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J Appl Physiol 81: 2571-2579, 1996;
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Journal of Applied Physiology
Vol. 81, No. 6, pp. 2571-2579, December 1996
EXERCISE AND MUSCLE

Muscular blood flow response to submaximal leg exercise in normal subjects and in patients with heart failure

Richard Isnard, Philippe Lechat, Hanna Kalotka, Hafida Chikr, Serge Fitoussi, Joseph Salloum, Jean-Louis Golmard, Daniel Thomas, and Michel Komajda

Service de Cardiologie et de Pharmacologie Clinique, Association Claude BernardCentre de Recherches Cardiologiques, Département de Biostatistiques et d'Informatique, Hôpital Pitié-Salpêtrière, and Institut Terrapharm 75013 Paris, France

ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES

ABSTRACT

Isnard, Richard, Philippe Lechat, Hanna Kalotka, Hafida Chikr, Serge Fitoussi, Joseph Salloum, Jean-Louis Golmard, Daniel Thomas, and Michel Komajda. Muscular blood flow response to submaximal leg exercise in normal subjects and in patients with heart failure. J. Appl. Physiol. 81(6): 2571-2579, 1996.---Blood flow to working skeletal muscle is usually reduced during exercise in patients with congestive heart failure. An intrinsic impairment of skeletal muscle vasodilatory capacity has been suspected as a mechanism of this muscle underperfusion during maximal exercise, but its role during submaximal exercise remains unclear. Therefore, we studied by transcutaneous Doppler ultrasonography the arterial blood flow in the common femoral artery at rest and during a submaximal bicycle exercise in 12 normal subjects and in 30 patients with heart failure. Leg blood flow was lower in patients than in control subjects at rest [0.29 ± 0.14 (SD) vs. 0.45 ± 0.14 l/min, P < 0.01], at absolute powers and at the same relative power (2.17 ± 1.06 vs. 4.39 ± 1.4 l/min, P < 0.001). Because mean arterial pressure was maintained, leg vascular resistance was higher in patients than in control subjects at rest (407 ± 187 vs. 247 ± 71 mmHg · l-1 · min, P < 0.01) and at the same relative power (73 ± 49 vs. 31 ± 13 mmHg · l-1 · min, P < 0.01) but not at absolute powers. Although the magnitude of increase in leg blood flow corrected for power was similar in both groups (31 ± 10 vs. 34 ± 10 ml · min-1 · W-1), the magnitude of decrease of leg vascular resistance corrected for power was higher in patients than in control subjects (5.9 ± 3.3 vs. 1.9 ± 0.94 mmHg · l-1 · min · W-1, P < 0.001). These results suggest that the ability of skeletal muscle vascular resistance to decrease is not impaired and that intrinsic vascular abnormalities do not limit vasodilator response to submaximal exercise in patients with heart failure.

congestive heart failure; vasodilation; oxygen consumption; Doppler ultrasonography

INTRODUCTION

EXERCISE INTOLERANCE, the most common complaint of patients with congestive heart failure (CHF), may be reported as dyspnea and muscular fatigue. The frequent dissociation between the hemodynamic parameters of left ventricular performance at rest and exercise capacity quantified by maximal oxygen uptake (4, 16) led to the concept that peripheral factors such as muscle perfusion and muscle metabolism play a key role in exercise limitation. Early skeletal muscle anaerobic metabolism has been reported as the most important limiting factor of exercise tolerance and has been shown to be due to reduced skeletal muscle perfusion (19, 21, 23, 25, 26) or to abnormalities of muscle oxidative metabolism (17, 18, 24). However, it is not clear whether reduced skeletal muscle perfusion is due essentially to an inadequate increase in cardiac output and a relative arterial hypotension during exercise or to an intrinsic impairment of skeletal muscle arteriolar vasodilation capacity.

Zelis et al. (30) first demonstrated impaired muscle vasodilation in patients with CHF after stimuli such as hyperemic vasodilation, exercise, or intra-arterial infusion of various vasodilators. More recent studies have shown an impairment of endothelium-dependent vasodilation in heart failure (8, 13). However, these findings were not confirmed by other studies, especially during exercise (2, 18, 24, 27), so that the question of an intrinsic impairment of muscle vasodilation during exercise remains open.

