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Hambrecht R, Gielen S, Linke A, et al. Effects of Exercise Training on Left Ventricular Function and Peripheral Resistance in Patients With Chronic Heart Failure: A Randomized Trial. JAMA. 2000;283(23):3095–3101. doi:10.1001/jama.283.23.3095
Context Exercise training in patients with chronic heart failure improves work
capacity by enhancing endothelial function and skeletal muscle aerobic metabolism,
but effects on central hemodynamic function are not well established.
Objective To evaluate the effects of exercise training on left ventricular (LV)
function and hemodynamic response to exercise in patients with stable chronic
Design Prospective randomized trial conducted in 1994-1999.
Setting University department of cardiology/outpatient clinic in Germany.
Patients Consecutive sample of 73 men aged 70 years or younger with chronic heart
failure (with LV ejection fraction of approximately 0.27).
Intervention Patients were randomly assigned to 2 weeks of in-hospital ergometer
exercise for 10 minutes 4 to 6 times per day, followed by 6 months of home-based
ergometer exercise training for 20 minutes per day at 70% of peak oxygen uptake
(n=36) or to no intervention (control group; n=37).
Main Outcome Measures Ergospirometry with measurement of central hemodynamics by thermodilution
at rest and during exercise; echocardiographic determination of LV diameters
and volumes, at baseline and 6-month follow-up, for the exercise training
vs control groups.
Results After 6 months, patients in the exercise training group had statistically
significant improvements compared with controls in New York Heart Association
functional class, maximal ventilation, exercise time, and exercise capacity
as well as decreased resting heart rate and increased stroke volume at rest.
In the exercise training group, an increase from baseline to 6-month follow-up
was observed in mean (SD) resting LV ejection fraction (0.30 [0.08] vs 0.35
[0.09]; P=.003). Mean (SD) total peripheral resistance
(TPR) during peak exercise was reduced by 157 (306) dyne/s/cm−5 in the exercise training group vs an increase of 43 (148) dyne/s/cm−5 in the control group (P=.003), with
a concomitant increase in mean (SD) stroke volume of 14 (22) mL vs 1 (19)
mL in the control group (P=.03). There was a small
but significant reduction in mean (SD) LV end diastolic diameter of 4 (6)
mm vs an increase of 1 (4) mm in the control group (P<.001).
Changes from baseline in resting TPR for both groups were correlated with
changes in stroke volume (r=−0.76; P<.001) and in LV end diastolic diameter (r=0.45; P<.001).
Conclusions In patients with stable chronic heart failure, exercise training is
associated with reduction of peripheral resistance and results in small but
significant improvements in stroke volume and reduction in cardiomegaly.
Until recently, exercise intolerance among patients with chronic heart
failure was regarded as a warning symptom precluding any strenuous physical
activity to avert cardiac decompensation. During the last decade, however,
it has become appreciated that this approach accelerates physical deconditioning
and may worsen heart failure symptoms. Carefully designed endurance training
programs can improve functional work capacity in patients with chronic heart
Training benefits have been attributed in particular to peripheral adaptations,
including enhanced oxidative capacity of the working skeletal muscle3,4,9 and correction of endothelial
dysfunction in the skeletal muscle vasculature.10-12
However, concerns have been raised that these peripheral adaptations
in response to short-term exercise training may worsen left ventricular (LV)
dimensions, contractile function, or both. Exercise training initiated early
following an anterior Q-wave myocardial infarction reportedly leads to a deterioration
in both global and regional function in patients with significant LV asynergy
at baseline.13 In this study, we investigated
the influence of a long-term, ambulatory exercise training program involving
patients with chronic heart failure on total peripheral resistance (TPR) at
rest and during exercise, LV diameter, and stroke volume.
