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Division of Cardiology, Toronto General and Mount Sinai Hospitals, University of Toronto, Toronto, Ontario M5G 1X5, Canada
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Peak oxygen uptake
(
O2 peak) in patients with heart
failure (HF) is inversely related to muscle sympathetic nerve activity
(MSNA) at rest. We hypothesized that the MSNA response to handgrip
exercise is augmented in HF patients and is greatest in those with low
O2 peak. We studied 14 HF patients and
10 age-matched normal subjects during isometric [30% of maximal voluntary contraction (MVC)] and isotonic (10%, 30%, and 50% MVC) handgrip exercise that was followed by 2 min of posthandgrip
ischemia (PHGI). MSNA was significantly increased during
exercise in HF but not normal subjects. Both MSNA and HF levels
remained significantly elevated during PHGI after 30% isometric and
50% isotonic handgrip in HF but not normal subjects. HF patients with
lower O2 peak (<56% predicted;
n = 8) had significantly higher MSNA during rest and
exercise than patients with
O2 peak > 56% predicted (n = 6) and normal subjects. The muscle metaboreflex
contributes to the greater reflex increase in MSNA during
ischemic or intense nonischemic exercise in HF. This
occurs at a lower threshold than normal and is a function of
O2 peak.
muscle sympathetic nerve activity; metaboreflex; O2 peak; left ventricular dysfunction; ischemia
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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SYMPTOMATIC HEART FAILURE due to left ventricular systolic dysfunction is characterized by limited exercise capacity, impaired peripheral vasodilation, and increases in central sympathetic outflow to hemodynamically important vascular beds (4, 16, 20, 28, 31). Plasma norepinephrine levels and cardiac norepinephrine spillover are increased in asymptomatic left ventricular dysfunction, are further increased in patients with severe heart failure (HF) (24), and are associated with poor prognosis (1, 9).
Several reflex mechanisms may contribute to sympathetic activation in HF (5). One of these is the muscle metaboreflex (18, 27, 29, 30), which in healthy young subjects matches blood flow and metabolism in exercising muscle (23). In animal models this reflex is activated by muscle ischemia (26). In experimental HF, which lowers the threshold for ischemia, the metaboreflex is evoked at moderate workloads (6). Whether this occurs in human HF is controversial; an overactive metaboreflex (18, 19, 29), an intact but ineffective metaboreflex (in that the resulting improvement in perfusion pressure did not enhance either muscle blood flow or oxidative metabolism) (27), and a desensitized metaboreflex (30) have all been described.
There have been no reports comparing sympathetic nerve traffic to muscle in HF and healthy subjects across a range of submaximal work rates under both rhythmic nonischemic (isotonic) and ischemic (isometric) conditions. If present, activation of the muscle metaboreflex at a lower threshold in HF patients could have two important implications: 1) comparisons under resting conditions would underestimate the magnitude and pathophysiological consequences of sympathetic activation (5), and 2) augmented neurogenic vasoconstriction during activity might further compromise exercise capacity (16, 27, 28).
We recently identified a significant inverse relationship between sympathetic outflow to calf skeletal muscle (measured at rest) and exercise capacity in HF patients. This relationship was absent in healthy controls (16). This finding is consistent with the concept that increased sympathetic outflow contributes to active muscle hypoperfusion during exhaustive dynamic exercise in human HF (11, 28, 31) and supports the concept of a peripheral neurogenic limit to exercise in this condition.
The purpose of the present study was to examine systematically the effect of ischemic and rhythmic handgrip exercise at different intensities on muscle sympathetic nerve activity (MSNA) in HF and age-matched normal subjects. In addition, we determined whether the sympathoneural response to handgrip exercise is augmented further in those HF patients with markedly reduced exercise capacity. To relate such changes in sympathetic activity to the stimulus of ischemic metabolites generated locally during handgrip exercise, responses to posthandgrip ischemia (PHGI) were also examined (13). We hypothesized that: 1) sympathetic traffic to muscle during both isometric and rhythmic isotonic handgrip exercise would be greater in HF patients, 2) sympathetic activation would be detected at a lower intensity of isotonic exercise in HF, and 3) patients with mildly to moderately impaired exercise tolerance would display a sympathoneural response intermediate between that of age-matched healthy subjects and patients with severely reduced exercise capacity.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
HF patients.