We hypothesized that if intrinsic abnormalities of muscle vasodilation contribute to muscle hypoperfusion during submaximal exercise, leg vascular resistance should decrease less in patients than in normal subjects. Until recently, measurements of leg blood flow during exercise were essentially performed with thermodilution catheters inserted in the femoral vein, but the use of these invasive techniques remains limited in clinical practice. The present study was therefore designed to compare the ability of skeletal muscle circulation to lower vascular resistance on submaximal exercise in both patients with CHF and normal subjects by a noninvasive approach.

METHODS

Patients. Thirty patients (26 men and 4 women, age 48 ± 11 yr, mean ± SD) with CHF were studied. All patients were in sinus rhythm and had left ventricular systolic dysfunction (ejection fraction 26 ± 10%, range 11-40%). Four patients were in the New York Heart Association functional Class I, seven were in Class II, 14 in Class III, and five in Class IV. Seven patients had coronary artery disease with no residual ischemia, and 23 had idiopathic dilated cardiomyopathy. All patients had stable heart failure conditions for at least 2 wk before the study, and none had peripheral edema. Fifteen patients were taking digoxin, and all patients were taking diuretics. All vasodilators (angiotensin-converting enzyme inhibitors and/or long-acting nitrates, calcium inhibitors) were stopped for at least 1 wk before the study in 20 patients. In 10 patients, withdrawal of vasodilators was not possible before the study, according to their primary physicians. In these patients, vasodilators were stopped 24 h before the study. Patients with a prior history of peripheral vascular disease were excluded.

Patients were compared with 12 normal subjects (9 men and 3 women) who received no medication and had normal physical examination and echocardiographic findings. The study protocol was approved by the Ethical Committee of Pitié-Salpêtrière Hospital, and informed consent was obtained from all patients and normal subjects before participation in the study.

Study design. All studies were performed in a quiet, temperature-controlled room (22-24°C). One to 7 days before the study, patients and controls underwent an upright graded bicycle exercise test with power increments of 20 W/2 min until exhaustion. Respiratory gas analysis was carried out with a Medical Graphics system, which was calibrated with standard gas of known concentration before each test. Expired gases were collected continuously during exercise. Oxygen uptake and carbon dioxide production were measured on a breath-by-breath basis, averaged at 15-s intervals and expressed in milliliters per kilogram per minute. Peak oxygen uptake was defined as the highest value of oxygen consumption obtained during the last 1-min period at the end of the test. Respiratory exchange ratio was calculated as carbon dioxide production/oxygen uptake.

The level of submaximal exercise was ~66% of the power of the preliminary maximal exercise. The submaximal exercise was performed in all patients in the morning, at least 2 h after a light breakfast. In a semisupine position, all patients performed a graded bicycle exercise starting at 20 W and with 3-min increments of 20 W to a submaximal exercise level as defined above. The exercise was performed on a bicycle ergometer with the subjects in a semisupine position to allow for the measurements of leg blood flow. Between each stage, the exercise was discontinued for 1 min for leg blood flow measurement purposes. Heart rate was continuously monitered by electrocardiography. Brachial artery blood pressure was measured in the right arm with the use of a mercury sphygmomanometer during the first 20 s after the end of each load increment, at the same time as the Doppler measurements. All the blood pressure measurements were performed by the same observer. Systolic arterial pressure was evaluated at phase 1 of Korotkoff sounds. Diastolic blood pressure was evaluated at phase 5 of Korotkoff sounds. The blood pressure measurements were rounded every 2 mmHg. Respiratory gas analysis was performed in a similar manner as during maximal exercise.

