervous system function at rest is changed by aging remains a matter of considerable uncertainty,1 2 3 4 and it is at present unknown whether responses of the sympathetic nervous system to different stressors are magnified by aging. The impetus for further study of possible influences of age on neural stress responses has come in particular from recognition that neural mechanisms could provide the precipitating cause for some clinical end points of coronary artery disease.
While a surge of sympathetic neural firing, either on wakening after overnight sleep5 or in relation to intense exercise in untrained people,6 has been proposed as a precipitating cause of myocardial infarction, it is in the genesis of ventricular tachyarrhythmias and sudden cardiac death that the case for a causal role of sympathetic nervous activation is strongest. Sudden cardiac death due to a ventricular tachyarrhythmia is a significant cause of cardiovascular mortality. The immediate precipitants of the ventricular arrhythmia are unknown, but it is clear that the majority of patients have underlying organic heart disease, most often coronary artery disease7 and poor left ventricular function.8 Although associations between ventricular arrhythmias, impaired left ventricular function, and sudden death are well established, the precise mechanisms involved are unclear. Sympathetic nervous system activation, particularly in the setting of reduced vagal influence on the heart in older people, may possibly provide the link between impaired left ventricular function and ventricular electrical instability.9 10 The well-documented age-related reduction in vagal function11 12 13 removes the normal opposing force for sympathetic stimulation and cardiac acceleration. The interplay between vagal and sympathetic efferent neural drive is crucial in dictating cardiac stress responses and, for diseased hearts, in determining the predisposition to ventricular arrhythmias.14 15 Additional pointers to the possible clinical importance of sympathetic nervous activation as a trigger for arrhythmogenesis and sudden cardiac death are the favorable effect of ß-adrenergic blockers on post–myocardial infarction ventricular arrhythmias and mortality,16 the prediction of overall mortality in congestive heart failure from the plasma concentration of norepinephrine,17 and the reported higher rates of norepinephrine spillover from the heart in patients resuscitated from life-threatening ventricular tachyarrhythmias.18 Continuing uncertainty as to whether sympathetic nervous stress responses are greater in older people arises in part from the imprecision of the available clinical methodology for studying human sympathetic nervous function. The most consistently, but by no means invariably, reported abnormality is a greater rise in the plasma concentration of norepinephrine in older than in younger people during the experimental application of stressors that stimulate the sympathetic nervous system.19 20 21 22 The extent to which the greater plasma norepinephrine responses derive from increased neuronal release by sympathetic nerves, from faulty transmitter reuptake, or from reduced plasma clearance of norepinephrine is arguable. The increase in nerve firing rates in skeletal muscle sympathetic efferents during the application of stressors is not greater in the elderly.23 Whether age magnifies sympathetic nerve stress responses in internal organs that are not accessible to microneurographic recording is not known. In the present study performed in younger and older healthy human volunteers, we have attempted to overcome some of these deficiencies in methodology by applying kinetic methods for the measurement of whole-body and cardiac norepinephrine release and reuptake during experimental stresses. The results lead us to the conclusion that while the spillover of norepinephrine from the heart is increased during stress in older men, this appears to be due to reduced norepinephrine reuptake rather than increased transmitter release.
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Methods |
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Experimental Subjects
Research volunteers were 21 men aged 20 to 30 years and 12 aged 60 to 75 years, all in good health and all recruited from the general community by advertisement. Women were excluded from the study because of an institutional ethics committee stipulation that radiotracers not be used in clinical research involving healthy women of childbearing age. A comprehensive clinical evaluation was performed in all experimental subjects by a specialist physician; testing included a chest roentgenogram, bicycle ergometry with exercise ECG, and hematology and multipanel serum biochemistry testing. None of the recruited volunteers had a past history of neurological or other disease known to affect autonomic nervous system function. Fasting blood glucose concentration was normal in all subjects and none had glycosuria. All were unmedicated. None were obese; mean body mass index was 22.3 kg/m2 in the younger men and 22.9 kg/m2 in the older men. No subject was a trained athlete, although many in both age groups participated in occasional recreational exercise. No attempt was made to quantify the subjects' level of fitness using measurements of maximum oxygen consumption during exercise. No subject had a history of hypertension, and at the time of clinical evaluation and entry into the research project, recorded clinic blood pressure was in every case less than 150/90 mm Hg. Only nonsmokers were recruited for the research. Coffee drinking habits were not recorded. All subjects gave written informed consent for their participation in the study, which was approved by the Alfred Hospital Ethics Review Committee.