Seventy-three men aged 70 years or younger with chronic heart failure
who were referred to the Leipzig Heart Center, Leipzig, Germany, for further
diagnosis during 1994-1999 were enrolled in this trial if they met the following
inclusion criteria: (1) documented heart failure by signs, symptoms, and angiographic
evidence of reduced LV function (LV ejection fraction [LVEF] <0.40) as
a result of dilated cardiomyopathy or ischemic heart disease; (2) physical
work capacity at baseline greater than 25 W; and (3) clinical stability for
at least 3 months before entry into the study.
Exclusion criteria were significant valvular heart disease, uncontrolled
hypertension, diabetes mellitus, hypercholesterolemia (≥6 mmol/L [232 mg/dL]),
peripheral vascular disease, pulmonary disease, or musculoskeletal abnormalities
precluding exercise training. All studies were performed according to a research
protocol approved by the University of Leipzig Ethics Committee and all patients
provided written informed consent before entry into the study.
Patients were randomly assigned to either a training group or an inactive
control group using a list of random numbers. Both groups underwent invasive
cardiopulmonary exercise testing and echocardiography at baseline and at 6-month
To ensure close supervision, the initial phase of the exercise program
was performed on an in-hospital basis. During the first 2 weeks, patients
exercised 4 to 6 times daily for 10 minutes using a bicycle ergometer. Workloads
were adjusted so that 70% of the symptom-limited maximum oxygen uptake was
reached. Before discharge from the hospital, peak symptom-limited ergospirometry
was performed to calculate training target heart rate for home training, which
was defined as the heart rate reached at 70% of the maximum oxygen uptake
during symptom-limited exercise. On discharge from the hospital, patients
were provided with bicycle ergometers for daily home exercise training. Patients
were asked to exercise close to their target heart rate daily for 20 minutes
every day for 6 months. In addition, they were expected to participate in
at least 1 group training session of 60 minutes each week. Group sessions
consisted of walking, calisthenics, and ball games.
Patients assigned to the control group continued their individually
tailored cardiac medications and were supervised by their physicians. All
examinations including exercise testing were repeated at 6-month follow-up.
Cardiopulmonary Exercise Testing and Variables. Prior to baseline measurements, all patients underwent a peak exercise
test and participated in 1 group training session with 24-hour Holter monitoring
to familiarize them with the examinations and to detect exercise-induced ventricular
Two days later, a catheter (Swan-Ganz 93A-131-7F, Edwards Laboratories,
Santa Ana, Calif) was introduced into the right pulmonary artery through the
right antecubital vein. Following a resting period of 30 minutes, 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. Exercise was terminated when patients were
physically exhausted or developed severe dyspnea or dizziness. Hemodynamic
and gas exchange measurements as well as blood samples were simultaneously
obtained at rest and at the end of each workload during bicycle exercise.
Heart rate was measured by continuous electrocardiographic monitoring.
Cardiac output was obtained using a thermodilution catheter that was
interfaced to a cardiac output computer (COM-2, Edwards Laboratories). Three
measurements of cardiac output were made at rest and at the end of each workload.