Measurements of arterial diameter and velocity time integral. Femoral artery imaging was performed with the use of a Kontron Sigma 1 ultrasound system connected to a 7.5-MHz duplex mechanical transducer. The transducer was applied to the common femoral artery below the inguinal ligament. An optimal image for vessel diameter measurements and Doppler angle determination was obtained by slightly moving the transducer until a longitudinal axis view demonstrating maximum vessel diameter was displayed; then the position of the transducer was marked on the skin. The cross-sectional area of the common femoral artery was obtained from its transverse diastolic diameter in two-dimensional mode, with the assumption that the area was a circle. The associated-pulse Doppler mode operated at 4-8 MHz. The Doppler sample volume was positioned across the common femoral artery 1 cm above its bifurcation. High-pass wall filters were set at 150 Hz. The ultrasound beam was angulated at the smallest possible angle from the artery axis and was <65° in all the cases. Doppler-shift spectra were automatically corrected for this angulation, using an on-screen cursor.

Doppler measurements were performed at rest and during the first 20 s after each exercise step during the 1-min rest period. Immediately after each exercise workload, patients and controls extended their legs, and the transducer was repositioned at the same place on the skin. The flow velocity curves were recorded on paper and on a videocassette recorder (Panasonic AG-6200), and then flow velocity time integrals (VTI) of maximal velocity were drawn on a digitizing tablet (Summagraphics). The diastolic reversed flow was subtracted from the forward flow, when it was present. The calculations were averaged over five consecutives cardiac cycles.

Derived variables. Arterial leg blood flow (l/min) was obtained by the following formula: diastolic femoral artery area (cm2) · VTI (cm) · heart rate beats/min · 1,000. In a subgroup of 20 patients and 10 normal subjects, we did not observe any significant changes in common femoral artery diameter between rest and exercise (Fig. 1). Thus we used the resting value of the diameter of the common femoral artery for all patients and normal subjects to calculate leg blood flow. Mean arterial pressure was calculated as the sum of diastolic arterial pressure plus one-third of the pulse pressure.
Fig. 1. Resting and exercise values of femoral arterial diameter in patients with chronic heart failure (CHF; open circle , n = 20) and in normal subjects (black-down-triangle , n = 10).
[View Larger Version of this Image (14K GIF file)]

Leg vascular resistance (mmHg · min · l-1) was calculated by the approximation of mean arterial pressure divided by leg blood flow. Leg vascular conductance (l · min-1 · mmHg-1) was calculated as the inverse of leg vascular resistance. Values of heart rate; oxygen uptake; systolic, diastolic, and mean arterial pressure; leg blood flow; and leg vascular resistance recorded at the same relative power were defined as the values obtained for each subject at the last level of submaximal exercise as defined above.

Reproducibility of measurements and comparison between Doppler ultrasonic and plethysmographic measurements of leg blood flow. In a preliminary experiment, we measured leg blood flow in six normal subjects who performed duplicate submaximal bicycle exercises separated by a 2-h rest period. Femoral arterial diameters and VTI were read in a blinded fashion by an independent observer. A coefficient of variation was defined as the ratio of the absolute difference of values measured during the first and the second test to the mean of the two values. The coefficient of variation was 2.7 ± 0.7% (SD) for common femoral arterial diameter; for leg blood flow, it was 9 ± 7% at rest, 13 ± 7% at 20 and 40 W, 10 ± 7% at 60 W, 12 ± 9% at 80 W, and 15 ± 11% at 100 W. The reproducibility of leg blood flow was assessed by the method of Bland and Altman (5) (Fig. 2).
Fig. 2. Graph shows reproducibility of Doppler measurements of common femoral artery blood-flow assessed by the Bland and Altman method. Horizontal lines correspond to mean of differences and the 2 SD above and below mean of differences between leg blood flow measured in the 2 tests (l/min).
[View Larger Version of this Image (17K GIF file)]

In another preliminary experiment, lower limb flow was determined by venous occlusion plethysmography in three control subjects and four patients to validate measurements of leg blood flow in the common femoral artery by Doppler ultrasonography. A double mercury-in-rubber strain gauge was calibrated and placed at the largest circumference of the calf and connected to a plethysmograph (Perivein, Janssen Scientific Instrument) (10, 28). The lower limb was elevated to an angle of 30° above the horizontal, and the cuff was placed on the lower part of the thigh. Rapid inflation to 50 mmHg was performed to prevent venous return. With the use of plethysmography and Doppler ultrasonography, lower limb flow was measured at rest and during peak hyperemic response after 5 min of arterial occlusion (Fig. 3). The correlation between the two techniques was 0.86 at rest (P < 0.02) and 0.81 (P < 0.05) during hyperemia.
Fig. 3. Scatterplots of leg blood flow determined by venous occlusion plethysmography on y-axis and common femoral artery blood flow determined by Doppler ultrasonography on x-axis in 3 control subjects and 4 patients at rest (black-triangle, r = 0.86, y = 5.2x + 1.2, P < 0.02) and during the peak hyperhemic response after 5 min of arterial occlusion (bullet , r = 0.81, y = 6.6x + 8.7, P < 0.05).
[View Larger Version of this Image (14K GIF file)]