General Procedure
We followed an isotope dilution technique
using radiolabeled
norepinephrine to measure cardiac and whole-body spillover of
norepinephrine to plasma during mental stress (difficult mental
arithmetic), isometric exercise (sustained hand grip), and dynamic
exercise (supine cycling). The overflow from the heart of the
norepinephrine precursor dihydroxyphenylalanine and the intraneuronal
metabolite of norepinephrine dihydroxyphenylglycol were measured to
investigate, respectively, rates of norepinephrine
synthesis24 25 and
metabolism.26 27 The
effect of aging on the neuronal reuptake of norepinephrine was assessed
by measuring the extraction of tritiated norepinephrine from plasma
during passage through the heart, this extraction having been
demonstrated to result principally from uptake into cardiac sympathetic
nerves.28
Two hours before arriving at the laboratory, all subjects ate a standardized light breakfast of juice and toast to minimize the risk of a vasovagal reaction occurring during the placement of the vascular catheters. We have demonstrated that even a large meal, although stimulating some sympathetic nervous outflows, spares the sympathetic nerves of the heart.29 Tea, coffee, and alcohol were not consumed for a minimum of 12 hours before the study. Measurements were made with subjects supine. Total body and cardiac sympathetic function was assessed both at rest and during the application of stimuli that activate the sympathetic nervous system, according to the methods described below. For this purpose, blood samples for plasma catecholamine assay were obtained from a central venous catheter and a brachial arterial cannula. These were inserted percutaneously under local anesthesia.30 The central venous catheter, a 7F coronary sinus thermodilution catheter (Webster Laboratories, type CCS-7U-90B) introduced through an antecubital venous sheath, was placed with fluoroscopic control in the coronary sinus to include the middle cardiac vein drainage. The catheter position was verified with 2 mL radiopaque contrast medium (Omnipaque, Winthrop Pharmaceuticals). Arterial blood samples were obtained from the brachial artery simultaneously with venous sampling, through a percutaneously placed 21-gauge cannula. Throughout the catheter study, tritiated norepinephrine was infused for the determination of plasma norepinephrine kinetics.30 31 32 Measurements of the spillover of norepinephrine to plasma from the heart and from the body as a whole were used to estimate cardiac and overall sympathetic activity (integrated nerve firing rate). Rather than the rate of release of norepinephrine from sympathetic nerve varicosities, which is unmeasurable clinically, the norepinephrine spillover measurement gives the rate at which released norepinephrine enters plasma: in humans this is approximately 10% to 20% of the norepinephrine synthesis rate.33
Application of Laboratory Stressors
Stressors that activate
the sympathetic nervous system and are
encountered by younger and older people in their everyday lives—mental
stress, isometric exercise, and dynamic exercise—were applied in the
cardiac catheterization laboratory.
Mental Stress
A
cognitive challenge with forced mental arithmetic was employed
to simulate a mental stress. Each subject was expected to add or
subtract one- or two-digit numbers from a three-digit number in a
serial fashion as rapidly as possible for 10 minutes. Tables of serial
additions of odd numbers between 7 and 19 were constructed for numbers
between 100 and 999 to standardize the challenge between subjects. The
task was supervised by a member of the staff at the Baker Medical
Research Institute who was previously unfamiliar but was common to all
subjects. The examiner was permitted to change the magnitude of the
addition or subtraction or the starting number (within the limits of
the constructed tables) as frequently as desired to maintain the
complexity of the challenge, given the subjects' differing abilities
in mental arithmetic. Throughout the task, subjects were encouraged to
improve their performance, against a background of impatience and
interruption. Mental stress testing was performed by 13 younger and 12
older men.
Isometric Exercise
This stressor was
examined by use of a handgrip dynamometer
(Harpenden Hand Grip, British Indicators). Subjects were requested to
sustain 10 minutes of isometric handgrip at 30% of maximum grip
strength using their dominant hand. Despite constant encouragement,
most subjects were unable to maintain this level for more than 7 to 8
minutes and were therefore permitted to reduce the effort to 25% for
the last 2 to 3 minutes. Isometric exercise was performed by 14 younger
and 9 older men.
