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(Circulation. 1998;98:2709-2715.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Regular Physical Exercise Corrects Endothelial Dysfunction and Improves Exercise Capacity in Patients With Chronic Heart Failure
Presented in part at the 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 9–12, 1997 and published in abstract form (Circulation. 1997;96[suppl I]:I-638.)
From the University of Leipzig, Heart Center, Department of Internal Medicine/Cardiology, Leipzig, Germany.
Correspondence to Priv-Doz Dr med Rainer Hambrecht, Herzzentrum der Universität Leipzig, Klinik für Kardiologie Russenstr 19, 04289 Leipzig, Germany. E-mail hamr{at}server3.medizin.uni-leipzig.de
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Abstract |
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Background—The purpose of this study was to determine the effects of systemic exercise training on endothelium-mediated arteriolar vasodilation of the lower limb and its relation to exercise capacity in chronic heart failure (CHF). Endothelial dysfunction is a key feature of CHF, contributing to increased peripheral vasoconstriction and impaired exercise capacity. Local handgrip exercise has previously been shown to enhance endothelium-dependent vasodilation in conduit and resistance vessels in CHF.
Methods and Results—Twenty patients were prospectively randomized to a training group (n=10, left ventricular ejection fraction [LVEF] 24±4%) or a control group (n=10, LVEF 23±3%). At baseline and after 6 months, peak flow velocity was measured in the left femoral artery using a Doppler wire; vessel diameter was determined by quantitative angiography. Peripheral blood flow was calculated from average peak velocity (APV) and arterial cross-sectional area. After exercise training, nitroglycerin-induced endothelium-independent vasodilation remained unaltered (271% versus 281%, P=NS). Peripheral blood flow improved significantly in response to 90 µg/min acetylcholine by 203% (from 152±79 to 461±104 mL/min, P<0.05 versus control group) and the inhibiting effect of L-NMMA increased by 174% (from -46±25 to -126±19 mL/min, P<0.05 versus control group). Peak oxygen uptake increased by 26% (P<0.01 versus control group). The increase in peak oxygen uptake was correlated with the endothelium-dependent change in peripheral blood flow (r=0.64, P<0.005).
Conclusions—Regular physical exercise improves both basal endothelial nitric oxide (NO) formation and agonist-mediated endothelium-dependent vasodilation of the skeletal muscle vasculature in patients with CHF. The correction of endothelium dysfunction is associated with a significant increase in exercise capacity.
Key Words: endothelium-derived factors • nitric oxide • skeletal muscles • oxygen uptake • blood flow
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Introduction |
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Chronic heart failure (CHF) is associated with peripheral vasoconstriction.1 2 This has been attributed to activation of the sympathetic nervous system,3 the renin-angiotensin system,4 or the pituitary-vasopressin axis.4 However, recent findings revealed a potential contributory role of the vascular endothelium. Endothelium-derived relaxing factor (EDRF), lately identified as nitric oxide (NO),5 6 is released in response to both endocrine mediators (eg, acetylcholine and bradykinin7 8 ) and mechanical stimuli (eg, changes in blood flow velocity and endothelial shear stress9). The basal release of NO accounting for the biologic activity of EDRF5 has been shown to contribute to the control of regional blood flow in humans10 by using NG-monomethyl-L-arginine (L-NMMA) as a selective inhibitor of the production of NO from L-arginine.11
Cell culture experiments have demonstrated that shear stress augments NO synthase expression in the endothelial cells.12 13 Chronic exercise training of dogs has been shown to be associated with an enhanced endothelium-dependent vasodilation in conduit coronary arteries and an increased NO production in isolated coronary microvessels.14 15 However, local forearm exercise training (ie, handgrip exercise) in patients with CHF yielded inconsistent results with regard to alterations of peripheral blood flow, despite an enhanced endothelium-dependent vasodilation in conduit16 or resistance vessels.17
Previous studies have demonstrated the beneficial effects of endurance training in patients with CHF, leading to an improvement of submaximal and peak exercise capacity. As submaximal cardiac output remains essentially unchanged in these patients,18 19 improvement of exercise tolerance may have resulted from a decrease of peripheral vascular resistance in the lower limb and a corresponding redistribution of blood flow to the working muscles. It remains unclear, however, whether these functional adaptations are mediated by a correction of endothelial dysfunction, or by other as yet undefined mechanisms.
The objective of this investigation was to determine in patients with CHF (1) whether endothelial dysfunction in lower limb skeletal muscle may be normalized by a long-term exercise training program and (2) whether exercise-induced changes in endothelial function are associated with changes in maximal exercise tolerance.