Statistical analysis. Results are presented as means ± SD. Comparisons between the two groups for values recorded at rest and at the same relative power were made using an analysis of variance (ANOVA) procedure. Comparisons between the two groups during exercise at the absolute work levels were restricted to the 20 patients and the 12 normal subjects who reached 60 W, to compare the same number of subjects at 0, 20, 40, and 60 W. The analysis was performed using ANOVA for repeated measures. F-values for group, exercise, and interaction between group and exercise were given, and comparisons between the means were made with the Newman-Keuls test. To assess the relation between the resting values and the changes in leg vascular resistance during exercise, we used the Blomquist method (6) with the recommendations of Hayes (9). A P value <0.05 was considered significant.

RESULTS

There was no significant difference in age and weight between patients and normal subjects (48 ± 11 vs. 41 ± 7 yr and 70 ± 11 vs. 73 ± 13 kg). Peak VO2 was markedly depressed in patients compared with controls (16 ± 6 vs. 35 ± 6 ml · kg-1 · min-1, P < 0.001), but the peak respiratory exchange ratio was not significantly different in the two groups (1.09 ± 0.11 vs. 1.16 ± 0.11).

The achieved power during submaximal exercise was lower in patients than in control subjects (57 ± 18 vs. 118 ± 28 W, P < 0.001; Table 1). The number of patients and control subjects who completed each power stage is indicated in Fig. 4, bottom.

Table 1. Hemodynamic and ventilatory parameters at rest and at the same relative power in normal subjects and in patients

Rest
Submaximal Exercise
Normal Subjects Patients Normal Subjects Patients
Power, W 118 ± 28  57 ± 18dagger
Heart rate, bpm 66 ± 12  88 ± 17* 142 ± 11  129 ± 22 
 VO2, ml · kg-1 · min-1 2.9 ± 0.8  2.5 ± 0.9  24.7 ± 7.0  11.3 ± 4.7dagger
SAP, mmHg 125 ± 16  118 ± 21  192 ± 30  155 ± 35*
DAP, mmHg 90 ± 11  88 ± 12  100 ± 15  100 ± 16 
MAP, mmHg 102 ± 13  98 ± 14  130 ± 19  118 ± 21 
LBF, l/min 0.45 ± 0.15  0.29 ± 0.14* 4.39 ± 1.40  2.17 ± 1.06dagger
LVR, mmHg · l-1 · min 247 ± 71  407 ± 187* 31 ± 13  73 ± 49*
VO2, oxygen uptake; SAP, systolic arterial pressure; DPA, diastolic arterial pressure; MAP, mean arterial pressure; LBF, leg blood flow; LVR, leg vascular resistance; bpm, beats per min; n, 12 normal subjects, 30 patients. * P < 0.01; dagger P < 0.001, patients vs. normal subjects.

Fig. 4. Resting and exercise heart rate and oxygen uptake in patients with CHF (open circle , n = 30) and normal subjects (black-down-triangle , n = 12). bpm, Beats/min. Bottom: no. of patients (CHF) and normal subjects (N) who completed each level of power.
[View Larger Version of this Image (21K GIF file)]

Heart rate was significantly higher in CHF patients at rest and at absolute powers than in normal subjects but did not differ significantly at the same relative power (Tables 1 and 2, Fig. 4). Oxygen consumption was similar in both groups at rest and at absolute powers, but was lower in patients than in control subjects at the same relative power (Tables 1 and 2, Fig. 4).

