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(Circulation. 1997;96:238-245.)
© 1997 American Heart Association, Inc.

Articles

Effect of Sympathoinhibition on Exercise Performance in Patients With Heart Failure

Chim C. Lang, MD; Glenn H. Rayos, MD; Don B. Chomsky, MD; Alastair J. J. Wood, MD; ; John R. Wilson, MD

From the Division of Cardiology and Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to John R. Wilson, MD, Division of Cardiology, 315 MRB II, Vanderbilt University Medical Center, Nashville, TN 37232.

	Abstract

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Background In patients with heart failure, excessive sympathetic activation during exercise could interfere with exercise performance by impairing arteriolar dilation in working muscle and by adversely altering skeletal muscle metabolic behavior. To test this hypothesis, we examined the effect of sympathoinhibition with clonidine, a central sympatholytic agent, on skeletal muscle blood flow and metabolism in patients with heart failure.

Methods and Results Swan-Ganz and femoral venous catheters were inserted in 20 patients with chronic heart failure and exercise intolerance (peak exercise O₂=9.3±1.4 [SEM] mL·min^-1·kg^-1). Central hemodynamic measurements, leg blood flow determined by thermodilution, and systemic and leg metabolic parameters were measured during maximal treadmill exercise before and 2 hours after clonidine 2 µg/kg IV (n=15) or 0.9% normal saline (n=5). During control exercise before the administration of clonidine, leg blood flow increased from 0.3±0.1 to 1.8±0.2 L/min and plasma norepinephrine increased from 485±61 to 2155±186 pg/mL (both P<.01). Treatment with clonidine markedly suppressed norepinephrine levels during exercise (matched peak exercise workload: control, 2137±187 versus clonidine, 1430±161 pg/mL), increased leg blood flow (control, 1.8±0.2 versus clonidine, 2.3±0.4 L/min), reduced systemic oxygen consumption (control, 1002±70 versus clonidine, 966±68 mL/min), reduced pulmonary artery lactate concentration (control, 3.2±0.3 versus clonidine, 2.6±0.2 mEq/L), and decreased minute ventilation (control, 39.7±2.1 versus clonidine, 34.9±2.4 L/min) (all P<.05).

Conclusions These findings suggest that sympathetic activation during exercise reduces leg blood flow, increases muscle glycolysis, and decreases muscle efficiency in patients with heart failure.

Key Words: heart failure • catecholamines • clonidine • regional blood flow • exercise • muscles

	Introduction

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Exercise intolerance is a nearly universal problem in patients with heart failure. Maximal exercise capacity is reduced not only in symptomatic patients^{1 2} but also in many asymptomatic patients.³ Therefore, identification of the factors responsible for this exercise intolerance remains a major investigative objective.

One potential contributor to this exercise intolerance is activation of the sympathetic nervous system. In patients with heart failure, activation of the sympathetic nervous system is frequently excessive at rest, as evidenced by increased plasma levels of norepinephrine⁴ and increased peroneal nerve activity.⁵ Exercise triggers even more excessive activation, with plasma levels of norepinephrine markedly exceeding those noted in normal subjects at comparable workloads.^{6 7} These findings have led investigators to speculate that excessive sympathetic activation may contribute to exercise intolerance in heart failure.

Two potential mechanisms could mediate this effect. First, excessive sympathetic vasoconstriction could interfere with exercise capacity by impairing skeletal muscle arteriolar vasodilatation and limiting oxygen delivery to exercising muscle.^{8 9} Second, sympathetic activation could adversely affect muscle performance by altering muscle metabolic behavior; prior observations in experimental animals^{10 11 12} and in normal humans^{13 14} suggest that sympathetic activation has direct metabolic effects on working muscle. In experimental animals, exposure of muscle to - and ß-adrenergic agonists has been shown to increase muscle oxygen consumption, increase glycogenolysis, and increase muscle lactate production.¹⁰ Such effects could adversely affect muscle efficiency and impair performance in patients with heart failure.