We studied 14 stable patients (13 males and 1 female) aged 51.4 ± 3.7 (mean ± SE) yr with moderate to severe left ventricular systolic dysfunction (ejection fraction by radionuclide
ventriculography 19 ± 2%). Seven patients had ischemic
and seven had dilated cardiomyopathy. Within this population, 12 patients (86%) were taking angiotensin-converting enzyme inhibitors;
13 (92%) were taking diuretics; 10 (71%) were taking
1-adenoceptor blocking drugs; 8 (57%) were taking
digitalis; and 5 (36%) were taking anticoagulants. Clinical management
also included dietary sodium and fluid restriction. Patients were free of congestion, significant edema, or orthopnea.
Healthy subjects. We recruited and screened 10 healthy volunteers (9 males and 1 female, ages 48.0 ± 3.9 yr). None were taking medication.
This protocol was approved by the Human Subjects Review Committee of the University of Toronto. Informed written consent was obtained from each subject before participation.Procedures
All studies were performed while patients were supine in a quiet, temperature-controlled laboratory under similar conditions. Blood pressure was monitored from the left arm every minute by an automated device (Lifestat 200, Physio-Control; Redwood, WA) and heart rate was derived from lead II of the electrocardiogram. Signal output was to an ink recorder (2800S, Gould; Cleveland, OH) and a computer that used a LabView software platform (National Instruments; Austin, TX).Sympathetic nerve recordings. Multiunit recordings of postganglionic MSNA were obtained with a unipolar tungsten electrode inserted selectively into a muscle-nerve fascicle of the right or left peroneal nerve, posterior to the fibular head (16). MSNA was expressed as bursts per minute (burst frequency) and as integrated MSNA (burst frequency × burst amplitude).
Venous occlusion plethysmography. Resting blood flow in the left forearm (FBF) was determined by venous occlusion plethysmography (model 270A, Parks Electronics Laboratory; Beaverton, OR) using a Whitney mercury-in-Silastic strain gauge (8).
Exercise capacity.
Oxygen consumption at peak exercise
(O2 peak) was determined on a separate
day by open-circuit spirometry (Horizon MMC System or Vmax Series 229, Sensormedics) during a graded bicycle ergometer test (17 W/min)
performed until the pedal speed could no longer be maintained
and the respiratory exchange ratio
(CO2/O2) exceeded 1.1. Heart rate (Quinton; Seattle, WA) and blood pressure were
monitored throughout the test. O2 peak
was expressed as both milliliters per kilogram per minute and as a
percentage of predicted O2 peak,
accounting for age, sex, body weight, and height (16).
Protocol
For subject comfort, diuretics were withheld the morning of the microneurography study. After instrumentation and a 20-min stabilization period, 7-10 min of baseline values were obtained. The following tests were then performed in random order: sustained handgrip (isometric or ischemic exercise) at 30% MVC and rhythmic handgrip (isotonic or nonischemic exercise) at 10, 30, and 50% MVC. Two minutes of handgrip were followed by 2 min of PHGI. An upper-arm cuff was inflated to 200 mmHg to trap metabolites released by the muscle contraction and to dissociate the biochemical from the mechanical effects of muscle contraction. Variables were averaged for the 2-min baseline, each minute of handgrip, the 2 min of PHGI, and the subsequent 2 min of recovery. To assess the integrity of efferent sympathetic responsiveness to a nonmetaboreflex-mediated stimulus, one hand was immersed in ice water for 1.5 min. Subjects rested for 10-12 min between handgrip tasks until heart rate and blood pressure were observed to return to preexercise levels.Low O2 peak versus high
O2 peak.