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Methods |
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Patient Selection
Twenty male patients aged
70 years with CHF as a result of
dilated cardiomyopathy or ischemic heart
disease were studied (NYHA functional class II to III). All patients
had clinical, radiological, and echocardiographic signs
of CHF and a reduced left ventricular ejection fraction
(LVEF40%), as assessed by angiography. Patients were in stable
clinical condition for 3 months before study entry. Symptom-free
exercise capacity of >25 W on bicycle ergometry was required.
Exclusion criteria were diabetes mellitus, hypertension, overt
atherosclerotic peripheral vascular disease,
hypercholesterinemia (
240 mg/dL; 6.2 mmol/L),
ventricular tachyarrhythmias (Lown class
>IVa), chronic obstructive lung disease, and primary
valvular heart disease.
A total of 6 age-matched men (aged 56±3 years), who were studied for nonspecific chest pain to rule out coronary artery disease, served as healthy controls. They were normal by physical examination, ECG, chest x-ray, 2-dimensional echocardiography, coronary angiography, and left ventriculogram (LVEF 71±1%). Healthy subjects had no evidence of hypertension and had normal findings on routine hematologic and biochemical blood analyses. No previous major medical illness was reported (including diabetes or any other cardiovascular diseases), and they were on no medication during the study.
Study Protocol
The protocol of this study was approved by the Ethics Committee
of the University of Leipzig, and written informed consent was obtained
from all patients and subjects at the beginning of the study.
Baseline Studies
At baseline, patients were studied in a fasting state, in a
quiet temperature- and humidity-controlled room. All
cardiovascular medications were withheld for 24 hours
before the measurement of endothelium-dependent
vasodilation. A right femoral artery puncture was performed under local
anesthesia (1% lidocaine). A 7F multipurpose catheter was
advanced into the left superficial femoral artery through a 0.038-in
arterial sheath inserted into the right femoral artery.
Small volume hand injections of contrast medium were delivered to
verify the position of the catheter tip in the left superficial femoral
artery. Two days after invasive assessment of
endothelial function, patients underwent
symptom-limited ergospirometry with determination of maximal oxygen
uptake. Exercise testing was performed on a calibrated, electronically
braked bicycle in an upright position. Workload was increased
progressively every 3 minutes in steps of 25 W beginning at 25 W.
Respiratory gas exchange was determined continuously throughout the
exercise test as previously described.20
Follow-Up Studies
Invasive assessment of endothelium-dependent
vasodilation as well as exercise testing were repeated after 6 months.
After baseline measurements were taken, CHF patients were randomized to
either a training group or an inactive nontraining control group.
Patients assigned to the training program stayed on an intermediate
care ward for the initial 3 weeks of the training program. Patients
exercised 6 times daily for 10 minutes on a bicycle ergometer under
close supervision at 70% of the heart rate at peak oxygen uptake. On
discharge from the hospital, patients were lent a bicycle ergometer for
use at home. They were asked to exercise close to their target heart
rate twice daily for a total of 40 minutes, 5 days per week. In
addition, they were expected to participate in 1 group training session
per week. Patients assigned to the control group stayed on their
previous medication, continued their sedentary lifestyle, and were
supervised by their private physicians.
Doppler Guidewire Measurements and Calculation of Blood
Flow
Superficial femoral artery blood flow velocity was determined
with a 0.018-in Doppler guidewire containing a 12-MHz pulsed
Doppler ultrasound crystal at its tip (FlowMAP, Cardiometrics, Inc)
connected to a real-time spectral analysis system. For the
purpose of this study, the tip of the Doppler guidewire was
positioned close to an anatomic landmark, usually a side branch
takeoff, to aid its precise positioning at follow-up. For measurement
of femoral blood flow, average peak velocity (APV) was multiplied by
the cross-sectional area of the vessel segment of interest, yielding
flow in mL/min.
Intra-arterial Infusions
Saline, acetylcholine (100 mg/10 mL, Dispersa),
NG-monomethyl-L-arginine
(L-NMMA) (Clinalfa), and nitroglycerin (1 mg/mL,
Schwarz Pharma) were infused via the guiding catheter. The agents were
given in the following order: (1) baseline (0.9% saline for 5
minutes); (2) increasing doses of acetylcholine (30, 60, and 90
µg/min); (3) L-NMMA infusion (20 nmol/min); and (4) bolus injection
of 0.5 mg nitroglycerin into the left superficial
femoral artery. The doses of acetylcholine were chosen based on
previous observations by Katz et al.21
Subsequent infusions were administered after 3-minute intervals when all variables had returned to prior baseline values. All drugs were infused with an infusion pump (Braun Inc) set to a flow rate of 2 mL/min.