Table 2. Hemodynamic and ventilatory parameters at rest and at absolute powers in normal subjects and in patients with congestive heart failure who reached the 60-W power

Subjects Rest 20 W 40 W 60 W F Group F Ex F Interact
Heart rate, beats/min
CHF 86 ± 16Dagger 103 ± 20Dagger 117 ± 19Dagger 128 ± 18Dagger 13.7 224 2.3
Normal 66 ± 12  85 ± 13  93 ± 16  103 ± 15  (0.008) (<0.001) NS
VO2, ml · kg-1 · min-1
CHF 2.7 ± 1.0  7.6 ± 2.3  11.5 ± 2.7  13.8 ± 3.4  0.8 179 0.9
Normal 2.9 ± 0.8  6.6 ± 1.8  10.2 ± 3.0  13.4 ± 3.8  NS (<0.001) NS
SAP, mmHg
CHF 123 ± 20  133 ± 17  144 ± 22  154 ± 24  0.11 60 2.3
Normal 125 ± 16  133 ± 20  141 ± 20  145 ± 23  NS (<0.001) NS
DAP, mmHg
CHF 90 ± 12  92 ± 12  96 ± 11  97 ± 10  0.26 5.6 0.9
Normal 90 ± 11  91 ± 12  93 ± 12  93 ± 14  NS (0.001) NS
MAP, mmHg
CHF 101 ± 13  106 ± 12  112 ± 14  116 ± 13  0.2 33.6 2.3
Normal 102 ± 13  105 ± 14  109 ± 13  111 ± 16  NS (<0.001) NS
LBF, l/min
CHF 0.29 ± 0.14  0.96 ± 0.48* 1.58 ± 0.67Dagger 2.09 ± 0.8dagger 5.9 148 1.7
Normal 0.45 ± 0.15  1.26 ± 0.43  2.14 ± 0.54  2.57 ± 0.57  (0.02)  (<0.001) NS
LVR, mmHg · l-1 · min
CHF 422 ± 175Dagger 144 ± 63  89 ± 38  68 ± 27  12 103 7.9
Normal 247 ± 71  98 ± 49  56 ± 17  46 ± 11  (0.001) (<0.001) (<0.001)
Values are means ± SD; P values in parentheses; NS, not significant. CHF, congestive heart failure subjects (n = 20); normal subjects, n = 12; F Group, F values for group; F Ex, F values for exercise; F Interact, F values for interaction between group and exercise. * P < 0.05; dagger P < 0.01; Dagger P < 0.001, normal subjects compared with CHF patients.

Systolic arterial pressure did not differ significantly in both groups at rest and absolute powers, but it was higher at the same relative power in normal subjects than in patients (Tables 1 and 2, Fig. 5). Diastolic and mean arterial pressures were not significantly different in the two groups at rest, at absolute powers, and at the same relative power (Tables 1 and 2, Fig. 5). No significant interaction between groups was observed for heart rate, oxygen consumption, and arterial pressure during exercise (Table 2).

Fig. 5. Resting and exercise systolic and diastolic arterial pressure (SAP and DAP, respectively), mean arterial pressure, resting and exercise leg blood flow, and leg vascular resistance in patients with CHF (open circle , n = 30) and in normal subjects (black-triangle, n = 12).
[View Larger Version of this Image (22K GIF file)]

Resting femoral arterial diameter and area were not significantly different in patients compared with normal subjects at rest (0.83 ± 0.13 vs. 0.91 ± 0.16 cm and 0.57 ± 0.17 vs. 0.68 ± 0.24 cm2, respectively).

The patterns of leg blood flow at rest and during exercise are indicated in Fig. 6. At rest, the blood flow velocity was characterized by an initial systolic forward flow velocity profile followed by an early diastolic flow reversal and later in diastole by a second phase of forward flow. During exercise, progressive changes in blood flow velocity profiles were characterized by an increase in peak and mean systolic forward velocity, by a disappearance of the early diastolic flow reversal, and by an increase in forward diastolic flow that continued until the end of the cardiac cycle. Qualitative changes in blood flow velocity profiles were identical in patients and normal subjects.