Stroke volume was calculated by dividing cardiac output by heart rate. Total
peripheral resistance was calculated as mean arterial pressure divided by
cardiac output and is expressed in dyne/s/cm−5. Free and
conjugated plasma catecholamine levels were analyzed by high-pressure liquid
chromatography with amperometric detection as described by Weicker.14
Respiratory gas exchange data were determined continuously throughout
the exercise test using a commercially available system (Oxycon Alpha, Erich
Jaeger, Höchberg, Germany). The ventilatory threshold was defined as
Echocardiography. All patients underwent a complete resting echocardiographic study at
both the initial and the final evaluations. Examinations were videotaped with
a long apical 4-chamber view sequence for final analysis. End systolic and
end diastolic diameters of the left ventricle were determined in the parasternal
long axis. Three consecutive cardiac cycles were analyzed on an HP Sonos 5500
echocardiography system (Hewlett-Packard Inc, Andover, Mass) and averaged
for each patient by an experienced cardiologist blinded to patient status
and assignment. Left ventricular volume and LVEF were calculated in the apical
4-chamber view using the disk method.16
Assessment of Lower-Limb Endothelial Function. In a subgroup of 18 patients, endothelial function in the superficial
femoral artery was assessed at baseline and 6-month follow-up as previously
described.12 Briefly, 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. Superficial femoral artery
blood flow velocity was determined with a 0.018-in Doppler guide wire containing
a 12-MHz pulsed Doppler ultrasonographic crystal at its tip (FlowMAP, Cardiometrics
Inc, Mountain View, Calif). Serial angiography in the same projection (anterior-posterior
view) was performed at the end of each infusion. Endothelial function was
assessed at baseline (after 0.9% saline infusion for 5 minutes; after increasing
doses of acetylcholine (30, 60, and 90 µg/min); after NG-monomethyl-L-arginine
infusion (20 nmol/min); and after a bolus injection of 0.5 mg of nitroglycerin.
Because 1 of the previously described 18 patients refused invasive hemodynamic
measurements, this subgroup analysis in the present study includes 17 patients.12
All variables were calculated as mean (SD). Data were tested for normal
distribution using the Kolmogorov-Smirnov test and for homogeneity of variances
with the Levene test. Both intragroup and intergroup comparisons were made
using 2-way repeated-measures analysis of variance followed by the Tukey post
hoc test (SigmaStat 2.0.3 for Windows, SPSS Inc, Chicago, Ill). New York Heart
Association functional class distribution was compared using the χ2 test. A P value of less than .05 was considered
Linear regression analysis was used to determine the relationship between
changes in peripheral vascular resistance and changes in stroke volume and
end diastolic diameter as well as to assess the effect of changes in endothelial
function and sympathetic drive on changes in peripheral vascular resistance.
Sample size calculation was based on the results of a pilot study with
the same study protocol involving 10 patients with chronic heart failure.
In this patient population, exercise training resulted in a reduction of TPR
at peak exercise from a mean (SD) of 739 (410) to 575 (188) dyne/s/cm−5. To detect a difference of 160 dyne/s/cm−5
between groups at peak exercise after the intervention at 90% power with a
2-sided parametric test, a minimum sample size of approximately 70 patients
No significant differences were observed between the 2 groups with regard
to demographic or clinical data, including age, weight, LVEF, LV end diastolic
diameter, New York Heart Association functional class, or maximum oxygen uptake.
Drug treatment was not changed during the last 4 weeks before the study or
during the study in any patient (excluding temporary medication changes during
hospitalization) (Table 1).
In the exercise training group, 3 patients (LVEF, 0.21 [0.04]; maximum
oxygen uptake [O2max], 17.8 [3.0] mL/kg/min) died of sudden cardiac
death unrelated to exercise during the study period. These patients were comparable
with the other randomized patients with respect to duration of disease and
hemodynamic parameters. After baseline testing, 1 patient was excluded from
further analysis because of atrioventricular node reentrant tachycardia. One
patient in clinically stable condition (LVEF, 0.38; O2max, 20.8
mL/kg/min) withdrew consent after the baseline examination. Data for the remaining
31 patients were used for subsequent analyses. Two patients in clinically
stable condition (LVEF, 0.31 [0.06]; O2max, 22.6 [3.3] mL/kg/min)
refused right heart catheterization during the follow-up examination; therefore,
data from invasive measurements are complete in 29 patients (Figure 1). During the study period, 2 patients (LVEF, 0.19 [0.08];
O2max, 16.5 [2.3] mL/kg/min) were admitted to the hospital because
of temporarily worsening symptoms. These patients continued the training program
In the control group, 2 patients died of sudden cardiac death during
the study (LVEF, 0.13 [0.10]; O2max, 15.5 [2.0] mL/kg/min). An
additional 2 patients withdrew consent after baseline examinations (LVEF,
0.23 [0.10]; O2max, 19.3 [0.6] mL/kg/min). Six-month follow-up
examinations were obtained for the remaining 33 patients. Invasive measurements
(right heart catheterization) during follow-up were refused by 3 patients
who were in clinically stable condition (LVEF, 0.16 [0.05]; O2max,
22.7 [12.0] mL/kg/min). Therefore, complete follow-up, including invasive
data, was available for 30 patients (Figure
1). One patient had right heart failure during the study period
and was readmitted to the hospital for an additional 2 weeks. Another patient
was hospitalized because of temporarily worsening dyspnea. Both of these patients
(LVEF, 0.22 [0.06]; O2max, 11.7 [0.6] mL/kg/min) continued the
study after hospital discharge and complete 6-month follow-up measurements
In the exercise training group, attendance for the group training sessions
was 60% (5%). Based on this result, the compliance for home training was estimated
to be 60%, amounting to an average of approximately 20 minutes of subpeak
exercise training per day.