Quantitative Angiography
Serial angiography in the same projection
(anterior-posterior view) was performed at the end of each infusion
period and after the administration of nitroglycerin. A
nonionic contrast agent (Xenetrix, Guerbet Inc) was manually injected
at low pressure through the guiding catheter. The mean diameter of a
10-mm segment of the infused vessel was measured 2 to 3 mm
distal to the tip of the Doppler guidewire. The artery of interest
was centered, magnified, and digitized for subsequent computer
analysis. Diameter measurements were performed in 2 consecutive
end-diastolic frames and averaged. With the contrast-filled
distal catheter used as the calibration standard, the minimal lumen
diameter and reference diameter were determined with an edge-detection
algorithm (Medis Inc).
Statistical Analysis
All data are expressed as mean±SEM. Both absolute values and
percentage changes from baseline were used for statistical
analysis and yielded similar P values. Intragroup
comparisons (beginning versus 6 months) were performed using the
nonparametric Wilcoxon's signed-rank test.
Statistical analysis was performed by ANOVA followed
by Student-Newman-Keuls test. Linear regression analysis was
used to determine the relation of changes of oxygen uptake to changes
in endothelium-dependent vasodilation. A value of
P<0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Baseline Characteristics
At baseline, patients in the control group did not differ significantly from those in the training group with respect to age, etiology of heart failure, NYHA functional class, duration of heart failure, LVEFEF, or left ventricular end-diastolic diameter (Table 1
). One
patient with ischemic cardiomyopathy
assigned to the training group (aged 67 years; LVEF 16%; maximum
oxygen consumption [
O2max] 19.9
mL · kg-1 ·
min-1; NYHA class II) and 1 patient with
ischemic cardiomyopathy in the control
group (aged 62 years; LVEF 15%;
[O2max] 14.1 mL ·
kg-1 · min-1) died
during the study period. Both events were unrelated to the study
protocol. The remaining 18 patients who completed the study were
included in the analysis.
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Medical Treatment
Patients were on angiotensin-converting enzyme
inhibitors (100% in both groups), diuretics
(training group 82%, control 70%), and digoxin (training 73%,
control 70%, P=NS). Drug treatment did not change between 4
weeks before enrollment and study termination.
Compliance With the Exercise Training Program
In the exercise group, mean attendance for the group
training sessions was 69.7±9.0%. On the basis of this result, the
compliance for home training was estimated to be 
70%, amounting to
an average of 25 minutes exercise training per day.
Baseline Lower Limb Blood Flow in Healthy Subjects and in Patients
With CHF
Healthy Subjects
At baseline, a resting leg blood flow of 673±62 mL/min was
measured in healthy subjects. Arterial infusion of
acetylcholine at a rate of 90 µg/min caused only minor (although
significant) changes in superficial femoral artery diameter
(0.64±0.11 mm, P<0.05 versus baseline). However, a
substantial increase in blood flow velocity was observed (from
23.0±2.5 to 44.0±3.5 cm/s, P<0.01 versus baseline), more
than doubling the calculated mean blood flow (from 673±62 mL/min to
1596±30 mL/min, +144%, P<0.01 versus baseline).
Administration of L-NMMA, a selective inhibitor of NO
synthase, reduced mean arterial blood flow by 172±44
mL/min or -25±6% (P<0.05 versus baseline) (Table 2).
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CHF Patients
Patients with CHF, both in the training and control groups,
demonstrated a reduced resting leg blood flow at baseline compared with
healthy subjects (435±30 versus 673±62 mL/min, P<0.05).
The arterial infusion of acetylcholine (90 µg/min) caused
small but significant changes in superficial femoral artery diameter
(0.52±0.09 mm, P<0.05 versus baseline). Calculated
blood flow showed only a slight, dose-dependent increase from 435±127
to 586±223 mL/min (+39%, P<0.05 versus baseline) (Table 2
). The extent of blood flow reduction during infusion of L-NMMA was
attenuated in patients with CHF compared with healthy subjects
(-48±13 versus -172±44 mL/min, P<0.05), suggesting a
reduced basal release of NO in the peripheral vasculature
of patients with heart failure. To determine whether CHF exerts any
direct effects on vascular smooth muscle function, the vasodilator
response to intra-arterial application of 0.5 mg
nitroglycerin was examined. The relative increase in
blood flow was not significantly different between patients with CHF
and healthy subjects (Table 2).
Effects of Exercise Training on Aerobic Exercise Capacity in
Patients With CHF
Training Group
After 6 months of regular physical exercise training, oxygen
uptake at peak exercise increased by 26%, from 18.1±1.2 to 22.8±1.2
mL · kg-1 ·
min-1 in CHF patients (P<0.05). The
NYHA functional status showed a tendency toward improvement from
2.4±0.2 to 1.9±0.1 (P=0.06 versus baseline).