The present study was undertaken to investigate the effect of sympathetic activation on skeletal muscle blood flow and metabolism in patients with heart failure. To this end, respiratory gases, central hemodynamic measurements, thermodilution leg blood flow, and lactate concentration were measured before and after administration of intravenous clonidine, an ₂-adrenergic agonist that decreases sympathetic activity via a central effect.¹⁵

	Methods

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Study Population
Twenty patients (mean age, 54±4 years) with chronic left ventricular dysfunction (left ventricular ejection fraction, 22±2% [SEM]) were studied. All patients had exertional breathlessness or fatigue, or both, despite therapy with ACE inhibitors, digoxin, and diuretic drugs, and all were classified in New York Heart Association functional class III to IV. None had peripheral edema, ascites, angina pectoris, intermittent claudication, or reduced pulses in their legs at the time of the study. Before enrollment in this study, all patients had received optimal diuretics and showed no evidence of fluid retention. Left ventricular dysfunction was attributed to coronary artery disease in 14 patients and to idiopathic dilated cardiomyopathy in 6. No patient had received any vasodilator therapy for at least 48 hours. The protocol was approved by the Institutional Review Board of Vanderbilt University. Written informed consent was obtained from all subjects.

Protocol
Fifteen patients performed maximal treadmill exercise before and after intravenous clonidine. To ensure reproducibility of exercise measurements, 5 additional patients underwent repeat studies after infusion of the equivalent volume of vehicle (0.9% sodium chloride solution) used to administer clonidine. The clonidine or saline infusion was administered in single-blind randomized fashion.

On the day of the study, patients arrived in the morning at the catheterization procedure laboratory of the Vanderbilt University Heart Failure Program, having fasted overnight. A 7F Swan-Ganz thermodilution catheter was inserted percutaneously through an internal jugular vein and positioned in the pulmonary artery. A 5F thermodilution catheter was inserted percutaneously into the left femoral vein and advanced to 15 to 16 cm anterograde into the iliac vein.

Thirty minutes after instrumentation, supine central hemodynamic measurements were obtained, including pulmonary artery pressure, right atrial pressure, and pulmonary capillary wedge pressure. Blood pressure was measured by a sphygmomanometer. Supine cardiac output was also determined by thermodilution, in triplicate. Blood samples were drawn from the pulmonary artery for measurement of plasma norepinephrine, hemoglobin O₂ saturation, and lactate concentration. Supine femoral vein flow was also determined by thermodilution, and femoral vein blood samples were obtained for measurement of mixed venous O₂ saturation and lactate concentration.

Patients then stood up on the treadmill, and after a 5-minute equilibration period, gas exchange analysis was performed with the patient breathing into a disposable pneumotac, with his or her nose clamped, with a Medgraphics Cardio O₂ combined VO₂/ECG Exercise System (Medical Graphics Corp). The patient's left index finger was also attached to a pulse oximeter to continuously monitor arterial hemoglobin O₂ saturation.

The patient then performed symptom-limited maximum exercise on the treadmill following a modified Naughton protocol. At each workload, the patient was asked to rate the level of dyspnea and leg fatigue on the Borg scale.¹⁶ This scale rates the level of perceived symptoms on a scale of 6 (none) to 20 (severe). All patients continued exercising until symptoms of dyspnea or fatigue, or both, forced them to stop. During each 3-minute exercise stage, leg flow was measured starting at 45 seconds with a total of at least three measurements. The average of these measurements was then taken as the mean flow for the exercise stage. Central hemodynamic measurements and respiratory gas exchange analysis were recorded simultaneously. Blood from both pulmonary artery and femoral vein was sampled during the last 45 seconds of the stage.

After exercise was terminated, patients were allowed to rest for 2 hours. After 1 hour of rest, patients received either clonidine (Catapres, Boehringer Ingelheim) 1 µg/kg in 0.9% sodium chloride solution (n=15) or 0.9% sodium chloride solution alone (placebo, n=5) by slow intravenous infusion over 10 minutes, followed in the clonidine group by an additional 1 µg/kg clonidine over 10 minutes. If the supine systolic blood pressure decreased by 30 mm Hg or the diastolic blood pressure by 15 mm Hg, the second dose of clonidine was not given.

Two hours after the control exercise study, the patients repeated the exercise protocol. Hemodynamic and metabolic measurements were made at the same times as in the control study. If a patient exercised longer after drug administration, measurements were also made at the new maximum exercise level.

Leg Blood Flow Measurements
Leg blood flow was determined by the thermodilution method described by Jorfeldt and Wabren.¹⁷ In brief, femoral vein flow was measured with a 50-cm, 5F thermodilution catheter with the thermistor at 2 cm and injection port 12 cm from the tip. Flow was determined by rapid injection of a 3-mL iced dextrose bolus with the aid of a commercially available thermodilution computer (Baxter Vigilance Monitor, Baxter Healthcare Corp). Output curves were displayed on a screen to ensure exponential decay. Jorfeldt and Wabren demonstrated that femoral venous flow measured by this technique agrees closely with leg flow determined by injection of indocyanine green into the femoral artery with sampling from the femoral vein. Leg blood flow was not measured in three of the patients randomized to clonidine because of technical difficulties.