Fig. 6. Doppler flow velocity spectra measured at rest and during exercise (40 and 80 W) in the common femoral artery of a patient with heart failure.
[View Larger Version of this Image (97K GIF file)]

Leg blood flow was lower at rest, at absolute powers, and at the same relative power in patients with CHF (Tables 1 and 2, Fig. 5), but there was no significant interaction between groups during exercise (Table 2). Leg vascular resistance was increased at rest and at the same relative power in patients compared with control subjects (Table 1, Fig. 5). At the beginning of exercise, leg vascular resistance dropped dramatically in both groups (Fig. 5). Although leg vascular resistance tended to remain higher in patients, the difference between the two groups lost significance from the 20-W level, when the comparison was given at absolute powers (Table 2). However, there was a significant interaction between groups in the reduction of leg vascular resistance during exercise, which was steeper in patients (Table 2).

The absolute increase of leg blood flow from rest to the same relative power was lower in patients (Fig. 7), although it was similar in both groups when divided by the power (31 ± 10 vs. 34 ± 10 ml · min-1 · W-1; Fig. 7). Similarly, the absolute increase of leg vascular conductance was lower in patients (33 ± 16 vs. 15 ± 8 10-3 · l · min-1 · mmHg-1, P < 0.001) but was similar in both groups when normalized to the power (0.28 ± 0.10 vs. 0.26 ± 0.14 10-3 · l · min-1 · mmHg-1 · W-1, P = 0.72). In contrast, the absolute decrease in leg vascular resistance was higher in patients during exercise (Fig. 7), and the ratio of the magnitude of decrease in leg vascular resistance divided by power was much higher in patients than in control subjects (5.9 ± 3.3 vs. 1.9 ± 0.94 mmHg · l-1 · min · W-1, P < 0.001). Thus, for a given power, the decrease in leg vascular resistance was higher in patients than in control subjects, and the increase in leg vascular conductance was similar in both groups.

Fig. 7. A: changes in leg blood flow (LBF) and leg vascular resistance (LVR) between rest and the same relative power in CHF patients (hatched bars) and in normal subjects (open bars); * P < 0.05; *** P < 0.001. B: changes in LBF and LVR between rest and the same relative power, divided by the power in CHF patients (hatched bars) and normal subjects (open bars); *** P < 0.001.
[View Larger Version of this Image (24K GIF file)]

In addition, we found a significant correlation between the decrease in leg vascular resistance at the same relative power and leg vascular resistance at rest in patients (r = 0.96, P < 0.0001) and control subjects (r = 0.98, P < 0.0001), and the slope of this relation was identical in both groups (Fig. 8). After adjustment of this relation to take into account a possible regression towards the mean (19, 20), there was still a strong correlation in both groups (0.83 and 0.94, respectively). On the contrary, no correlation was found between leg blood flow at rest and change in leg blood flow during exercise, nor was there a correlation between mean arterial pressure at rest and change in mean arterial pressure during exercise.

Fig. 8. Plots of relation of resting LVR on x-axis and the maximal magnitude of decrease in LVR (dLVR) in CHF patients (open circle ) and in normal subjects (). r = 0.96, y = -1.01x - 68.9, and r = 0.98, y = -0.99x - 33.3, respectively; P < 0.0001.
[View Larger Version of this Image (15K GIF file)]

No difference was found in leg hemodynamic changes between patients with vasodilators and patients without vasodilators (Table 3) or between patients with ischemic heart disease and patients with dilated cardiomyopathy.

Table 3. Hemodynamic and ventilatory parameters at rest and at same relative power in patients with vasodilators and in patients without vasodilators