The median for O2 peak in these HF
patients was 56% of that predicted by age, sex, and body size.
Patients were allocated to a high (n = 6) or low
(n = 8) O2 peak group,
depending on whether their values were above or below this median.
Statistical Analysis
Data are presented as means ± SE. Unpaired t-tests were performed to test for differences between group means. Two-way ANOVA with repeated measures (SigmaStat for Windows 1.0, Jandel Scientific; San Rafael, CA) was performed with groups (HF patients and normal subjects) and intervention (prehandgrip, 1- and 2-min handgrip, PHGI, and recovery) as the two factors. A post hoc Student-Newman-Keuls test was applied to assess the effects of specific interventions.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Comparison of HF and Normal Subjects
The two groups of subjects were similar in age, height, weight, resting heart rate, blood pressure, and resting forearm blood flow, which suggested optimal medical management of their HF (Table 1). However, HF patients had significantly higher resting sympathetic nerve burst frequency and burst incidence (P < 0.0001) and lowerO2 peak and percentage of predicted
O2 peak (P < 0.0001;
Table 1).
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Mean arterial blood pressure (MAP) at baseline and during handgrip
exercise was similar in both HF and normal subjects. In both groups,
MAP increased significantly during the second minute of 30%
ischemic and 50% isotonic handgrip and remained elevated during PHGI after isometric handgrip. In HF subjects only, 10% isotonic exercise elicited a significant increase in MAP that was
sustained during PHGI (P < 0.05; Fig.
1).
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Mean heart rates at baseline and during handgrip exercise were similar
in both groups. There were significant increases in heart rate during
the second minute of 30% isometric handgrip and the first and second
minutes of 50% rhythmic handgrip (P < 0.05). However,
in contrast to normal subjects, heart rate in HF patients did not
return to baseline values during PHGI after these two exercise tasks
(P < 0.05; Fig. 2).
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MSNA burst frequency was significantly greater in HF patients under all
experimental conditions (main effect of group, all P < 0.001; Fig. 3), and in contrast to normal
subjects, each of these exercise protocols evoked a significant
increase in MSNA above baseline (P < 0.05). Moreover,
in HF patients MSNA remained elevated during PHGI after both 30%
isometric and 50% isotonic handgrip (P < 0.05) and
during the recovery period after sustained handgrip exercise
(P < 0.05; Fig. 3).
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A similar pattern was noted for the integrated MSNA response in HF patients. Normal subjects demonstrated an increase in the integrated MSNA response to 50% isotonic handgrip (P < 0.05) and a nonsignificant trend toward higher integrated MSNA during the second minute of 30% isometric handgrip exercise. However, integrated MSNA during PHGI was elevated only in HF patients and only at the highest intensity of isotonic handgrip (P < 0.05).
The increase in heart rate and MSNA with the cold pressor test was similar in HF and normal subjects (+5.0 ± 1.3 beats/min and +11 ± 2.6 bursts/min; +5.5 ± 2.4 beats/min and +6 ± 2 bursts/min, respectively; P = 0.77 for heart rate, and P = 0.15 for MSNA). Both HF and normal subjects had a significant increase in MSNA burst frequency in response to the cold pressor test (HF: 53.6 ± 2.5 to 64.5 ± 3.0, P = 0.003; normal: 37.0 ± 2.2 to 42.8 ± 2.9, P = 0.014).
Influence of O2 peak
O2 peak values resulted in two groups
of similar age, body size, and blood pressure (Table
2). Mean heart rate was significantly higher in HF subjects with low O2 peak
(P = 0.03), even though seven of eight patients in this
group versus three of six patients in the
high-O2 peak group were receiving
-adrenoceptor antagonists. There was a trend, not significant,
toward lower FBF at rest in the
O2 peak < 56% group. MSNA burst
frequency at rest was significantly higher in the
low-O2 peak group (P = 0.007) whereas burst incidence was not.