Measured Variables
Hemoglobin concentration was measured by a Coulter counter; hemoglobin O₂ saturation was measured with a co-oximeter precalibrated with human blood. Blood O₂ content was calculated as the product of hemoglobin, 1.34 mL O₂/g hemoglobin, and percent O₂ saturation. Blood for lactate determination was deproteinized with cold perchloric acid and assayed with a spectrophotometric technique.¹⁸ Normal resting values for this technique in our laboratory are 3 to 12 mg/dL. Blood for norepinephrine determination was collected in cooled tubes with EGTA and centrifuged at 3000 rpm at 4°C, and the plasma was stored at -70°C until assayed. Norepinephrine concentrations were measured by high-performance liquid chromatography with electrochemical detection.¹⁹ The intraday and interday coefficients of variation were 7.8% and 7.6%, respectively.

Derived Variables
Systemic vascular resistance was calculated as (mean arterial pressure minus right atrial pressure) divided by cardiac output. Resting supine cardiac outputs were obtained by thermodilution, and exercise cardiac outputs were determined by the Fick principle. Leg vascular resistance was calculated as (mean arterial pressure minus femoral venous pressure) divided by leg flow. The respiratory gas exchange ratio was determined as CO₂/O₂.

Reproducibility
The period between exercise tests was 2 hours. To ensure that exercise results were reproducible when repeated at this interval, 5 patients were randomized to receive 0.9% sodium chloride. At peak exercise, the following key measurements were found to be reproducible (first versus second exercise): exercise duration (13.8±1.2 versus 14.2±1.4 minutes), mean arterial pressure (93±2 versus 95±1 mm Hg), cardiac output (6.8±0.7 versus 7.3±0.7 L/min), systemic maximum O₂ (1126±87 versus 1151±124 mL/min), leg blood flow (2.24±0.44 versus 2.14±0.31 L/min), leg O₂ (376±62 versus 366±27 mL/min), and femoral venous lactate concentration (3.9±1.0 versus 3.6±1.3 mEq/L).

Statistical Analysis
Values are presented as mean±SEM. The effect of clonidine on three distinct physiological issues was analyzed. First, the effects of clonidine on supine resting variables were compared before and after clonidine by paired Student's t test. Second, the effect of clonidine during exertion was evaluated. Individual study patients exercised for different lengths of time and therefore generated different numbers of exercise measurements. To permit comparison of patients regardless of exercise duration, a modified "area-under-the-curve analysis" was used. Specifically, all exercise measurements made during control exercise in a patient were added together to yield a composite value. For example, in a patient who exercised for 9 minutes, cardiac outputs measured at 3 minutes (load 1), 6 minutes (load 2), and 9 minutes (load 3) were added together. Measurements made at the same time periods after clonidine were similarly combined to yield a treatment composite score. Composite scores for the entire study population were then compared before and after clonidine by paired Student's t test. Third, maximal exercise values were compared by paired Student's t test. A two-tailed value of P<.05 was considered statistically significant.

	Results

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Control Exercise
Before clonidine, resting plasma norepinephrine was elevated (485±61 pg/mL, P<.05) compared with a group of 10 normal subjects 57±6 years old (243±36 pg/mL).²⁰ Pulmonary wedge pressure was elevated at 19±2 mm Hg, whereas the cardiac index was decreased at 2.0±0.1 L·min^-1·m^-2.

During control exercise, patients exercised for 13.0±1.3 minutes to a markedly reduced peak O₂ level of 1002±70 mL/min (12.5±0.9 mL·min^-1·kg^-1) and were limited by progressive dyspnea and fatigue. Exercise was associated with an impaired cardiac output response to exercise, markedly elevated pulmonary pressures, and an early increase in lactate (Figs 1 through 3). In all patients, treadmill exercise increased leg blood flow and decreased leg vascular resistance (Fig 4). There was also a sharp rise in plasma norepinephrine (Fig 5).

View larger version (18K): [in this window] [in a new window]   Figure 1. Effects of clonidine on systemic hemodynamics during exercise in patients with heart failure. HR indicates heart rate; MAP, mean arterial pressure; SVR, systemic vascular resistance; CO, cardiac output; STD, SD; and Ex1, Ex2, and Ex3, first, second, and third measurements during exercise. P values refer to comparison of total exercise responses, not individual data points.