Improved New York Heart Association functional class was observed in
the exercise training group but not in the control group (P<.001; Figure 2).
In the exercise training group, oxygen uptake at the ventilatory threshold
increased by 3.4 (4.0) mL/kg/min, whereas it decreased by 0.4 (2.6) mL/kg/min
in the control group (P<.001). During peak exercise,
oxygen uptake increased by 4.8 (3.7) mL/kg/min vs an increase of 0.3 (2.8)
mL/kg/min in the control group (P<.001) (Table 2). Concomitant significant increases
in maximum ventilation, exercise time, and exercise capacity were observed
in the exercise training group. In control patients, oxygen uptake at the
ventilatory threshold and at peak exercise, as well as exercise time, and
exercise capacity, remained unchanged. Exercise time to ventilatory threshold
increased significantly in the exercise training group from 296 (150) seconds
to 454 (295) seconds, whereas it decreased in the control group from 319 (146)
seconds to 301 (132) seconds (exercise training vs control group, P<.001).
After 6 months, resting heart rate in the exercise training group decreased
by 9 (13) beats/min vs by 3 (11) beats/min in the control group (P=.04). Heart rate at peak exercise increased by 6 (12) beats/min in
the exercise training group vs decreasing by 5 (14) beats/min in the control
group (P=.001). In both groups, no changes were observed
with respect to arterial blood pressure at rest. Exercise training led to
a significant increase in resting stroke volume (+13  mL vs −2 
mL in the control group; P=.002) and at peak exercise
(+14  mL vs +1  mL in the control group; P=.03)
(Table 3). In the exercise training
group, 6-month changes in stroke volume during subpeak exercise did not reach
statistical significance (89  mL vs 98  mL at 75 W; P=.07).
There was a trend toward an increase in resting cardiac output, from
4.9 (1.4) L/min to 5.2 (1.3) L/min (P=.14 vs baseline),
whereas cardiac output during subpeak exercise remained essentially unchanged
because the increase in stroke volume was offset by a concomitant decrease
in heart rate. As a result of improved stroke volume and increased heart rate
in the exercise training group, maximum cardiac output was enhanced significantly
by 2.7 (3.3) L/min vs −0.3 (2.6) L/min in the control group (P<.001).
There were no significant changes observed in the control group with
regard to heart rate, stroke volume, or cardiac output at rest and during
exercise. Mean pulmonary artery pressure at rest and in response to exercise
remained unchanged at 6-month follow-up compared with baseline in both groups.
After 6 months of exercise training, LV end diastolic diameters was
significantly decreased by 3 (6) mm vs an increase of 1 (4) mm in the control
group (P<.001) and LV end systolic diameter was
decreased by 5 (7) mm vs an increase of 1 (6) mm in the control group (P<.001), respectively. Decreases in LV diameters were
accompanied by a significant reduction in LV end diastolic and end systolic
volumes by 22 (53) mL vs an increase of 11 (41) mL in the control group (P=.008) and by 24 (36) mL vs an increase of 1 (40) mL in
the control group (P=.009), respectively. Resting
LVEF in the exercise training group improved from 0.30 (0.08) at baseline
to 0.35 (0.09) at 6-month follow-up (P=.003) (Table 4). Left ventricular end diastolic
and end systolic diameters remained essentially unchanged at 6-month follow-up
in the control group.
