(Circulation. 1997;95:1764-1767.)
© 1997 American Heart Association, Inc.
Articles |
Nonselective ß-Adrenergic Blockade With Carvedilol Does Not Hinder the Benefits of Exercise Training in Patients With Congestive Heart Failure
From the Department of Medicine (L.D., M.Y., M.G., R.B., M.J., T.H.L.), Division of Cardiology, The Albert Einstein College of Medicine, Bronx, NY; Ospedale Casa Sollievo della Sofferenza (M.T.), San Giovanni, Rotundo, Italy; and Division of Circulatory Physiology (S.D.K., D.M.), Columbia Presbyterian Hospital, New York, NY.
Correspondence to Thierry H. LeJemtel, MD, Albert Einstein College of Medicine, 1300 Morris Park Ave, Forchheimer G-42, Bronx, NY 10461.
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Abstract |
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Background Long-term ß-adrenergic blockade does not appear to be associated with drug-induced training in patients with congestive heart failure (CHF); whether exercise training can increase peak aerobic capacity in patients with CHF who are treated with ß-adrenergic blockers is currently unknown.
Methods and Results We studied 23 patients with CHF who were treated with carvedilol or propranolol in addition to ACE inhibitors, furosemide, and digoxin. Of the patients treated with carvedilol, 8 underwent exercise training and 8 remained sedentary. All 7 patients treated with propranolol underwent exercise training. Peak oxygen consumption (mL·kg-1·min-1) was serially measured in trained and sedentary patients. Peak reactive hyperemia (mL·min-1·100 mL-1) was determined in the calf and forearm immediately before and after 12 weeks of training. The peak oxygen consumption of trained patients treated with either carvedilol or propranolol increased from 12.9±1.4 to 16.0±1.6 (P<.001) and 12.4±1.0 to 15.7±0.9 (P<.001) mL·kg-1·min-1, respectively, whereas it did not change in the sedentary patients. Peak reactive hyperemia increased significantly in the calves but not the forearms of trained patients.
Conclusions Long-term, nonselective ß-adrenergic blockade with carvedilol or propranolol does not prevent patients with CHF from deriving systemic and regional benefits from physical training.
Key Words: carvedilol • receptors, adrenergic, beta • heart failure • exercise • regional blood flow • vasculature
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Introduction |
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Long-term therapy with carvedilol improves resting LV performance and functional class and may enhance survival in patients with CHF.1 2 3 However, long-term therapy with carvedilol does not increase peak
O2 in patients with
CHF.4 5 The apparent discrepancy between improved
functional class and LV performance and unchanged peak
O2 may be related to the
ß-adrenergic–blocking properties of carvedilol.6
ACE inhibition, which is similarly associated with improved functional
class in patients with CHF, is also associated with an increase in peak
O2, a "training" effect that
presumably results from a spontaneous increase in patient activity as
symptoms decrease (ie, drug-induced physical
conditioning).7 Of note, in addition to blunting the heart
rate response to maximal exercise, long-term ß-adrenergic blockade
may prevent drug-induced physical conditioning.8 9 10
Attenuation or abolition of drug-induced physical conditioning may
result from the lack of reversal of the peripheral
abnormalities that primarily limit peak aerobic capacity in patients
with advanced CHF.11
The present study was undertaken to evaluate the potential
interaction between long-term, nonselective ß-adrenergic blockade and
exercise training. Of 16 patients with CHF treated with carvedilol for
4 months, 8 underwent exercise training and 8 remained sedentary. An
additional 7 patients with CHF who had been treated for 4 months with
propranolol underwent training that was similar to that of
the patients who had been treated with carvedilol. These patients
served as an additional control group to exclude the influence of
non–ß-blocking effects of carvedilol (ie, its vasodilating and
antioxidant properties).
