Nonselective β-Adrenergic Blockade With Carvedilol Does Not Hinder the Benefits of Exercise Training in Patients With Congestive Heart Failure
Background Long-term β-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 β-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 β-adrenergic blockade with carvedilol or propranolol does not prevent patients with CHF from deriving systemic and regional benefits from physical training.
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 V̇o2 in patients with CHF.4 5 The apparent discrepancy between improved functional class and LV performance and unchanged peak V̇o2 may be related to the β-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 V̇o2, 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 β-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 β-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–β-blocking effects of carvedilol (ie, its vasodilating and antioxidant properties).
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.
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 V̇o2
Peak V̇o2 was determined with patients on an upright bicycle ergometer using a 10 W/min ramp (Medical Graphics CPX System). Peak V̇o2 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 V̇o2 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 V̇o2. Initial sessions lasted 15 minutes, but patients were able to train for 60 minutes by the fourth week. Workload was adjusted after peak V̇o2 was evaluated at the midpoint of the training period to maintain a training level corresponding to 50% of peak V̇o2.
Results are expressed as mean±SD. Peak V̇o2 measurements obtained in patients who trained or remained sedentary while treated with carvedilol were compared using a two-factor within-subject ANOVA model. Peak V̇o2 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).
Peak V̇o2 was unchanged in all patients for the 3 weeks before exercise training (Fig 1⇓). Peak V̇o2 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 V̇o2 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 V̇o2 similarly increased in patients who underwent exercise training while being treated with propranolol (Fig 1⇓).
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 V̇o2 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.
The present data indicate that long-term β-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 V̇o2, respectively, which is similar to the 30% increase previously reported in patients who were treated with only triple therapy (without β-adrenergic blockade).13
Exercise Training and Nonselective β-Adrenergic Blockade in Normal Subjects
When assessed on the basis of changes in peak V̇o2, the effects of exercise training during long-term nonselective β-adrenergic blockade are controversial in normal subjects. After 6 to 13 weeks of exercise training, some investigators14 15 have reported an increase in peak V̇o2, whereas others have not.8 9 10 16 All investigators, even those who failed to observe an increase in peak V̇o2, 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 β-Adrenergic Blockade in Patients With Coronary Artery Disease
Unlike normal subjects, patients with coronary artery disease who are treated with nonselective β-adrenergic–blocking agents experience a consistent increase in peak V̇o2 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 V̇o2 when patients are treated with nonselective β-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 β-adrenergic–blocking agents.21 22 23 24 Exercise training at conventional and low workloads increases peak V̇o2 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 β-adrenergic blockade in addition to triple therapy.
Carvedilol Therapy and Exercise Training
Despite symptomatic relief, long-term β-adrenergic blockade with carvedilol does not improve peak V̇o2 in patients with CHF.2 4 6 Such a lack of improvement in peak V̇o2 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 V̇o2 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 V̇o2 in untrained patients with CHF whose peak V̇o2 is primarily limited by peripheral abnormalities remains to be studied.
Exercise training increased peak V̇o2 in patients with CHF who were treated with nonselective β-adrenergic blockade therapy in addition to conventional pharmacological treatment.
Selected Abbreviations and Acronyms
|CHF||=||congestive heart failure|
|LV||=||left ventricular; left ventricle|
|PRH||=||peak reactive hyperemia|
|V̇ o 2||=||oxygen consumption|
- Received December 16, 1996.
- Revision received February 7, 1997.
- Accepted February 20, 1997.
- Copyright © 1997 by American Heart Association
Australia–New Zealand Heart Failure Research Collaborative Group. Effects of carvedilol, a vasodilator-β-blocker, in patients with congestive heart failure due to ischemic heart disease. Circulation. 1995;92:212-218.
Krum H, Sackner-Bernstein JD, Goldsmith RL, Kukin ML, Schwartz B, Penn J, Medina N, Yushak M, Horn E, Katz SD, Levin HR, Neuberg GW, DeLong G, Packer M. Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation. 1995;92:1499-1506.
Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yanowitz FD, Bristow MR. Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study. J Am Coll Cardiol. 1995;25:1225-1231.
Metra M, Nardi M, Giubbini F, Dei Cas L. Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1994;24:1678-1687.
Gilbert EM, Anderson JL, Deitchman D, Yanowitz FG, O’Connell JB, Renlund DG, Bartholomew M, Mealy PC, Larrabee P, Bristow MR. Long-term β blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo. Am J Med. 1990;88:223-229.
Minotti JR, Massie BM. Exercise training in heart failure patients: does reversing the peripheral abnormalities protect the heart? Circulation. 1992;85:2323-2325.
Sable DL, Brammell HL, Sheehan MW, Nies AS, Gerber J, Horwitz LD. Attenuation of exercise conditioning by β-adrenergic blockade. Circulation. 1982;65:679-684.
Wolfel EE, Hiatt WR, Brammell HL, Carry MR, Ringel SP, Travis V, Horwitz LD. Effects of selective and nonselective β-adrenergic blockade on mechanisms of exercise conditioning. Circulation. 1986;74:664-674.
Jondeau G, Katz SD, Zohman L, Goldberger M, McCarthy M, Bourdarias J-P, LeJemtel TH. Active skeletal muscle mass and cardiopulmonary reserve: failure to attain peak aerobic capacity during maximal bicycle exercise in patients with severe congestive heart failure. Circulation. 1992;86:1351-1356.
Demopoulos L, Bijou R, Fergus I, Jones M, Strom J, LeJemtel TH. Exercise training in patients with congestive heart failure: enhancing peak aerobic capacity while minimizing the rise in ventricular wall stress. J Am Coll Cardiol. In press.
Svedenhag J, Henriksson J, Juhlin-Dannfelt A. β-Adrenergic blockade and training in human subjects: effects on muscle metabolic capacity. Am J Physiol. 1984;247:E305-E311.
Pratt CM, Welton DE, Squires WG Jr, Kirby TE, Hartung H, Miller RR. Demonstration of training effect during chronic β-adrenergic blockade in patients with coronary artery disease. Circulation. 1981;64:1125-1129.
Vanhees L, Eagard R, Amery A. Influence of beta adrenergic blockade on effects of physical training in patients with ischaemic heart disease. Br Heart J. 1982;48:33-38.
Sullivan MJ, Higginbotham MB, Cobb FR. Exercise training in patients with severe left ventricular dysfunction: hemodynamic and metabolic effects. Circulation. 1988;78:506-515.
Coats AJS, Adamopoulos S, Radaelli A, McCance A, Meyer TE, Bernardi L, Solda PL, Davey P, Ormerod O, Forfar C, Conway J, Sleight P. Controlled trial of physical training in chronic heart failure: exercise performance, hemodynamics, ventilation, and autonomic function. Circulation. 1992;85;2119-2131.
Hambrecht R, Niebauer J, Fiehn E, Kalberer B, Offner B, Hauer K, Riede U, Schlierf G, Kubler W, Schuler G. Physical training in patients with stable chronic heart failure: effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscles. J Am Coll Cardiol. 1995;25:1239-1249.
Minotti JR, Johnson EC, Hudson TL, Zuroske G, Murata G, Fukushima E, Cagle TG, Chick TW, Massie BM, Icenogie MV. Skeletal muscle response to exercise training in congestive heart failure. J Clin Invest. 1990;86:751-758.