Control Group
In the control group of untrained CHF patients,
O2max (18.6±1.3 versus 17.9±1.7
mL · kg-1 ·
min-1, P=NS) and NYHA
functional status (2.1±0.1 versus 2.0±0.0, P=NS) remained
virtually unchanged.
Effects of Exercise Training on Lower Limb Blood Flow
Baseline
At the beginning of the study, there was no difference between the
training and control groups with respect to vessel diameter and APV at
baseline (saline infusion): vessel diameter for the training group was
6.06±0.24 mm compared with 6.06±0.37 mm for the control
group; APV in the training group was 14.7±1.0 cm/s and in the control
group was 15.7±1.4 cm/s.
Training Group
After 6 months of aerobic exercise training,
peripheral blood flow measured in the superficial femoral
artery was significantly improved in response to 60 µg/min
acetylcholine (by 187%: from 112±92 to 321±103 mL/min;
P<0.05 versus control group). The
intra-arterial application of 90 µg/min acetylcholine
yielded an even more pronounced increase of 203% (from 152±79 to
461±104 mL/min; P<0.05 versus control group) (Figure 1). The improvement of
peripheral blood flow after physical exercise training was
mainly the result of a significant increase in blood flow velocity from
1.6±2.4 to 7.6±3.4 cm/s (P<0.05 versus control group) at
60 µg/min acetylcholine, and from 2.0±2.0 to 10.9±3.4 cm/s
(P<0.05 versus control group) at 90 µg/min acetylcholine
(Table 3). The extent of conduit vessel
dilation accounted for only a small proportion of flow increase, both
at the beginning (10±2%) and after 6 months (10±3%).
|
) and after 6 months
(
). Regular physical exercise leads to a significant increase in
agonist-mediated, endothelium-dependent blood flow (A)
after acetylcholine infusion of 60 and 90 µg/min, whereas
acetylcholine-induced increase of peripheral blood flow
remained essentially unchanged (B) in patients of the control group.
#P<0.05 vs beginning; *P<0.05 vs
control.
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Acetylcholine-induced increase in peripheral blood flow
correlated with acetylcholine-induced increase in average peak blood
flow velocity (r=0.85, P<0.001), suggesting that
physical exercise improves peripheral blood flow by
correcting endothelium-dependent vasodilation in
peripheral resistance vessels. At the beginning of the
study, the increase in lower limb blood flow in response to
acetylcholine was significantly correlated with
O2 attained during bicycle
ergometry (r=0.55, P<0.02), indicating a
relation between blunted endothelial function and
exercise intolerance. Changes in
O2 after 6 months were closely
related to changes (6 months versus beginning) in acetylcholine-induced
blood flow (r=0.64, P<0.005) (Figure 2).
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VO2max) was correlated with change (6 months vs
beginning) in endothelium-dependent
peripheral blood flow during acetylcholine infusion (90
µg/min). 
indicates patients from the training group;
After training, the inhibitory effect of L-NMMA on
peripheral blood flow was significantly increased by 174%
(from -46±25 to -126±19, P<0.05 versus control group)
compared with the beginning of the study (Figure 3). The maximum increase in
peripheral blood flow caused by the
endothelium-independent vasodilator
nitroglycerin was 271% (from 426±44 to 1587±232
mL/min, P<0.05 versus baseline) at the beginning and 281%
(from 469±41 to 1785±258 mL/min; P<0.05 versus baseline)
after 6 months (P=NS); this is similar to the effect of
nitroglycerin in the control group.
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Control Group
With regard to vessel diameter and blood flow velocity at
baseline, after acetylcholine or L-NMMA infusion and after
nitroglycerin injection, there were no significant
changes observed after 6 months versus the beginning of the study
(Table 3).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This is the first randomized study to investigate the effects of regular aerobic exercise training on endothelium-dependent vasodilation of the lower limb skeletal muscle vasculature and its clinical implications for patients with CHF. Three important messages emerge from this study:
1. Correction of Endothelium-Dependent
Arteriolar Vasodilation
Leg blood flow during acetylcholine infusion was significantly
enhanced by regular aerobic exercise. This is primarily due to an
augmented endothelium-mediated vasodilation of the
peripheral vasculature.
2. Improvement of Basal NO Formation
A significant decrease in peripheral blood flow by
NG-monomethyl-L-arginine,
an inhibitor of NO synthase, suggests that regular exercise
increases basal NO formation in resistance vessels.