Rest
Submaximal Exercise
Patients with vasodilators Patients without vasodilators Patients with vasodilators Patients without vasodilators
Power, W 54 ± 19  59 ± 18 
Heart rate, beats/min 93 ± 12  86 ± 18  128 ± 28  129 ± 19 
 VO2, ml · kg-1 · min-1 2.2 ± 0.6  2.7 ± 1.1  10.9 ± 1.5  13.3 ± 2.1 
SAP, mmHg 114 ± 21  121 ± 21  155 ± 46  155 ± 29 
DAP, mmHg 84 ± 12  90 ± 12  99 ± 20  101 ± 14 
MAP, mmHg 93 ± 13  100 ± 14  117 ± 28  119 ± 17 
LBF, l/min 0.25 ± 0.15  0.31 ± 0.12  1.72 ± 0.96  2.4 ± 1.05 
LVR, mmHg · l-1 · min 491 ± 241  365 ± 141  93 ± 60  63 ± 41 
 Delta LBF, l/min 1.47 ± 0.96  2.09 ± 1.04 
 Delta LVR, mmHg · l-1 · min 398 ± 231  302 ± 140
Values are means ± SD. Delta LBF, change in leg blood flow; Delta LVR, change in leg vascular resistance. Patients with vasodilators (n = 10) vs. patients without vasodilators (n = 20), all values were not significantly different.

DISCUSSION

The present study demonstrates that in patients with heart failure 1) leg blood flow is lower at rest and during exercise than in normal subjects; 2) arterial pressure is maintained at the expense of higher leg vascular resistance at rest and at the same relative power; 3) however, the magnitude of the decrease of leg vascular resistance during submaximal exercise is higher in patients than in normal subjects.

The decrease of skeletal muscle perfusion during exercise in patients with heart failure remains controversial. Zelis et al. (30) first demonstrated that the increase in forearm blood flow during exercise and reactive hyperhemia with venous occlusive plethysmography is reduced in patients with CHF. As forearm exercise is unlikely to exhaust cardiac reserve or activate neurohormonal factors, the authors postulated the existence of an intrinsic impairment of muscle vasodilation (30). However, these results were not confirmed by others, who observed similar levels of forearm blood flow and vascular resistance at rest and during exercise in patients with heart failure and in control subjects (2, 18, 24, 27). Several factors can explain these discrepancies, including differences in heart failure severity and the presence or absence of peripheral edema.

We studied leg rather than forearm blood flow because exercise of the lower limbs involves a larger muscular mass and is likely to play a more important role in the exercise intolerance of patients with heart failure. Patients underwent an imposed submaximal exercise at the same relative power as normal subjects, since submaximal exercise is clinically more relevant than maximal exercise to patient tolerance of daily life activities. Unlike forearm blood flow, leg blood flow has always been found reduced both at rest and with exercise in patients with heart failure, whatever the techniques used (15, 21, 26), a finding consistent with our results. However, we did not find a significant interaction in the increase of leg blood flow during exercise between patients and controls. The discrepancy observed between upper and lower limb flow results may be due to a regional specificity related to differences in muscle deconditioning (12). Nevertheless, as opposed to forearm handgrip exercise, lower limb bicycle exercise causes a significant increase in cardiac output and may exhaust cardiac reserve. Therefore the mechanisms of reduced leg muscle perfusion during exercise may be related to an inadequate increase in cardiac output and arterial perfusion pressure, to an intrinsic impairment of muscle vasodilation capacity, or to both.

Unlike Wilson et al. (26), we did not find any reduction in mean arterial blood pressure during exercise in patients with heart failure. Our results are consistent with those of Sullivan et al. (21), who showed an even steeper slope of the relation between mean arterial pressure vs. work rate in patients than in control subjects during exercise. However, the maintenance of mean arterial pressure depends not only on leg vascular resistance during exercise but also on the contribution of the nonexercising circulations, which play a greater role as cardiac output response is decreased (29).

As reported in previous studies (21, 26), we observed higher leg vascular resistance in patients at rest and at the same relative power. However, there was a dramatic fall of leg vascular resistance (~60% of the resting values) in both groups from the onset of exercise, at a work rate unable to exhaust cardiac reserve. This fall was steeper in patients than in normal subjects, as assessed by the significant interaction between the two groups. During further levels of exercise, the decrease in leg vascular resistance became more gradual in both groups, and leg vascular resistance did not become significantly higher in patients at absolute powers. Moreover, for a given power, the magnitude of the decrease in leg vascular resistance was even greater in patients than in control subjects during submaximal exercise. When the results are expressed in vascular conductance, a similar increase for a given power was observed in both groups. We also observed a significant correlation between the decrease in leg vascular resistance during exercise and the level of leg vascular resistance at rest, in patients and in normal subjects, and the slope of this relation was similar in both groups. This relation remained significant after taking into account a possible regression toward the mean (6, 9). Thus, unexpectedly, the higher the leg vascular resistance at rest, the higher the decrease in leg vascular resistance during exercise. This finding suggests that a highly constricted muscle arteriole may be particularly sensitive to exercise-induced metabolic vasodilation. Consistent with previous studies by others of circulation in the forearm (2, 18, 24, 27) and in the leg (20), these data suggest that the ability of skeletal muscle vasculature to dilate is not intrinsically impaired during submaximal exercise in ambulatory patients with heart failure. Our results differ from those of LeJemtel et al. (15), but these authors studied patients with more severe chronic heart failure than ours and at peak exercise level. In our study, we cannot exclude a limited vasodilation capacity during maximal exercise.

