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EXERCISE AND HEART FAILURE
EXERCISE IN SECONDARY PREVENTION AND CARDIAC REHABILITATION
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EXERCISE AND HEART FAILURE Andrew J. S. Coats, MA, DM, FRACP, FRCP
Chronic heart failure (CHF) is a common condition with a poor prognosis. It is associated with debilitating limiting symptoms even with optimal modern medical management. Foremost among these symptoms is severe exercise intolerance with marked fatigue and dyspnea at low exercise work loads. The severity of symptomatic exercise limitation varies between patients, and this appears to bear little relationship with the extent of the left ventricular systolic dysfunction measured at rest, or to markers of hemodynamic disturbance. In studying factors limiting exercise capacity in heart failure patients, it is necessary to compare their situation to factors limiting exercise in normal subjects. EXERCISE CAPACITY IN NORMAL SUBJECTS
In normal subjects, exercise is usually possible until maximal cardiac output is achieved, at which time a further increase in work load will produce extra CO, but with no increase in 0, uptake.14 This is termed maximal oxygen uptake (Vo,max). At between 85% and 95% of Vo,max, a point in Professor Coats is supported by the Viscount Royston Trust, the British Heart Foundation, the Clinical Research Committee of the Royal Brompton Hospital and the Asmarley Trust.
exercise is reached where there is an excessive release of CO, for the rate of 0, uptake due to a limitation in the rate of delivery of 0, leading to the onset of anaerobic muscular metabolism with lactate production. This produces arterial acidosis and directly stimulates the chemoreceptors to produce relative hyperventilation. This point is called the anerobic threshold, although whether it truly represents a distinct transition point is highly debatable." In most normal subjects, exercise is limited by cardiac reserve, with lung function rarely being the limiting factor. Training status and genetic factors determine the overall fitness to exercise, and in some people the limitation may be peripheral with impaired peripheral muscle function, and evidence that exercise is terminated before maximal 0, extraction is achieved by exercising muscle. There have been numerous studies of normal subjects undergoing training or detraining to show that exercise capacity can be increased 25% to 50% by training. Major training effects can be seen in the heart; control of ventilation; blood O2carrying capacity; peripheral blood vessels; endothelial function; and skeletal muscle bulk, function and fatigability. EXERCISE CAPACITY IN CHRONIC HEART FAILURE
In nonedematous stable and optimally treated patients with CHF, submaximal exer-
From the National Heart and Lung Institute, Imperial College of Science, Technology, and Medicine, Royal Brompton Hospital, London, United Kingdom CARDIOLOGY CLINICS VOLUME 19 NUMBER 3 * AUGUST 2001
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cise and the hemodynamic response accompanying it may be remarkably normal, with only an increase in nonessential vascular bed vasoconstrictor drive being evidence of a limited cardiac reserve. There is, however, despite preservation of arterial gas concentrations, an exaggerated ventilatory response even at low-level exercise. Most patients with CHF fail to achieve their Vo2max, and it has been shown that in contrast to normal subjects, the addition of arm exercise for a patient already performing maximal leg exercise leads to a further increase in the rate of O2 uptake.33This shows that O2delivery, and by extrapolation, cardiac output, was not maximal during the maximal leg exercise test in the CHF patients. The true limiting factor to exercise appears to reside in the periphery; either the peripheral vasculature or the skeletal muscle is failing, ie either an inability of the muscle to accept adequate blood flow or to efficiently metabolize oxygen delivered to it. A subset of CHF patients has been described in whom exercise is clearly limited by skeletal muscle metabolic inefficiency despite nonlimiting cardiac output and normal leg blood flow responses.66In others, blood flow to the muscle is limited and limiting due to the combined effects of vascular rarefaction and endothelial dysfunction. Features of the Chronic Heart Failure Syndrome
The hemodynamic profile of patients limited by fatigue differs in no substantial measure from those patients limited predominantly by dyspnea.12Ambulatory pulmonary arterial pressure monitoring has shown virtually no correlation between the hemodynamic disturbances and the symptoms noted by the patients at the time of the disturbance.26No measure of hemodynamics (with the possible exception of measures of right ventricular performance) has demonstrated a convincing capacity to predict variations in exercise capacity between patients as well as do measures of peripheral function, such as skeletal muscle strength, endothelial function or ventilatory abnormalities. Whatever treatments are used (with a few exceptions in selected patients), there is a delay between hemodynamic effect and any objective change in exercise tolerance.20Treatments such as angiotensin-converting enzyme (ACE) inhibitors and cardiac transplantation require weeks or
months to improve exercise tolerance. The delay may be due to the need to reverse some of the peripheral pathophysiological changes that have become the weakest link in the chain of oxygen delivery and utilization necessary for muscular exercise. Correlates of Exercise Capacity in Chronic Heart Failure