View larger version (15K): [in this window] [in a new window]   Figure 2. Effects of clonidine on right atrial and pulmonary pressures during exercise in patients with heart failure. RAP indicates right atrial pressure; PAP, pulmonary artery pressure; and PCWP, pulmonary capillary wedge pressure. Other abbreviations as in Fig 1. P values refer to comparison of total exercise responses, not individual data points.

View larger version (18K): [in this window] [in a new window]   Figure 3. Effects of clonidine on O2, ventilatory levels, and mixed venous lactate concentration during exercise in heart failure patients. RER indicates respiratory exchange ratio. Other abbreviations as in Fig 1. P values refer to comparison of total exercise responses, not individual data points.

View larger version (20K): [in this window] [in a new window]   Figure 4. Effects of clonidine on leg hemodynamics and metabolic variables during exercise in heart failure patients. LVR indicates leg vascular resistance. Other abbreviations as in Fig 1. P values refer to comparison of total exercise responses, not individual data points.

View larger version (14K): [in this window] [in a new window]   Figure 5. Effects of clonidine on plasma norepinephrine during exercise in heart failure patients. Abbreviations as in previous figures. P values refer to comparison of total exercise responses, not individual data points.

Effects of Clonidine
At Rest
The effects of clonidine on resting systemic and regional variables are summarized in Tables 1 and 2. All patients tolerated the intravenous clonidine without adverse effects. Clonidine decreased supine plasma norepinephrine from 485±61 to 299±46 pg/mL (P<.05). This was accompanied by a decrease in mean arterial pressure from 84±3 to 75±2 mm Hg (P<.01, Table 1). Cardiac output was not significantly altered by clonidine (3.2±0.5 versus 3.1±0.5 L/min). Clonidine decreased both pulmonary artery pressure (P=.06) and pulmonary capillary wedge pressure (P<.05). Resting leg blood flow and leg vascular resistance were not altered by clonidine.

View this table: [in this window] [in a new window]   Table 1. Effects of Clonidine 2 µg/kg IV on Hemodynamic Measurements, Plasma Norepinephrine Levels, and Ventilatory and Metabolic Variables in 15 Patients With Heart Failure

View this table: [in this window] [in a new window]   Table 2. Effects of Clonidine 2 µg/kg IV on Resting Supine and Exercise Leg Hemodynamic and Metabolic Variables in Patients With Heart Failure

During Exercise
Treatment with clonidine markedly suppressed norepinephrine levels during exercise (Table 1 and Fig 5). This was associated with increased leg blood flow during exercise (P<.05) and reduced leg vascular resistance (P<.01, Table 2 and Fig 4). These peripheral hemodynamic changes were accompanied by reduced femoral venous lactate concentration and higher femoral venous O₂ saturation (Table 2 and Fig 4). Mixed venous lactate concentration sampled from the distal pulmonary artery was also significantly reduced by clonidine (Table 1 and Fig 3). This was associated with reductions in both the respiratory gas exchange ratio and ventilatory levels (Table 1 and Fig 4). Systemic O₂ was significantly lowered by clonidine throughout exercise (Table 1 and Fig 4), although the maximal systemic O₂ was unchanged (from 1002±70 to 993±66 mL/min).

There were also marked changes in central hemodynamic measurements (Table 1, Figs 1 and 2). Heart rate and mean arterial pressure were decreased by clonidine. Both pulmonary artery pressure and pulmonary wedge pressure were decreased, whereas the cardiac output and systemic vascular resistance were unchanged.

Exercise duration was unchanged (13.0±1.3 versus 13.5±1.1 minutes, control versus clonidine), as were Borg symptom scores (results not shown). Three patients exercised further after clonidine.