The common femoral artery diameter was slightly smaller in patients than in normal subjects, a finding in agreement with previous studies (1), although the difference was not significant. No significant change of this diameter was observed during exercise in patients and normal subjects, but no data are available concerning the effect of exercise on the diameter of large muscular conduit arteries, such as the femoral artery.

Study limitations. Measurements of limb blood flow during exercise remain technically difficult, and the relative distribution of flow in the muscle vascular bed is impossible to assess, whatever the approach used (14). In preliminary experiments, we demonstrated the feasibility and accuracy of Doppler ultrasonic measurements of leg blood flow, although we did not study the reproducibility and validity of this technique during exercise in patients with heart failure. This noninvasive evaluation of leg blood flow has already been reported in several studies involving normal subjects and patients with intermittent claudication (11, 22). The variability of repeated measurements of arterial diameter and leg blood flow observed here was comparable to that reported by both noninvasive and invasive techniques at rest and during exercise (3, 7, 21, 26). Moreover, leg blood flow measured by Doppler ultrasonography and venous occlusion plethysmography at baseline and during reactive hyperhemia responses correlated closely, even if Doppler-derived flow was not normalized for muscle mass.

We did not measure muscle mass in the present study. Even though the weight of patients and normal subjects was similar in both groups, we cannot exclude a lower mass of limb muscle in patients. However, this would be unlikely to influence our conclusion, because in this case, leg vascular resistance of patients would be lower than our values. Flow measurements were performed in the immediate postexercise period at each power, and this probably led to underestimation of true exercise flow, even if all the measurements took place in the first 20 s after stopping exercise. However, all flow measurements were affected to the same extent, and this potential problem would therefore be unlikely to affect the interpretation. For the same reason, the unreliability of noninvasive blood pressure measurements during exercise might be reduced in this study, as they took place immediately after each exercise period. Indeed, the values of leg blood flow and leg vascular resistance measured in the present study at rest and during exercise were very similar to those reported by studies using thermodilution techniques (21, 26). As we did not observe any significant variation in arterial diameter in patients and normal subjects, we used the value of rest arterial diameter for the measurement of leg blood flow. However, it is possible that the resolution of a 7.5-MHz Doppler probe is not sufficient to detect very small changes in arterial diameter. Nevertheless, we can hypothesize that these changes could not significantly modify leg blood flow, which increased ~10-fold in both groups during this submaximal exercise. For the same reason, we determined arterial diameter in diastole.

In conclusion, our data indicate that in patients with CHF, leg blood flow is decreased at rest and during exercise, and arterial pressure is maintained at the expense of higher leg vascular resistance at rest and at the same relative power. However, the decrease of leg vascular resistance is higher in patients than in control subjects during submaximal exercise. Therefore these results suggest that the ability of skeletal muscle vascular resistance to decrease is not impaired and that intrinsic vascular abnormalities are unlikely to affect vasodilator response to submaximal exercise in patients with heart failure.

ACKNOWLEDGEMENTS

This study was supported by grants from the Fédération Française de Cardiologie and from the Association Française contre les Myopathies.

FOOTNOTES

Address for reprint requests: R. Isnard, Service de Cardiologie, Hôpital Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75013 Paris, France.

Received 15 April 1996; accepted in final form 2 August 1996.

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0161-7567/96 $5.00 Copyright © 1996 the American Physiological Society


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