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In contrast to healthy subjects, MSNA rose significantly above baseline
values during 30% isometric and 50% rhythmic handgrip exercise in
both HF patient groups, with burst frequency significantly higher in
the low O2 peak group. When
compared with both high O2 peak
patients and normal subjects, MSNA burst frequency was significantly
higher in low O2 peak patients at
baseline, during handgrip at all intensities, PHGI, and recovery (P = 0.0001; Fig. 4).
Results were similar for integrated MSNA except for 50% isotonic
handgrip, which showed only a nonsignificant trend toward higher values
in the low O2 peak group.
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Despite the profound reduction in ejection fraction in the high
O2 peak patients, with one exception
there was no significant difference in sympathetic activity between
this HF group and age-matched normal subjects. Burst frequency during the second minute of 30% isometric exercise was significantly lower in
control subjects (Fig. 4). The lowest intensity of exercise (10% of
rhythmic handrip) elicited a significant increase in MSNA from baseline
in patients with high O2 peak, but not low O2 peak or control subjects (Fig.
4).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The new findings of this study are the following: 1) in
HF, significant reflex increases in MSNA can be induced by
ischemic and nonischemic handgrip exercise at
intensities without effect on MSNA in age-matched subjects with normal
left ventricular function, even at intensities of rhythmic handgrip as
low as 10% MVC; 2) HF patients with low
O2 peak have consistently higher MSNA
during and after exercise, whereas patients with left ventricular systolic dysfunction and high O2 peak
display responses to handgrip that are either intermediate with respect
to the other two groups or virtually indistinguishable from normal
subjects; and 3) MSNA and heart rate remain elevated during
PHGI after both isometric exercise at 30% MVC and isotonic exercise at
50% MVC in HF but not normal subjects. Taken together, these
observations indicate that sympthoexcitatory reflexes arising from
exercising muscle are stimulated at a lower threshold in advanced HF
patients than in subjects with normal ventricular function and are
triggered by local ischemia during isometric and intense
rhythmic handgrip exercise.
Hemodynamic and sympathoneural responses to handgrip exercise. In healthy young (age <30 yr) volunteers, sustained handgrip at 30% MVC causes immediate increases in heart rate and blood pressure, whereas MSNA does not increase until the second minute of exercise (13). During forearm PHGI, heart rate returns to baseline whereas blood pressure and MSNA remain elevated. This sustained elevation in MSNA and blood pressure has been attributed to the muscle metaboreflex which is mediated via chemosensitive type III and type IV muscle afferents (13). Metabolites such as lactic acid, arachidonic acid products, and adenosine, which are generated by muscle contraction, can stimulate these nerve endings (2, 22). Infusion of adenosine into the brachial artery at a concentration without systemic effect causes a marked reflex increase in the rate of total body norepinephrine appearance into plasma (21). However, the role of endogenous adenosine in triggering the sympathetic pressor response to static exercise remains controversial (12).