3. No Effects on Endothelium-Independent
Arteriolar Vasodilation
Regular exercise did not alter the responsiveness of smooth muscle
cells of the peripheral vasculature to exogenous
application of NO. These results suggest that impaired
endothelium-dependent arteriolar vasodilation in
patients with CHF can be restored by long-term aerobic exercise
training, probably because of endothelial relaxing
factors released in response to cell membrane shear stress induced by
pulsatile blood flow. Moreover, correction of
endothelial dysfunction in skeletal muscle vasculature
of the lower limb after exercise training was associated with an
enhanced exercise capacity. Thus, one fundamental
hemodynamic derangement encountered in CHF may be at
least partially corrected by exercise training-induced increase in
blood flow.
Lower Limb Blood Flow in Healthy Subjects and Patients With
CHF
The extent of dilation of the superficial femoral artery induced
by acetylcholine and nitroglycerin was similar in
healthy subjects and patients with CHF. Thus, in the present study,
changes in superficial artery diameter are negligible and the
assessment of peripheral blood flow after acetylcholine
infusion accurately determines the vasodilation capacity of resistance
vessels. Our findings with regard to lower limb peripheral
vasculature are in agreement with previous
studies2 21 22 23 24 that demonstrated impaired
acetylcholine-mediated endothelium-dependent
vasodilation in the forearm and in the coronary circulation of
patients with CHF. As the mean blood flow velocity obtained by
Doppler ultrasound closely correlates with blood flow measurements
obtained by venous occlusion plethysmography, the current finding is in
agreement with previous work by Katz et al21;
they demonstrated a reduction in blood flow velocity by 40% in the
superficial femoral artery in patients with CHF compared with normal
subjects.
When L-NMMA was applied to inhibit basal NO-formation in the lower limb vasculature, a significant reduction of blood flow was observed in healthy control subjects, although it remained nearly unchanged in patients with CHF. Therefore, not just maximal but also basal endothelial function is impaired in CHF. These findings are in accord with clinical trials22 and with experimental studies that demonstrated impaired basal NO synthesis in vitro in isolated vascular rings and in vivo.25 26 However, the current findings contrast 2 previous studies which demonstrated that a decrease in blood flow induced by L-NMMA was similar in patients with CHF and normal subjects, indicating a preserved basal release of NO from endothelium.23 27 The differences between the results of these previous clinical studies and the present work may be related to differences in study protocol or in the severity of disease in the study cohorts.
Nitroglycerin was administered to assess the functional integrity of cGMP-dependent vasorelaxation in the vascular smooth muscle. In agreement with previous reports,21 28 the peripheral vasodilator response to nitroglycerin was slightly reduced in patients with CHF versushealthy subjects. Therefore, the present data suggest that abnormal cGMP-mediated vascular smooth muscle relaxation in patients with CHF may be partially responsible for the attenuated response to acetylcholine.21
Improvement of Endothelium-Dependent Perfusion of
the Lower Limb in Response to Exercise Training
CHF is characterized by peripheral
vasoconstriction1 and abnormal vascular
compliance.29 Both factors are at least partially
related to endothelial dysfunction of
peripheral resistance and conduit vessels. In the
present study, acetylcholine-induced increase in blood flow of the
lower limb was blunted compared with healthy subjects. Regular physical
exercise led to an increase in endothelium-dependent
peripheral perfusion of 203% and to a decrease in
peripheral perfusion after L-NMMA infusion of 174%. These
findings suggest that the improvement in peripheral blood
flow was attributed to an enhanced formation and/or release of NO at
basal conditions and after stimulation.
Several Mechanisms Are Involved in the Exercise-Induced Enhancement
of Endothelial Function
- In patients with CHF, local handgrip exercise improves flow-mediated vasodilation of the radial artery during hyperemia16 as well as agonist-mediated endothelium-dependent vasodilation of forearm resistance vessels.17 This is consistent with animal studies in dogs, which detected an improved endothelium-mediated of epicardial coronary arteries after short-term exercise-training15 and demonstrated increased NO synthase-expression.14
- Chronic increase in blood flow also affects the release of prostaglandins. This may be particularly important in skeletal muscle microvasculature, in which prostaglandins are substantially involved in flow-mediated vasodilation.30
- Inactivation of NO by increased vascular superoxide or other oxygen-derived radicals also accounts for endothelial dysfunction in the human circulation. This may be counterbalanced by shear stress–induced expression of NO synthase and cytosolic copper/zinc–containing superoxide dismutase, a free radical scavenger.31
- Several other mechanisms may be involved in shear stress-induced vasodilation. Increases in flow enhance Ca2+ influx32 in endothelial cells, which is necessary for both NO and prostaglandin synthesis. The sensitivity of the rheo- (flow) receptors and/or the cellular signal transduction pathways for the initiation of the synthesis of NO may be upregulated after exercise training.