Dynamic Exercise
Cycling was
performed in the cardiac catheter laboratory on an
electrostatically braked bicycle, with subjects lying supine and
exercising for 10 minutes at 60% of the previously determined maximum
work capacity. Dynamic exercise was performed by 7 younger and 8 older
men.
Each subject performed one to three stress tests, with adequate time being allowed between the stressors for blood pressure and heart rate to return to baseline. The order of testing was randomized, with the exception that when dynamic exercise was tested, it was always the last procedure, to avoid the confounding effect of postexercise sympathetic inhibition.34 The subjects were rather homogeneous in terms of physical characteristics and habits, being lean, nonsmoking, normotensive men, and there were no substantial differences in these characteristics between the subgroups who participated in the different stresses. Arterial pressure and heart rate were monitored continuously throughout the application of the stressors. Arterial and coronary sinus blood sampling for subsequent plasma catecholamine assay and measurement of coronary sinus blood flow by thermodilution were performed during the final 2 minutes of stress testing in each case.
Total Body Norepinephrine Spillover
The total body
norepinephrine spillover rate was measured by the
radiotracer method developed in our laboratory.31 In
brief, the method involves the continuous intravenous infusion of a
tracer dose of norepinephrine (0.70 mCi/min
L-[7-3H]norepinephrine, specific
activity 12 to 20 Ci/mmol, New England Nuclear) to a steady-state
concentration in plasma. The rate of total norepinephrine spillover to
plasma was calculated by use of the equation
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where NE is norepinephrine, dpm is disintegrations per minute of tritium-labeled norepinephrine, and [3H]NE is tritium-labeled norepinephrine.
Cardiac Norepinephrine Spillover
The rate of norepinephrine
spillover from the heart was
calculated according to the Fick principle, corrected for the
fractional extraction of tritium-labeled norepinephrine across the
heart:30 32 Cardiac NE
spillover=[(NECS-NEA)+NEA · NEEX]CSPF
where
NE is norepinephrine, NECS is plasma norepinephrine
concentration in the coronary sinus, NEA is arterial plasma
norepinephrine concentration, NEEX is the steady-state
fractional extraction of plasma tritiated norepinephrine across the
heart, and CSPF is the coronary sinus plasma flow (mL/min). Coronary
sinus plasma flows were derived from thermodilution-determined blood
flows and the hematocrit.30
Cardiac Spillovers of Dihydroxyphenylalanine and
Dihydroxyphenylglycol
The rate of cardiac spillover of
dihydroxyphenylalanine was
calculated according to the formula30 Cardiac
DOPA
spillover=(DOPACS-DOPAA)CSPF where
DOPA is dihydroxyphenylalanine, DOPAA and
DOPACS are the dihydroxyphenylalanine concentrations in
arterial and coronary sinus plasma, and CSPF is the coronary sinus
plasma flow. Plasma flow was used to calculate the cardiac spillover of
dihydroxyphenylalanine on the basis of results from our laboratory
showing that 86% of exogenous dihydroxyphenylalanine added to whole
blood is recoverable from the plasma compartment.
The rate of cardiac spillover of dihydroxyphenylglycol was calculated according to the formula Cardiac DHPG spillover=(DHPGCS-DHPGA)CSBF where DHPG is dihydroxyphenylglycol, DHPGA and DHPGCA are the dihydroxyphenylglycol concentrations in the arterial and coronary sinus effluent plasma, and CSBF is the coronary sinus blood flow. Blood flow rather than plasma flow was used in the calculations on the basis of the finding that dihydroxyphenylglycol added to whole blood is equally distributed between plasma and the red cell compartment.35
Cardiac Extraction of Plasma Tritiated Norepinephrine
The
fractional extraction of tritiated norepinephrine from
plasma at steady state during passage through the heart was calculated
from the equation
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where NE is norepinephrine and [3H]NEA and [3H]NECS are the concentrations of tritiated norepinephrine in arterial and coronary sinus plasma.
Assays of Catechols
Arterial blood samples were transferred
immediately to
ice-chilled tubes containing an anticoagulant and antioxidant (EGTA
plus reduced glutathione). Plasma was separated by centrifugation at
4°C, and samples were subsequently stored at -70°C until
assayed.
Endogenous norepinephrine, dihydroxyphenylalanine, and
dihydroxyphenylglycol plasma concentrations were measured by
high-performance liquid chromatography with electrochemical detection,
according to our previously published
methods.30 35 36
Fractions of the eluant leaving the electrochemical cell were collected
into scintillation vials for measurement of tritium-labeled
norepinephrine by liquid scintillation spectroscopy.