Rhythmic handgrip, in contrast, whether at 10, 30, or 50% MVC, does not increase MSNA in healthy young volunteers, presumably because the intermittent muscle relaxation permits rapid washout of any ischemic metabolites that are generated (32). However, if washout is interrupted by occlusion of forearm venous return, 30% rhythmic handgrip does elicit a significant increase in MSNA (32). The MSNA response to isometric exercise is attenuated with age (15). This has been attributed in part to the higher baseline levels of MSNA that are characteristic of older subjects and are present in the middle-aged control group in the current study (see Ref. 8 for comparison). In young subjects with normal ventricular function, 30% isometric handgrip increases MSNA during the second minute of exercise (13). In the present study there was a trend toward higher MSNA during the second minute of 30% isometric handgrip, a finding that is consistent with that obtained by Stearns and colleagues (30) in a similar older but healthy group of subjects. Of the several tasks performed in the present series, only rhythmic exercise at 50% MVC increased integrated MSNA significantly in control subjects. In advanced HF, skeletal muscle metabolism is altered (14) and blood flow to small and large muscle groups is reduced at rest and during dynamic exercise (1, 10, 20, 33). Patients with the lowestO2 peak have the greatest
impairment in blood flow (33). As a consequence, low
levels of rhythmic handgrip exercise that are insufficient to elicit
sympathetic excitation in healthy subjects might induce
ischemia and trigger the muscle metaboreflex in patients with
HF due to systolic dysfunction. Indeed, in experimental canine HF, the
muscle metaboreflex is tonically active during moderate exercise, is
stimulated at a lower threshold, and raises blood pressure primarily by
means of reflex neurogenic vasoconstriction rather than through an
increase in cardiac output (6). However, there is
disagreement as to whether this reflex contributes to the increase in
resting adrenergic tone in human HF or becomes active and functionally
important during exercise (18, 19, 27, 29, 30).
Sterns and co-workers (30) observed similar increases in
MSNA (which was expressed as the percent change in total amplitude) in
response to static handgrip at 30% MVC in HF and control
subjects. MSNA rose further during PHGI in controls but
diminished in HF subjects. These authors concluded that the
metaboreceptor reflex is impaired in HF. In contrast, in a subsequent
report from the same laboratory, rhythmic handgrip (25% MVC) produced
greater percentage increases in integrated MSNA in HF than control
subjects. These were sustained during PHGI after fatiguing exercise in
the HF group only (29). Although the pressor response to
handgrip exercise in HF could be augmented further under
ischemic conditions, this did not improve limb perfusion or
muscle metabolism, two determinants of exercise capacity
(27).
In another study, the effects of 50% rhythmic handgrip exercise on
diastolic blood pressure, heart rate, and leg vascular resistance were
greater in HF than control subjects. Forearm training attenuated these
responses (18). There was a direct relation between the
muscle ergoreflex (metaboreflex) contribution to the ventilatory
response to handgrip and New York Heart Association class and an
inverse relationship with O2 peak
(19), suggesting a neural link among impaired exercise
capacity, exertional dyspnea, and an augmented ergoreceptor reflex in HF.
Differences in patient characteristics or experimental protocols may be
responsible for these discordant results. The present experiments were
undertaken to resolve these ambiguities by recording MSNA directly in
patients with HF due to left ventricular systolic dysfunction and in
age-matched healthy subjects during both isometric and rhythmic
handgrip exercise according to a similar timed protocol, including a
broad range of intensities of isotonic handgrip and the application of
PHGI. We hypothesized that compared with normal subjects, sympathetic
traffic to muscle in HF would be augmented during both isometric
handgrip and rhythmic handgrip exercises, and that this increase would
be maintained during PHGI after those exercise tasks that induced sympathoexcitation.
MSNA burst frequency was significantly higher in HF patients under all
experimental conditions, and in contrast to normal subjects, each of
these exercise protocols evoked a significant increase in MSNA above
baseline. This novel finding is consistent with the concept that HF
lowers the threshold to muscle ischemia and metaboreflex
stimulation during handgrip exercise. This concept is supported by
experimental evidence from a canine model of HF (6). It is
also concordant with the observation in human HF that the
metaboreflex-induced pressor response can be enhanced during
low-intensity prolonged rhythmic handgrip exercise if muscle blood flow
is constrained by the application of external positive pressure
(27). In the present study, MSNA in HF patients remained elevated during PHGI after both 30% isometric and the highest intensity (50% MVC) of isotonic handgrip exercise and during the recovery period after sustained handgrip. This suggests that these tasks reduced oxygen delivery to muscle to the point where the threshold for activation of the muscle metaboreflex was exceeded, resulting in the generation of sufficient ischemic metabolites to sustain this sympathetic activation even after the termination of
exercise. The return of MSNA to baseline values immediately after lower
intensities of rhythmic handgrip exercise would be anticipated if the
local concentration of ischemic metabolites generated by these
two tasks was less but still greater than in the control subjects with
normal ventricular function.