Chronic exercise training leads to a significant increase in maximal oxygen uptake (26%). In the present study, changes in functional work capacity were significantly correlated with changes in agonist-induced endothelium-dependent blood flow. In rats, systemic inhibition of NO synthase during exercise and with L-NMMA significantly reduced blood flow to muscles with a high percentage of oxidative fibers but did not change blood flow to muscles with a high percentage of glycolytic fibers.33 Restoring endothelial function by chronic exercise training may contribute to the regulation of skeletal muscle blood flow as part of a coordinated system that preferentially supplies blood flow to oxidative muscles during submaximal exercise. These findings may at least partially account for the increase in oxidative enzyme capacity of the working skeletal muscle regularly observed in patients with CHF, which is closely related to the improved functional work capacity after exercise training.19 34 However, other mechanisms unrelated to blood flow are also proposed as potential mediators of the positive effects of exercise training: improvement of skeletal muscle metabolism,35 increase in mitochondrial volume density,19 34 and reduced activity of the muscle ergoreflex.36
Limitations of the Study
To date, no consensus has been reached about the optimal exercise
protocol for CHF patients. The protocol used in the present study
was comparable to a number of previous training
studies18 37 and less vigorous than a few
others.38 39 On the basis of our previous
experience with exercise training, we estimated that patient compliance
would be in the range of 70%. Therefore, we set the goal of 40 minutes
of home exercise training per day to achieve a minimum of 20 minutes
submaximal exercise training per day in the majority of patients. In
fact, given the patient compliance of 70% (as calculated from
participation in group training sessions), the average exercise
duration per week turned out to be 3 hours per week. The present
study was designed to analyze the effects of aerobic endurance
training on endothelial function in CHF. To draw an
analogy to pharmacological studies, this was a phase 1 trial in
the sense that the efficacy of the intervention was examined. Future
studies will compare different levels of exercise training to determine
the optimal protocol.
Although great care was taken to standardize flow measurements, we observed a considerable variation of values within the groups, as indicated by relatively large standard errors. However, the use of paired statistics, in which every patient serves as his own control, yielded significant intraindividual blood flow differences before and after exercise training of CHF patients. In contrast, no change was observed in the untrained control group. It is known that up to 20% of CHF patients have normal peripheral blood flow at baseline.40 Obviously, this finding may partly explain the wide range of flow velocities within the groups because no strict linear relation between LVEF and the degree of reduction of peripheral perfusion could be identified.
Clinical Implications
The results of this study provide evidence that long-term aerobic
exercise training in patients with CHF restores
endothelial function of the skeletal muscle
microvasculature of the lower limb. Therefore, a carefully and
individually tailored program of physical activity should be made
available to patients with CHF to reverse the deleterious effects of
endothelial dysfunction, ie, increased
peripheral resistance and reduced oxygen delivery to the
working skeletal muscle. The present study demonstrates that
chronic exercise training has the potential to correct
peripheral endothelial dysfunction and to
improve the debilitating key symptom of patients with CHF: exercise
intolerance.
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Acknowledgments |
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This study was supported by grant Ha 2165/3–2 from the Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany.
Received May 12, 1998; revision received August 24, 1998; accepted September 3, 1998.