	Discussion

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Exercise intolerance is a widespread clinical problem in patients with heart failure.^{1 2 3} During maximal exercise testing, maximal exercise O₂ is usually reduced and is associated with increased muscle lactate release, excessive ventilatory levels, and frequently but not always, reduced leg blood flow.²¹

The purpose of this study was to determine whether excessive sympathetic activation contributes to these metabolic and flow abnormalities. Excessive sympathetic activation could limit skeletal muscle blood flow by impairing arteriolar vasodilation in working muscle.^{8 9} Sympathetic activation could also impair muscle performance by directly altering muscle metabolic behavior.^{10 11 12 13 14} Richter et al,¹⁰ for example, found that infusion of epinephrine into the perfused rat hindquarter increased muscle oxygen uptake and lactate release both at rest and during electrical stimulation at 60 Hz. During stimulation, oxygen uptake and lactate release increased 30%; the effect on oxygen uptake was abolished by -adrenergic blockade, whereas the effect on lactate release was abolished by combined - and ß-blockade. Stainsby et al^{11 12} observed similar responses in the contracting gastrocnemius-plantaris muscle of the dog during infusion of epinephrine and of norepinephrine. Jansson et al¹³ observed that infusion of epinephrine into the femoral artery of normal subjects increased leg lactate release, whereas Hartling and Trap-Jensen¹⁴ noted that infusion of isoproterenol into the forearm of normal subjects increased forearm lactate release.

We previously tried to investigate the effect of sympathetic activation on exercise performance in heart failure by studying patients before and after adrenergic blockade either with prazosin or with injection of phentolamine into the femoral artery.²² Prazosin increased the cardiac output and decreased the pulmonary wedge pressure during exercise but had no significant effect on leg blood flow or muscle lactate release. Systemic blood pressure was markedly reduced, leading to concerns that a baroreflex-mediated increase in sympathetic activation might have been triggered and that this increase in sympathetic activity could have counteracted any beneficial regional effect of prazosin on working muscle. Phentolamine had no effect on leg blood flow but significantly decreased systemic lactate levels during exercise, suggesting that phentolamine might have altered muscle metabolic behavior.

Adrenergic blockade with prazosin in heart failure has been studied in several randomized, long-term trials. No demonstrable long-term effects on mortality and exercise performance were noted.²³ However, other studies have shown an extremely high incidence of tolerance in patients receiving chronic prazosin therapy,^{24 25} making interpretation of randomized long-term trials problematic.

To further clarify the effect of sympathetic activation on exercise behavior in heart failure, we examined the acute effect of clonidine on systemic and leg circulatory and metabolic responses in patients with chronic heart failure. Clonidine is a central ₂-adrenergic receptor agonist that acts primarily by reducing sympathetic outflow from the central nervous system.¹⁵ This agent has major advantages over prazosin, because baroreflex-mediated increases in sympathetic outflow are unlikely to occur with this intervention.

In this study, administration of clonidine produced sustained decreases in plasma norepinephrine levels both at rest and during exertion. Before clonidine administration, resting norepinephrine levels were markedly elevated. Systemic and regional tritiated norepinephrine kinetics studies have shown that this increased level of plasma norepinephrine results from both increased norepinephrine spillover and decreased clearance of norepinephrine from the plasma.²⁶ Increased sympathetic activity has recently been confirmed by peroneal nerve recordings of sympathetic nerve traffic in heart failure.⁵ As in previous studies,^{27 28} clonidine treatment was associated with marked sympathoinhibition, reflected by a reduction in plasma norepinephrine to levels (299 pg/mL) comparable to those in plasma obtained from a group of matched healthy control subjects of similar age from a previous study (243 pg/mL).²⁰

This degree of sympathoinhibition resulted in substantial hemodynamic effects, including a decrease in blood pressure, decrease in pulmonary wedge pressure, and increase in leg blood flow. The decrease in pulmonary capillary wedge pressure is consistent with animal studies by Nayler et al²⁹ and observations in humans^{27 28} suggesting that clonidine also reduces venous tone and, consequently, cardiac preload. Heart rate diminished in conjunction with a drop in systemic arterial pressure. Although this was most likely due to a reduction in sympathetic output, it may be related in part to heightened parasympathetic activity, because clonidine appears to exert some parasympathetic effects.³⁰ Overall, these findings serve to reinforce prior observations indicating that activation of the sympathetic nervous system is an important mechanism in heart failure for sustaining resting arterial blood pressure.

Of greater interest, however, were the changes during exercise. During control exercise, norepinephrine levels were markedly elevated compared with levels previously reported in normal subjects.^{6 7} Clonidine decreased plasma norepinephrine by 40% throughout exercise. This sympathoinhibition was associated with an increase in leg blood flow and a decrease in leg vascular resistance. Cardiac output during exercise did not change, however, suggesting that clonidine redistributed blood flow to the legs during exercise.