Statistical Methods
Data are expressed as means±SD.
Between-group comparisons of
catecholamine measurements were made using Student's t test
for normally distributed values and the Mann-Whitney U test
for nongaussian data. Blood pressure and heart rate responses were
compared using ANOVA. The null hypothesis was rejected at
P<.05.
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Results |
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Plasma Catecholamines, Blood Pressure, and Heart Rate at Rest
The mean plasma concentration of norepinephrine at rest was 66% higher in the older than in the younger men (P<.01), attributable in part to a 29% higher rate of total spillover of norepinephrine to plasma (Table 1
). The spillover of
norepinephrine from the heart at rest was also higher in the
older men (21±11 ng/min compared with 11±9 ng/min,
P<.05). The concentrations of dihydroxyphenylalanine and
dihydroxyphenylglycol in arterial plasma and their overflow from the
heart at rest were independent of age. Blood pressure and heart rate
were similar at rest in the younger and older men (Table 1).
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Norepinephrine Spillover During Application of Stressors
The
spillover of norepinephrine to plasma from the whole body and
from the heart increased in both younger and older men during all three
stimuli (Fig 1). Although the increases in total
norepinephrine spillover were similar in the two groups, the increase
in norepinephrine spillover from the heart during mental stress,
isometric exercise, and dynamic exercise was greater in older men,
significantly so for mental stress and isometric exercise (Fig
1),
during which the increase in cardiac norepinephrine spillover in older
men was two to three times greater than in the younger men
(P<.05). This difference was not attributable to a
flow-dependent washout of transmitter to plasma during the stimuli,
because in each case the venoarterial step-up in plasma norepinephrine
concentration across the heart was greater in the older men, and
coronary sinus plasma flows during the stimuli were similar in both
groups (Table 2).
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Cardiac Extraction of Plasma Tritiated Norepinephrine
The
extraction of tritiated norepinephrine from plasma
during transit through the heart, which is predominantly into cardiac
sympathetic nerves,28 was lower in the older men,
suggesting that neuronal uptake of norepinephrine by the cardiac
sympathetic nerves was reduced (Fig 2). The steady-state
transcardiac extraction of plasma tritiated norepinephrine in older men
was 70±15% at rest compared with 82±7% in the younger men
(P<.01), 60±14% compared with 77±6% during mental
stress (P<.01), and 60±14% versus 72±10% during
isometric exercise (P<.05) (Fig 2). At the higher
myocardial blood flows associated with dynamic exercise, this
difference in cardiac extraction of tritiated norepinephrine from
plasma was no longer apparent (Table 2
).
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Cardiac Overflows of Dihydroxyphenylalanine and
Dihydroxyphenylglycol
Despite the increased norepinephrine spillover
from the heart in
the older men, the cardiac overflow of dihydroxyphenylalanine and
dihydroxyphenylglycol was normal at rest and during the application of
all three stressors (Fig 3), suggesting that cardiac
norepinephrine synthesis and release were not
increased.24 25 26 27 At rest
and during mental stress and
isometric exercise, the ratio of norepinephrine to
dihydroxyphenylglycol spillover from the heart, which is determined in
part by capacity for neuronal reuptake of norepinephrine and elevated
by impairment of reuptake,27 was increased in older men
(Fig 3). The values were 0.180±0.071 in older men
compared with
0.099±0.048 in younger men at rest (P<.01),
0.447±0.273
compared with 0.152±0.098 during mental stress (P<.01),
and 0.503±0.356 versus 0.248±0.182 during isometric exercise
(P<.05). During dynamic exercise, the ratio was higher in
older men, 1.525±0.994 compared with 1.124±0.664, but not
significantly so.
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Heart Rate and Arterial Pressure During Stress
The increase
in heart rate during mental stress and isometric
exercise in older men was identical to that in the younger men, despite
the older men's greater cardiac spillover of norepinephrine during the
stimuli. The heart rate response to dynamic exercise was reduced in the
older men (P<.01) (Fig 4). The increase in
mean arterial pressure during isometric and dynamic exercise was
greater in the older men.