Much work has recently concentrated on abnormalities in peripheral blood flow, endothelial function, skeletal muscle and lung function in CHF.", 8, 15,25 These changes acting alone or in combination may lead to early muscle fatigue and dyspnea. Better correlations with exercise tolerance are seen with these peripheral abnormalities than for hemodynamic measurements.61 These limiting changes are only slowly corrected by heart failure treatments and only by treatments with an effect on the disordered periphery, either directly31or via the effects of increased physical activity producing secondary training effects. It is easy to see how major alterations in skeletal muscle and endothelial function could contribute to fatigue, and with the major abnormalities described within the lung and in two major ventilatory control reflexes (the muscle ergo or metaboreflexes and the arterial chemoreflexes),it is now also easy to understand how exercise dyspnea can be exaggerated in CHF even when hemodynamics are relatively well controlled)P, lo,27 These may also be important pathophysiological mechanisms, as abnormalities of ventilatory control have consistently been shown to accurately predict a poor prognosis in CHE6 These may be more important in predicting symptomatic limitation than even the underlying cause of the heart fail~re.3~ Patients with heart failure exhibit a subnormal peripheral blood flow response to both exercise and pharmacological vasodilatation,68 due to a combination of persistent vasoconstrictor drive, a relative paucity of peripheral blood vessels, a deficient nitric oxide vasodilator system and an enhancement of the vasoconstrictor endothelin system.21CHF patients can demonstrate evidence of early muscular lactate release despite normal skeletal muscle blood flow. An inherent defect in skeletal muscle metabolism independent of blood flow has been described in this condition.& There are abnormalities in histology, mitochondria1 structure and function, oxida-
EXERCISE AND HEART FAILURE
tive enzymes and a shift in fiber-type distributions with a predominance of type IIb over IIa fibers and many of reduced fiber dimension.% Metabolic abnormalities have also been described, including early dependence on anaerobic metabolism, excessive early depletion of high-energy phosphate bonds, and excessive early intramuscular acidification. Biopsy studies have confirmed defects in oxidative and lipolytic enzymes, succinate dehydrogenase and citrate synthetase, and p hydroxyacyl dehydrogenase. Muscle is also abnormal in gross function, showing early fatigability and reduced maximal strength in particular.8 The cause, progress and best management of these abnormalities in muscle structure and function remain unknown. Physical inactivity is likely to play a role in some cases, along with activation of catabolic processes and loss of normal anabolic function, such as insulin resistance,58elevated levels of tumor necrosis factor-a, and excessive norepinephrine levels., Anorexia and intestinal malabsorption may also play a role in some patients. We have demonstrated in the rat coronary artery ligation model of heart failure that the classical magnetic resonance spectroscopy abnormalities of muscle of heart failure (early high-energy phosphate bond depletion and early acidification) can be completely avoided by regular exercise training commencing 6 weeks after the index infarction.6 In human CHF patients, we have also demonstrated a partial correction of these muscle abnormalities by exercise training.' Respiratory muscle is also abnormal in CHF. Early muscle deoxygenation, respiratory muscle fatigue and histological changes have all been de~cribed.4~ These may contribute to the sensation of dyspnea. Whether these abnormalities can explain the excessive ventilatory response to exercise seen frequently in CHF remains unknown. The relationship between minute ventilation (VE) and CO, production (Vco,) during progressive exercise, the VE/VCO, slope, is approximately linear for most subjects at least until near maximal exercise. There are deviations from linearity in more severe heart failure cases.13 This slope is increased in heart failure. Possible causes include ventilation-perfusion mismatch within the lung, causing excessive but noncontributory ~entilation:~along with enhanced sensitivity of ventilatory control mechanisms described above. The ergoreflex system senses the metabolic state of exercis-
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ing skeletal muscle and reflexively increases ventilation. It is sensed by small work-sensitive afferents and carried by small myelinated or unmyelinated nerve fibres. Overactivity of these fibers and the resultant reflex responses have recently been described in CHF47;interestingly, it was also shown that the overactivity could be partially reduced by localized muscle training, highlighting the possible importance of muscle deconditioning in this abnormal response. The second overactive ventilatory control system in CHF is the chemoreceptor system. We have recently described augmentation of peripheral hypoxic and central CO, sensitivity in CHF patients.'O These alterations could explain the heightened ventilatory responses and also lead to excessive sympathoexcitation. The cause of the heightened chemosensitivity itself remains undetermined, but it is possible that there is a direct interaction between the ergoreflex and chemoreflex systems. EXERCISE TRAINING IN CHRONIC HEART FAILURE