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U. Landmesser, S. Spiekermann, S. Dikalov, H. Tatge, R. Wilke, C. Kohler, D. G. Harrison, B. Hornig, and H. Drexler Vascular Oxidative Stress and Endothelial Dysfunction in Patients With Chronic Heart Failure: Role of Xanthine-Oxidase and Extracellular Superoxide Dismutase Circulation, December 10, 2002; 106(24): 3073 - 3078. [Abstract] [Full Text] [PDF]
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C. K. Roberts, N. D. Vaziri, and R. J. Barnard Effect of Diet and Exercise Intervention on Blood Pressure, Insulin, Oxidative Stress, and Nitric Oxide Availability Circulation, November 12, 2002; 106(20): 2530 - 2532. [Abstract] [Full Text] [PDF]
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E. De Sousa, P. Lechene, D. Fortin, B. N'Guessan, S. Belmadani, X. Bigard, V. Veksler, and R. Ventura-Clapier Cardiac and skeletal muscle energy metabolism in heart failure: beneficial effects of voluntary activity Cardiovasc Res, November 1, 2002; 56(2): 260 - 268. [Abstract] [Full Text] [PDF]
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A. Radzewitz, E. Miche, G. Herrmann, M. Nowak, U. Montanus, U. Adam, Y. Stockmann, and M. Barth Exercise and muscle strength training and their effect on quality of life in patients with chronic heart failure Eur J Heart Fail, October 1, 2002; 4(5): 627 - 634. [Abstract] [Full Text] [PDF]
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 P. A. Lanfranchi and V. K Somers Arterial baroreflex function and cardiovascular variability: interactions and implications Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2002; 283(4): R815 - R826. [Abstract] [Full Text] [PDF]
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G. Fuchsjager-Mayrl, J. Pleiner, G. F. Wiesinger, A. E. Sieder, M. Quittan, M. J. Nuhr, C. Francesconi, H.-P. Seit, M. Francesconi, L. Schmetterer, et al. Exercise Training Improves Vascular Endothelial Function in Patients with Type 1 Diabetes Diabetes Care, October 1, 2002; 25(10): 1795 - 1801. [Abstract] [Full Text] [PDF]
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U. Landmesser and H. Drexler Allopurinol and Endothelial Function in Heart Failure: Future or Fantasy? Circulation, July 9, 2002; 106(2): 173 - 175. [Full Text] [PDF]
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I. Shiotani, H. Sato, H. Sato, H. Yokoyama, Y. Ohnishi, E. Hishida, K. Kinjo, D. Nakatani, T. Kuzuya, and M. Hori Muscle pump-dependent self-perfusion mechanism in legs in normal subjects and patients with heart failure J Appl Physiol, April 1, 2002; 92(4): 1647 - 1654. [Abstract] [Full Text] [PDF]
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S. Adamopoulos, J. Parissis, D. Karatzas, C. Kroupis, M. Georgiadis, G. Karavolias, J. Paraskevaidis, K. Koniavitou, A. J. S. Coats, and D. T. Kremastinos Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fasligand system in patients with chronic heart failure J. Am. Coll. Cardiol., February 20, 2002; 39(4): 653 - 663. [Abstract] [Full Text] [PDF]
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M. de Lorgeril, P. Salen, M. Accominotti, M. Cadau, J.-P. Steghens, F. Boucher, and J. de Leiris Dietary and blood antioxidants in patients with chronic heart failure. Insights into the potential importance of selenium in heart failure Eur J Heart Fail, December 1, 2001; 3(6): 661 - 669. [Abstract] [Full Text] [PDF]
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 A. L. Farre and S. Casado Heart Failure, Redox Alterations, and Endothelial Dysfunction Hypertension, December 1, 2001; 38(6): 1400 - 1405. [Abstract] [Full Text] [PDF]
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A. Maiorana, G. O'Driscoll, C. Cheetham, L. Dembo, K. Stanton, C. Goodman, R. Taylor, and D. Green The effect of combined aerobic and resistance exercise training on vascular function in type 2 diabetes J. Am. Coll. Cardiol., September 1, 2001; 38(3): 860 - 866. [Abstract] [Full Text] [PDF]
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J. Bauersachs, I. Fleming, D. Fraccarollo, R. Busse, and G. Ertl Prevention of endothelial dysfunction in heart failure by vitamin E: Attenuation of vascular superoxide anion formation and increase in soluble guanylyl cyclase expression Cardiovasc Res, August 1, 2001; 51(2): 344 - 350. [Abstract] [Full Text] [PDF]
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P. V. Ennezat, S. L. Malendowicz, M. Testa, P. C. Colombo, A. Cohen-Solal, T. Evans, and T. H. LeJemtel Physical training in patients with chronic heart failure enhances the expression of genes encoding antioxidative enzymes J. Am. Coll. Cardiol., July 1, 2001; 38(1): 194 - 198. [Abstract] [Full Text] [PDF]
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L TAVAZZI and P GIANNUZZI Physical training as a therapeutic measure in chronic heart failure: time for recommendations Heart, July 1, 2001; 86(1): 7 - 11. [Full Text] [PDF]
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R. Belardinelli, I. Paolini, G. Cianci, R. Piva, D. Georgiou, and A. Purcaro Exercise training intervention after coronary angioplasty: the ETICA trial J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1891 - 1900. [Abstract] [Full Text] [PDF]