Exercise training led to a significant decrease in resting TPR by 126
(485) dyne/s/cm−5 vs an increase of 120 (433) dyne/s/cm−5 in the control group (P=.04). During
peak exercise, TPR decreased by 158 (306) dyne/s/cm−5 in
the exercise training group vs an increase of 43 (148) dyne/s/cm−5 in the control group (P=.003) (Table 3 and Figure 3).
During subpeak exercise in the exercise training group, TPR was not significantly
changed for the 6-month follow-up (841  dyne/s/cm−5
vs 832  dyne/s/cm−5 at 75 W; P=.88).
No differences between baseline and follow-up tests were observed among control
patients with regard to TPR at rest and during exercise.
Changes in TPR at rest and during peak exercise were inversely correlated
with changes in stroke volume at rest (r=−0.76; P<.001) and during peak exercise (r=−0.60; P<.001). The change in resting
TPR was also significantly related to changes in LV end diastolic diameter
Exercise training improved agonist-mediated endothelium-dependent vasodilation
of the skeletal muscle vasculature as assessed in a subgroup of patients with
chronic heart failure, as reported previously.12
In the present study, changes in acetylcholine-induced blood flow of the lower
limb were significantly correlated with changes in TPR at peak exercise (r=−0.53; P=.03). However,
no correlation was found between NG-monomethyl-L-arginine–induced
changes in peripheral blood flow and changes in resting TPR (r=0.25; P=.38).
In the exercise training group, resting plasma epinephrine levels decreased
significantly by 0.13 (0.28) nmol/L vs an increase of 0.03 (0.28) nmol/L in
the control group (P=.03). In the exercise training
group at 6-month follow-up, there was a trend toward decreased plasma norepinephrine
levels at rest (2.9 [2.8] nmol/L at baseline vs 2.0 [1.3] nmol/L at 6-month
follow-up) and during subpeak exercise (8.5 [4.7] nmol/L at baseline vs 7.0
[4.4] nmol/L at 6-month follow-up). Changes in epinephrine and norepinephrine
were not significantly correlated with changes in TPR. In the control group,
there was no change in plasma catecholamine levels over time, either at rest
or during exercise.
In this randomized trial, we evaluated the effects of 6 months of exercise
training in patients with stable chronic heart failure and moderate-to-severe
LV dysfunction. Three key findings emerged. First, aerobic endurance training
leads to an increase in LV stroke volume at rest and during exercise and to
a small but significant decrease in LV end diastolic diameter and volume.
Cardiac output at rest and during subpeak exercise remains essentially unchanged.
Second, long-term exercise training is associated with a considerable reduction
of TPR at rest and, in particular, at peak exercise. In addition, we found
a correlation between improved endothelium-dependent vasodilation of the skeletal
muscle vasculature and reduction of total peripheral resistance during exercise.
Third, changes in TPR are related to changes in stroke volume and LV end diastolic
diameter. These results suggest that in patients with stable chronic heart
failure, regular physical exercise for 6 months is associated with a significant
afterload reduction. This beneficial training effect leads to a small but
significant improvement in LV stroke volume and reduction in cardiomegaly.