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Methods |
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Patient Population
Carvedilol. We studied 16 patients who had CHF despite therapy with ACE inhibitors, furosemide, digoxin, and carvedilol. Therapy with carvedilol had been initiated in all patients
4 months before enrollment. Ten patients were treated with
25 mg carvedilol BID, 3 patients received 50 mg BID, and the remaining
3 patients received 12.5 mg BID. The first 8 patients who were treated
with carvedilol were assigned to exercise training, whereas the
remaining 8 patients served as control subjects.
Propranolol. We studied 7 patients who had CHF
despite therapy with ACE inhibitors, furosemide, digoxin,
and propranolol. Therapy with propranolol had
been initiated 4 months before the study. Three patients were treated
with 40 mg QID, 3 with 20 mg QID, and 1 with 60 mg QID.
The baseline characteristics of the study population are detailed in
the Table
. No patient had a change in their medical
regimen for the duration of the study.
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The exercise training protocol was approved by the Committee on Clinical Investigations at the Albert Einstein College of Medicine for patients with CHF, all of whom gave written informed consent.
Measurement of Peak O2
Peak O2 was determined with
patients on an upright bicycle ergometer using a 10 W/min ramp (Medical
Graphics CPX System). Peak O2 was
measured 3 weeks before and at the time of enrollment in the study and
6 and 12 weeks after enrollment. Each patient performed at least three
maximal graded exercise tests at each time point until two values were
obtained for peak O2 that were within
10% of each other. The highest value was then used for
analysis.
Limb Peak Hyperemic Blood Flow Determination
Mercury-in-Silastic strain-gauge plethysmography with venous
occlusion was used to measure forearm and calf blood flows in
mL · min-1 · 100 mL-1 of limb volume
before and after 12 weeks of training.12 Baseline blood
flow in the forearm or calf was recorded for 2 minutes and
calculated as the mean of at least three values. Reactive
hyperemic flows were measured after release of 5 minutes of
arterial occlusion at 5 seconds, 15 seconds, and then every
15 seconds thereafter for 1 minute. The highest measurement was
considered the peak reactive hyperemic flow (PRH).
Exercise Training Protocol
Patients exercised on a semirecumbent bicycle (Tunturi E803)
four times per week for 12 weeks at a workload corresponding to 50% of
baseline peak O2. Initial sessions
lasted 15 minutes, but patients were able to train for 60 minutes by
the fourth week. Workload was adjusted after peak
O2 was evaluated at the midpoint of the
training period to maintain a training level corresponding to 50% of
peak O2.
Statistical Analysis
Results are expressed as mean±SD. Peak
O2 measurements obtained in patients who
trained or remained sedentary while treated with carvedilol were
compared using a two-factor within-subject ANOVA model. Peak
O2 measurements obtained in patients who
trained while treated with propranolol were
analyzed using a one-factor repeated-measurement ANOVA.
Statistical significance was accepted at the 95% confidence level
(P<.05).
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Peak
O2 was unchanged in all
patients for the 3 weeks before exercise training (Fig 1). Peak O2 of patients
who underwent exercise training while being treated with carvedilol
increased from 12.9±1.4 to 14.8±1.5 and to 16.0±1.6
mL·kg-1·min-1
after 6 and 12 weeks, respectively (P<.001 for both
baseline versus 6 weeks and 12 weeks versus 6 weeks [Fig 1]). At the
completion of the study, peak O2 was
significantly higher in patients who underwent exercise training
compared with those who did not: 16.0±1.6 versus 12.9±2.1
mL·kg-1·min-1
(P<.001). Peak O2 similarly
increased in patients who underwent exercise training while being
treated with propranolol (Fig 1).
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), in 7 patients who
underwent exercise training while treated with propranolol
(
), and in 8 patients who were asked to continue their usual
daily activities and serve as controls while treated with carvedilol
(
). Peak 
P<.001 vs 6 weeks for both carvedilol- and
propranolol-treated patients. Error bars have been omitted
for clarity.