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S Adamopoulos, J Parissis, C Kroupis, M Georgiadis, D Karatzas, G Karavolias, K Koniavitou, A.J.S Coats, and D.T. Kremastinos Physical training reduces peripheral markers of inflammation in patients with chronic heart failure Eur. Heart J., May 1, 2001; 22(9): 791 - 797. [Abstract] [PDF]
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A.C. Mendes Ribeiro, T.M.C. Brunini, J.C. Ellory, and G.E. Mann Abnormalities in L-arginine transport and nitric oxide biosynthesis in chronic renal and heart failure Cardiovasc Res, March 1, 2001; 49(4): 697 - 712. [Abstract] [Full Text] [PDF]
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A. Linke, N. Schoene, S. Gielen, J.u. Hofer, S. Erbs, G. Schuler, and R. Hambrecht Endothelial dysfunction in patients with chronic heart failure: systemic effects of lower-limb exercise training J. Am. Coll. Cardiol., February 1, 2001; 37(2): 392 - 397. [Abstract] [Full Text] [PDF]
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Recommendations for exercise training in chronic heart failure patients Eur. Heart J., January 2, 2001; 22(2): 125 - 135. [PDF]
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T. Rankinen, T. Rice, L. Perusse, Y. C. Chagnon, J. Gagnon, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, and C. Bouchard NOS3 Glu298Asp Genotype and Blood Pressure Response to Endurance Training : The HERITAGE Family Study Hypertension, November 1, 2000; 36(5): 885 - 889. [Abstract] [Full Text] [PDF]
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A. Maiorana, G. O'Driscoll, L. Dembo, C. Cheetham, C. Goodman, R. Taylor, and D. Green Effect of aerobic and resistance exercise training on vascular function in heart failure Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1999 - H2005. [Abstract] [Full Text] [PDF]
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C. A. DeSouza, L. F. Shapiro, C. M. Clevenger, F. A. Dinenno, K. D. Monahan, H. Tanaka, and D. R. Seals Regular Aerobic Exercise Prevents and Restores Age-Related Declines in Endothelium-Dependent Vasodilation in Healthy Men Circulation, September 19, 2000; 102(12): 1351 - 1357. [Abstract] [Full Text] [PDF]
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J. Bauersachs, D. Fraccarollo, P. Galuppo, J. Widder, and G. Ertl Endothelin-receptor blockade improves endothelial vasomotor dysfunction in heart failure Cardiovasc Res, July 1, 2000; 47(1): 142 - 149. [Abstract] [Full Text] [PDF]
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 R. Hambrecht, S. Gielen, A. Linke, E. Fiehn, J. Yu, C. Walther, N. Schoene, and G. Schuler Effects of Exercise Training on Left Ventricular Function and Peripheral Resistance in Patients With Chronic Heart Failure: A Randomized Trial JAMA, June 21, 2000; 283(23): 3095 - 3101. [Abstract] [Full Text] [PDF]
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A. Maiorana, G. O'Driscoll, C. Cheetham, J. Collis, C. Goodman, S. Rankin, R. Taylor, and D. Green Combined aerobic and resistance exercise training improves functional capacity and strength in CHF J Appl Physiol, May 1, 2000; 88(5): 1565 - 1570. [Abstract] [Full Text] [PDF]
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Y. Tanabe, M. Takahashi, Y. Hosaka, M. Ito, E. Ito, and K. Suzuki Prolonged recovery of cardiac output after maximal exercise in patients with chronic heart failure J. Am. Coll. Cardiol., April 1, 2000; 35(5): 1228 - 1236. [Abstract] [Full Text] [PDF]
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R. Hambrecht, L. Hilbrich, S. Erbs, S. Gielen, E. Fiehn, N. Schoene, and G. Schuler Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation J. Am. Coll. Cardiol., March 1, 2000; 35(3): 706 - 713. [Abstract] [Full Text] [PDF]
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R. Hambrecht, A. Wolf, S. Gielen, A. Linke, J. Hofer, S. Erbs, N. Schoene, and G. Schuler Effect of Exercise on Coronary Endothelial Function in Patients with Coronary Artery Disease N. Engl. J. Med., February 17, 2000; 342(7): 454 - 460. [Abstract] [Full Text] [PDF]
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M. R. Rinder, R. J. Spina, and A. A. Ehsani Enhanced endothelium-dependent vasodilation in older endurance-trained men J Appl Physiol, February 1, 2000; 88(2): 761 - 766. [Abstract] [Full Text] [PDF]
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A. Lavrencic, B. G. Salobir, and I. Keber Physical Training Improves Flow-Mediated Dilation in Patients With the Polymetabolic Syndrome Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 551 - 555. [Abstract] [Full Text] [PDF]
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T. Munzel and D. G. Harrison Increased Superoxide in Heart Failure : A Biochemical Baroreflex Gone Awry Circulation, July 20, 1999; 100(3): 216 - 218. [Full Text] [PDF]
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P. G. Snell and J. H. Mitchell Physical Inactivity : An Easily Modified Risk Factor? Circulation, July 6, 1999; 100(1): 2 - 4. [Full Text] [PDF]
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