Two recent studies in postinfarction patients with systolic dysfunction
have demonstrated that exercise training may attenuate the unfavorable remodeling
response and even improve ventricular function over time.5,6
Although improved LV diastolic filling rate has been observed after exercise
training in patients with dilated cardiomyopathy,17
the long-term effect of exercise training on LV systolic function and cardiomegaly
The major goals of any therapy for chronic heart failure continue to
be reduction of LV wall stress, increase of cardiac output, and reduction
of afterload. An important finding of the present study was the observation
that after 6 months of exercise training, stroke volume increased while at
rest and, in particular, during peak exercise. Because resting heart rate
significantly declined after 6 months of training, it could be argued that
the lengthened diastolic filling period augmented stroke volume by the Frank-Starling
mechanism. However, the decrease in LV end diastolic diameter strongly suggests
that the reduction in heart rate cannot completely explain the increase in
either LVEF or stroke volume.
In 1 of the first exercise training trials in patients with chronic
heart failure, Sullivan et al1 observed a trend
toward an increase in stroke volume during exercise. Although more studies
are needed in this area, the available evidence does not suggest that training
causes any worsening of central hemodynamic responses to exercise. A recently
published single-center study even postulated a reduction of mortality after
exercise training.18 Most studies have reported
improved cardiac output response to exercise with no elevation of pulmonary
In the present study, both resting and peak exercise pulmonary vascular resistance
were reduced after training therapy, indicating that the improvement in LV
systolic function may have led to a decreased preload, that an improvement
of endothelial function may also have affected pulmonary resistance vessels,
A major finding of the present study was the observation that TPR decreased
at rest and, in particular, during peak exercise in the exercise training
group. Several mechanisms may be responsible for this reduction of TPR. First,
endothelial dysfunction in chronic heart failure is characterized by a reduced
endothelium-dependent vasodilation in response to acetylcholine and impaired
ischemic vasodilation during reactive hyperemia.19,20
During exercise, small resistance vessels exhibit a blunted vasodilatory capacity,
which contributes to increased TPR and peripheral hypoperfusion. Recently,
we demonstrated that exercise corrects endothelium-dependent vasodilation
of the skeletal muscle vasculature after stimulation with acetylcholine and
even improves basal endothelial nitric oxide formation.12
In the subset of patients included in the present study, changes in endothelial
function of the skeletal musculature of the lower limb were related to changes
in TPR. This observation is consistent with the hypothesis that exercise therapy
exerts its primary effects on the endothelial function of peripheral resistance
vessels, contributing to the TPR reduction at rest and at peak exercise.
Second, peripheral vascular resistance also may be reduced by an attenuation
of sympathetic activity and an increased vagal tone as noted after exercise
training in healthy subjects and heart failure patients.21
In the present study, however, changes in plasma catecholamine levels were
not correlated with changes in TPR, indicating that training-induced afterload
reduction is not solely caused by reduced plasma catecholamines.
The reduction in TPR after exercise training was significantly correlated
to changes in stroke volume and LV end diastolic diameter, suggesting that
an afterload reduction leads to an increase in stroke volume and reduction
in cardiomegaly in patients with chronic heart failure. However, with regard
to the formula used for calculating TPR, an inverse correlation between stroke
volume and TPR is to be expected in the absence of major changes in blood
pressure gradient and heart rate. Thus, the changes in LV stroke volume should
be thought of as secondary effects of exercise therapy related to improved
Our study should be interpreted in light of several limitations. The
study was conducted at only 1 center, involved only men, and was limited to
a relatively young (mean age, 55 years) group of patients with chronic heart
failure. The results may not be generalizable to all patients with chronic
heart failure. Moreover, a relatively small proportion of patients in this
study were taking β-blockers. We cannot predict from our data how these
findings may apply to patient groups with more use of β-blockers for
treatment of chronic heart failure.
In summary, the present study demonstrates that in addition to well-known
peripheral adaptations, home-based exercise training in patients with chronic
heart failure results in a considerable reduction of TPR, a small but significant
improvement in LV stroke volume, and reduction in cardiomegaly. Although several
questions regarding optimal training protocol and training intensity remain
unanswered, the present findings may have important implications for rehabilitation
of patients with chronic heart failure.
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