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Discussion |
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The extent to which human sympathetic nervous system function is changed by aging remains a matter of considerable uncertainty. On the basis of measurements of the concentration of the sympathetic nervous neurotransmitter norepinephrine in plasma,19 kinetic analysis of rates of norepinephrine overflow to and clearance from plasma,1 2 3 4 and microneurographic recording from sympathetic nerves to skeletal muscle,37 38 39 the consensus view is that resting sympathetic nervous activity increases progressively with aging. The mechanism of this sympathetic activation is unknown, and whether the sympathetic outflows to internal organs such as the heart are involved in addition to the sympathetic nerves to skeletal muscle remains unclear. Also unclear is the degree to which responses of the sympathetic nervous system to different stressors are magnified by aging. An impetus for further study of possible influences of age on neural stress responses has been provided by the recognition that neural mechanisms can initiate clinical complications in patients with cardiac disease.17 18
The rise in the plasma concentration of norepinephrine during reflex activation of the sympathetic nervous system has commonly19 20 21 but not invariably40 41 been reported to be greater in older than in younger people. This has been noted with a variety of stimuli, including upright posture, isometric exercise, dynamic exercise, and hypoglycemia. The accentuated rise in plasma norepinephrine often seen in the elderly may well reflect exaggerated reflex release of norepinephrine, but this has not been demonstrated directly. Reduced norepinephrine plasma clearance1 3 4 could possibly be involved. In a study in which sympathetic nerve firing in skeletal muscle nerves was recorded by microneurography during laboratory mental stress, cold exposure, and isometric exercise, the degree of sympathetic activation produced by the stressors did not differ in younger and older human subjects.23
We found that, as expected, spillover of norepinephrine to plasma from the whole body and from the heart increased in both younger and older men during all three stimuli applied. While the increases in total norepinephrine spillover were similar in each case, the increase in norepinephrine spillover from the heart during mental stress, isometric exercise, and dynamic exercise was larger in older men, and significantly so for mental stress and isometric exercise, during which the increase in cardiac norepinephrine spillover in older men was two to three times that in the younger men. Because reduced neuronal reuptake facilitates the overflow of the transmitter into plasma, it is pertinent to ask whether the increased cardiac norepinephrine spillover rate we found during mental stress and isometric exercise in the older subjects could have been due to impaired norepinephrine reuptake. Active removal of released norepinephrine from the synaptic cleft by neuronal reuptake is the principal mechanism by which postsynaptic receptor activation is terminated. Most of the norepinephrine released is recaptured by sympathetic nerves, where it is stored for subsequent release or metabolized.42 In the human heart, norepinephrine reuptake is of particular importance as a disposition mechanism for the transmitter after its release.27 28 32
Neuronal norepinephrine uptake can be quantified in humans by studying the kinetics of tritiated norepinephrine.28 30 32 We found the extraction of tritiated norepinephrine across the heart to be reduced in older men at rest and during mental stress and isometric exercise, providing presumptive evidence of reduced neuronal uptake of norepinephrine. At the high coronary sinus blood flows present during dynamic exercise, transcardiac fractional extraction of tracer from plasma was lower, and differences between younger and older men were no longer apparent. Although differences in tracer diffusibility and extraneuronal uptake capacity with aging might also affect extraction of the tracer from plasma, in the heart, removal of norepinephrine in transit is largely due to uptake into sympathetic nerves,28 30 so that transcardiac fractional extraction of tracer provides a guide to neuronal norepinephrine uptake.