These hemodynamic changes were accompanied by several key metabolic and ventilatory changes. Compared with measurements made at identical exercise loads, systemic oxygen consumption and pulmonary artery lactate were reduced after clonidine administration. Pulmonary artery lactate during exercise is determined primarily by the total amount of lactate released from working muscle. Therefore, a reduction in this variable suggests reduced skeletal muscle lactate release. Ventilatory levels and the respiratory gas exchange ratio were also decreased after clonidine administration, probably because of the reduction in lactate release during exercise.

The decreases in systemic oxygen consumption at a given workload are consistent with the previous experimental studies suggesting that catecholamines increase muscle oxygen consumption.^{10 11 12 13 14 15} The decrease in lactate release may also be due to inhibition of catecholamine-induced muscle glycolytic activity. Alternatively, lactate release may have decreased because of improved muscle oxygen delivery, a conclusion supported by the observation that leg blood flow increased after clonidine administration. However, it should be emphasized that an increase in leg blood flow does not necessarily indicate improved muscle oxygen delivery. The increased flow may have been directed to the skin or to nonworking skeletal muscle. The fact that clonidine also decreased femoral venous hemoglobin O₂ saturation and femoral venous lactate concentration also does not necessarily indicate improved muscle oxygen delivery. These changes could be due to a dilutional effect resulting from increased nonmuscle flow.

Despite changes in lactate, leg blood flow, and ventilatory levels during exercise, maximal exercise O₂ and exercise duration were unchanged after clonidine administration. This is typical of previous studies in which apparently beneficial metabolic changes were not accompanied by improved exercise performance. For example, previous studies have demonstrated that dobutamine and hydralazine can increase cardiac output and leg blood flow during exercise in patients with heart failure but that these changes do not improve maximal exercise performance.^{31 32} The reason for this apparent dissociation between exercise performance, flow, and metabolic effects remains to be clarified. One attractive hypothesis is that flow improvements produce beneficial intramuscular changes, such as alterations in protein or mitochondrial levels, that take time to develop. Thus, although acute changes in oxygen delivery may not improve exercise performance, chronic increases in flow may have a beneficial effect.

This hypothesis is consistent with the general observation that agents such as ACE inhibitors must be administered for several weeks before beneficial effects on exercise performance are noted.³³ These beneficial effects are associated with increased leg flow, suggesting that they are mediated by flow alterations.³³ However, one cannot exclude the possibility that ACE inhibitors work by other mechanisms. For example, such agents could potentially change lung compliance and thereby allow a patient to become more active and reverse muscle deconditioning.

Limitations of the Study
This study has a number of limitations. First, the use of skeletal muscle glycolysis as a indirect marker of muscle oxygenation is supported by previous observations that reducing muscle blood flow augments glycolysis.³⁴ However, glycolysis also occurs normally in well-oxygenated working muscle and is affected by pH and substrate availability.³⁵ We cannot totally exclude the possibility that changes in these other variables may have affected our results.

Second, leg blood flow was determined by measurement of femoral venous flow with a thermodilution technique. This technique provides useful information about directional changes in total leg flow but does not provide information about flow distribution and probably does not yield extremely precise quantitative information. Femoral vein flow during exercise is influenced by the degree of muscle contraction in the leg when the bolus of saline is injected. If injection occurs when leg muscles are contracting, the venous pump sends a higher flow to the femoral vein than when leg muscles are not contracting. Veins entering the femoral vein also influence mixing of the bolus and alter flow measurements. Despite these limitations, the thermodilution method is widely regarded as the optimal method for measuring volumetric blood flow to an exercising limb.³⁶

Clinical Implications
The present study suggests that excessive sympathetic activation during exercise in patients with heart failure has several potentially harmful effects. This activation appears to reduce leg blood flow and augment muscle glycolysis and muscle oxygen consumption. In addition, sympathetic activation appears to increase pulmonary wedge pressures during exercise, an effect that could impair lung compliance. These findings in turn suggest that long-term administration of sympatholytic agents such as clonidine may be useful in the treatment of exercise intolerance in heart failure. Long-term studies should be undertaken to test the clinical utility of this approach.

	Acknowledgments

 
This study was supported by grant RO-1-HL-53059 from the National Institutes of Health and a Grant-in-Aid from the American Heart Association National Center. Dr Lang was a recipient of a Merck International Fellowship in Clinical Pharmacology. We are grateful to Dr C.M. Stein for his advice and to H.B. He and P. Gothard for their technical assistance.

Received October 31, 1996; revision received January 7, 1997; accepted January 17, 1997.

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