Heart rate responses to handgrip exercise. O'Leary (17) noted an increase in heart rate that was maintained in dogs given atropine during muscle ischemia after whole body exercise. Thus in the present study, decreased vagal tone in the HF group (3) might unmask underlying sympathetically induced increases in heart rate. Consistent with this concept and in contrast to control subjects, the heart rate of HF patients remained elevated during PHGI after both isometric exercise and isotonic exercise at 50% MVC. This additional novel finding suggests that the muscle metaboreflex has an important role in determining the heart rate response to exercise in human HF.
Impact of exercise capacity.
Controversy in the literature with respect to effects of handgrip
exercise and PHGI on MSNA may arise from differences in patient
characteristics. When compared with both high
O2 peak patients and normal subjects,
patients with low O2 peak had
consistently higher MSNA during and after exercise. This observation is
consistent with our recent demonstration of an inverse relationship between MSNA at rest and O2 peak in HF
(16).
O2 peak group was remarkably
similar to that in control subjects. However, MSNA increased
significantly from baseline during 30% isometric and 10% and 50%
rhythmic handgrip exercise. Thus an exaggerated sympathetic response to
exercise is present in HF even in patients without activation of MSNA
at rest and relatively preserved
O2 peak. Interestingly, the significant
increase in MSNA in response to 10% handgrip was confined to the high
O2 peak group, suggesting that
activation of the metaboreflex at very low levels of exercise might be
a characteristic of the early stages of HF, which is attenuated with
disease progression.
In subjects with normal ventricular function, physical conditioning has
no effect on MSNA at rest or in the response to handgrip exercise
(25). Furthermore, all subjects were exercised at a workload relative to their own maximum voluntary contraction. Therefore
it is unlikely that the observed differences between high
O2 peak and low
O2 peak patients are simply a result of
physical deconditioning.
The limitations of this study are the following. The present
experiments do not address the question as to whether an activated muscle metaboreflex at rest contributes to the marked increase in
adrenergic drive observed in patients with advanced HF. Because previous experiments in normal subjects demonstrated that the muscle
metaboreflex evokes parallel sympathetic activation to exercising and
nonexercising muscle (7), it was assumed that MSNA
measured in the peroneal nerve supplying calf muscle reflects sympathetic activation in the exercising forearm. These patients were
receiving medications that might affect baseline values and heart rate
responses to exercise. However, the present observations in treated
subjects avoid the adverse effects of drug withdrawal and are directly
relevant to the effect of exercise in optimally managed HF patients.
In conclusion, this study shows that the sympathetic response to
both isometric and rhythmic handgrip exercise of various intensities is
exaggerated in patients with HF compared with normal subjects.
Sympathetic activation is greatest in patients with low
O2 peak who have higher
resting, exercise, and recovery MSNA compared with patients with
higher O2 peak and normal subjects.
However, patients with higher O2 peak
also show a significant increase in MSNA in response to
ischemic and nonischemic handgrip exercise. Stimulation
of the muscle metaboreflex elicits an augmented MSNA and heart rate
response to ischemic or intense nonischemic exercise in
HF, which could further limit exercise capacity and accelerate disease
progression in such patients.
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ACKNOWLEDGEMENTS |
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This work is supported by the Heart and Stroke Foundation of Ontario Grants T-3054 and T-4050. J. S. Floras holds a Career Investigator Award from the Heart and Stroke Foundation of Ontario.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. S. Floras, 1614, 600 University Ave., Toronto, Ontario M5G 1X5, Canada (E-mail: john.floras{at}utoronto.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 10 August 2000; accepted in final form 18 October 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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) and normal subjects
(
). Pre, pre-HG; HG1 and HG2, first and second minutes,
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