Further evidence that the increased cardiac spillover of norepinephrine may have resulted from an impairment of norepinephrine reuptake with aging rather than increased cardiac sympathetic nerve firing was provided by consideration of the relative washouts of norepinephrine, dihydroxyphenylalanine, and dihydroxyphenylglycol from the heart into the circulation during stress. The overflow of dihydroxyphenylalanine from the heart was at all times unremarkable in older men, suggesting that there was no increase in norepinephrine synthesis. Greater rates of norepinephrine synthesis and of dihydroxyphenylalanine overflow from the heart to plasma would be expected in the older men if their cardiac sympathetic nerves had been more stimulated by the stressors.24 25 Overflow of the intraneuronal metabolite dihydroxyphenylglycol from the heart was also at all times similar in older and younger men, despite the higher rates of norepinephrine spillover in the older subjects. With stimulation of the cardiac sympathetic nerves, the overflow of norepinephrine and dihydroxyphenylglycol from the heart increases in proportion, while with diminution of neuronal reuptake of norepinephrine there is a disproportionately greater increase in norepinephrine overflow,32 42 much as we found in our older subjects. Our findings are in general agreement with those from an earlier study of elderly subjects by Hoeldtke and Cilmi,2 who described increased overall rates of spillover of norepinephrine into the circulation despite normal total body synthesis rates of the transmitter and lower rates of excretion of dihydroxyphenylglycol in urine. The results of these studies taken together suggest that neuronal reuptake of norepinephrine in the heart is diminished by aging. The reason norepinephrine spillover from the heart but not the body at large is increased in older subjects during stress is most likely the greater importance of neuronal reuptake to neurotransmitter disposition after release in the heart than in other organs.32
Although the evidence presented does suggest that aging elevates the synaptic concentration of norepinephrine in the heart through reduced neuronal reuptake of transmitter, this increase in synaptic neurotransmitter concentration is not necessarily translated into greater adrenergic responses. We did observe greater increases in blood pressure during isometric and dynamic exercise, a finding in contrast with the more usual experience that the increase in blood pressure during physical and mental stresses is no greater in the elderly.11 41 43 44 However, the increase in heart rate during mental stress and isometric exercise in the older men was identical to that in the younger men, despite the greater cardiac spillover of norepinephrine during the stimuli in the older men. The heart rate response to dynamic exercise was reduced in the older men.
In assessing the possible significance of sympathetic nervous activation in triggering ventricular arrhythmias, a range of additional changes in neural cardiac regulation with aging do need to be considered but were not examined in the present study. Preeminent among these is the well-documented age-related reduction in vagal function.11 12 13 The loss of vagal tone removes the normal opposing force for sympathetic stimulation and cardiac acceleration. The interplay between vagal and sympathetic efferent neural drive is crucial in dictating cardiac stress responses and, in diseased hearts, in determining the predisposition to ventricular arrhythmias.14 15 Additional changes in the heart with aging, the relevance of which is not fully apparent in the present context, are the partial degeneration of sympathetic neurons, best described in the rat,45 although not accompanied by a reduction in cardiac norepinephrine content in the human heart46 ; a diminution in the number of myocardial ß1-adrenergic receptors46 and adrenergic responsiveness46 47 ; and structural changes in the sinoatrial node, with reductions in cell numbers of such a degree48 49 that the capacity for chronotropic responses might possibly be impaired. Factors such as these could blunt end-organ responsiveness in the elderly and might have been the basis for the lower-than-expected heart rate responses to the stressors in the older men, given their high rates of cardiac norepinephrine spillover.
A clinical impetus for continuing interest in the influence of normal aging on sympathetic nervous system function and catecholamine metabolism has come in part from the recognition that in a range of cardiovascular disorders in which incidence rises markedly with age, activation of the sympathetic nervous system may be an important causal component.14 15 17 18 32 The extent to which aging influences neural stress responses is of particular interest because surges of sympathetic neural firing, either on wakening after overnight sleep5 or in relation to intense exercise in untrained people,6 have been proposed as a precipitating cause of myocardial infarction, and stress-induced activation of the cardiac sympathetic outflow has been implicated in the genesis of ventricular tachyarrhythmias and sudden cardiac death.14 15 18 We have provided evidence here for age-dependent changes in sympathetic nervous function, including diminished neuronal reuptake of norepinephrine, that could possibly be relevant in this context—doubly so because the protective influence of the vagus nerve against catecholamine-triggered ischemia-induced arrhythmias14 15 might be diminished in the elderly, in whom vagal tone is reduced.11 12 13 It should be noted, however, that although failure of transmitter inactivation at postjunctional receptors with aging would amplify the neural signal and in the presence of myocardial disease could trigger adverse stress-induced cardiovascular events, reduction of postsynaptic adrenergic responsiveness with aging might possibly protect against this. Our finding that in no case was the heart rate increase during stress greater in older men, despite their larger increases in cardiac norepinephrine spillover, may be illustrative of such a phenomenon, although, as indicated, mechanisms other than adrenergic subsensitivity may have been responsible for the smaller-than-expected tachycardia response.
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Acknowledgments |
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This study was supported by grant R01 AG-06537-07 from the United States Public Health Service, National Institute on Aging, and a National Health and Medical Research Council of Australia Institute grant to the Baker Medical Research Institute.
Received May 25, 1994; accepted August 19, 1994.
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