Calf PRH was increased by exercise training: from 19.0±6.1 to
26.7±7.0 mL·min-1·100
mL-1 (P<.001) and from 18.0±5.7
to 26.8±6.2 mL·min-1·100
mL-1 (P<.001) in the carvedilol
and propranolol groups, respectively (Fig 2). Forearm PRH was unchanged by exercise training. The
increases in calf PRH and peak O2 values
tended to be linearly related in both patients treated with carvedilol
and those treated with propranolol (ie, r=.65,
P<.09 and r=.59, P=.16,
respectively). Rest and exercise heart rate and systolic blood
pressure were unchanged by exercise training in both groups.
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)
12 weeks of exercise training in patients who were treated with
carvedilol (n=8) or propranolol (n=7) in addition to
standard therapy (*P<.001). |
Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present data indicate that long-term ß-adrenergic blockade does not interfere with exercise training in patients with CHF. After 12 weeks of exercise training, patients who were treated with carvedilol or propranolol in addition to triple therapy experienced a 24% and 27% increase in peak
O2, respectively, which is similar to
the 30% increase previously reported in patients who were treated with
only triple therapy (without ß-adrenergic
blockade).13
Exercise Training and Nonselective ß-Adrenergic Blockade in
Normal Subjects
When assessed on the basis of changes in peak
O2, the effects of exercise training
during long-term nonselective ß-adrenergic blockade are controversial
in normal subjects. After 6 to 13 weeks of exercise training, some
investigators14 15 have reported an increase in peak
O2, whereas others have
not.8 9 10 16 All investigators, even those who failed to
observe an increase in peak O2, have
noted an improvement in respiratory capacity, capillary supply, and
lipoprotein lipase activity in the trained skeletal muscles of normal
subjects.10 14 17
Exercise Training and Nonselective ß-Adrenergic Blockade in
Patients With Coronary Artery Disease
Unlike normal subjects, patients with coronary
artery disease who are treated with nonselective
ß-adrenergic–blocking agents experience a consistent
increase in peak O2 in response to an
exercise training program.18 19 20 Of interest, Pratt et
al18 suggested that peripheral mechanisms (ie,
increased oxygen extraction and oxidative capacity) may be responsible
for the training-induced rise in peak O2
when patients are treated with nonselective ß-adrenergic
blockade.
Exercise Training in Patients With CHF
The benefits of exercise training have been previously
demonstrated in patients with CHF who were treated with digoxin,
furosemide, and ACE inhibitors but not in those treated
with ß-adrenergic–blocking agents.21 22 23 24 Exercise
training at conventional and low workloads increases peak
O2 and reverses the abnormalities of the
skeletal muscle metabolism and vasculature in patients with
CHF.13 21 23 Mitochondrial content and oxidative capacity
are consistently increased by exercise training, whereas
capillary density has been reported to be
unchanged.24 25 26
The present study extends the benefits of exercise training to patients with CHF who were treated with nonselective ß-adrenergic blockade in addition to triple therapy.
Carvedilol Therapy and Exercise Training
Despite symptomatic relief, long-term ß-adrenergic
blockade with carvedilol does not improve peak
O2 in patients with
CHF.2 4 6 Such a lack of improvement in peak
O2 suggests that a drug-induced
regression of peripheral abnormalities does not occur with
carvedilol, unlike that reported with ACE
inhibitors.27 However, because
peripheral abnormalities were not the primary determinants
of peak O2 in most patients treated so
far with carvedilol, the hypothesis has not been really
tested.2 4 6 Accordingly, whether long-term therapy with
carvedilol enhances peak O2 in untrained
patients with CHF whose peak O2 is
primarily limited by peripheral abnormalities remains to be
studied.
Conclusions
Exercise training increased peak O2
in patients with CHF who were treated with nonselective ß-adrenergic
blockade therapy in addition to conventional pharmacological
treatment.
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Selected Abbreviations and Acronyms |
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Received December 16, 1996; revision received February 7, 1997; accepted February 20, 1997.
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