Exercise training in carefully selected patients with stable mild to moderate CHF can increase exercise capacity and lessen dyspnea and fatigue.ls Early suggestions of this effect came from studies of cardiac rehabilitation in In patients with left ventricular dy~function.6~ mild to moderate CHF exercise tolerance, leg blood flow and ventilatory control was improved.56,55 In a prospective, controlled comparison of training versus restI6 in class 11-111 patients, we showed that 8 weeks of training, exercising at 60% to 80% of peak heart rate for 20 to 60 minutes 3 to 5 days per week leads to significant increases in exercise tolerance and a reduction in the symptoms during daily life. These improvements have been seen with no consistent effect on left ventricular ejection fraction, either beneficial or detrimental. Most of the beneficial effects seem to depend on training-induced adaptations in the periphery, such as are described below. History of Exercise Training in Chronic Heart Failure
Participation in an exercise program was considered an absolute contraindication in patients with significant left ventricular im-
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pairment until the 1980s. Until then, avoidance of physical exercise was the standard recommendation for all patients suffering from heart failure. This was initially challenged by uncontrolled studies that showed that selected patients with significantly impaired left ventricular function could increase their exercise tolerance after a period of exercise training.40,39, l9 In these studies, there was no detectable deterioration in left ventricular function. The earliest reports of training patients with significant left ventricular impairment were case reports or small series. The prize for the report of the first training of a heart failure patient goes to Russian investigators,4I who in 1987 reported the effects of exercise training in 15 post-myocardial infarction (MI) patients showing clinical signs of heart failure with 17 patients taken as controls. The drills continued for 11 months and included exercise therapy, bicycle ergometry and walks. In addition to a considerable increase in physical working capacity, the patients doing exercise showed a more favorable hemodynamic response to stress with a higher stroke index, a reduced heart rate increment and a greater fall in systemic peripheral resistance. Sullivan and colleagues5, 56 found that patients with severe left ventricular dysfunction, some of whom had previously suffered heart failure, improved their maximal exercise performance after a prolonged regime of physical training. They demonstrated both an increased blood flow to exercising muscle and an increased ability of skeletal muscle to extract oxygen from the nutritive blood flow. Ventilatory function was also improved, with a reduction in the respiratory exchange ratio at submaximal exercise and a delay in the anaerobic threshold. The first controlled study was published soon after. It was controlled cross-over trial in 11 subjects with stable class 11-111 CHF.16 These were carefully selected patients with CHF who could exercise without serious ventricular arrhythmias and in whom there were no other medical conditions limiting exercise tolerance. After baseline evaluation and familiarization with laboratory procedures, all patients performed 8 weeks of exercise training and 8 weeks of exercise avoidance in a randomized cross-over study. The training regime lead to approximately a 20% to 25% increase in exercise tolerance and peak oxygen consumption. There was also a significant reduction in questionnaire-rated symptoms attributable to heart failure and a coincident increase in both the extent and ease of per-
forming daily activities. In a later report on 17 subjects, it was reported17 that there was an improvement in sympatho-vagal balance, and an increase in submaximal and peak cardiac output and a reduction in the ventilatory response to exercise. Published Cross-Over Trials of Training in Chronic Heart Failure
In addition to the two reports by Coats and colleagues referred to in the paragraph above, other cross-over studies explored the physiological effects of training in patients with stable mild to moderate CHF. Adamopoulos' trained 12 patients with a homebased 8-week program of cycling at 60% to 80% maximum heart rate three times per week and showed improvements in muscle metabolism by magnetic resonance spectroscopy, including a reduced intramuscular phosphocreatine (PC) depletion and adenosine diphosphate (ADP) accumulation, P <0.003. Radaelli?' using a similar program in six patients 5 days per week for 5 weeks, showed a 15% increase in peak oxygen consumption, P <0.05, and an improved autonomic control of both heart rate and the peripheral circulation. Tyni-Lenne,'jO in 16 female heart failure patients, showed that 8 weeks of knee extensor endurance training could increase skeletal muscle citrate synthase activity by 44%, P <0.0001 and lactate dehydrogenase activity by 23%, P <0.002. There was an increase in oxidative capacity in relation to the glycolytic capacity of 23% ( P <0.002), showing plasticity of the skeletal muscle abnormalities described as accompanying CHF. In addition, peak oxygen uptake was increased 14% ( P <0.0005), and peak work rate increased 43% ( P
EXERCISE AND HEART FAILURE
weeks and showed that 6-minute walk distances increased 2070, P <0.012. Finally, Maiorana” showed in 13 patients that a circuit weight training program for 8 weeks increased peak oxygen uptake 11.8% (P <0.01) and exercise time by 18.4%, P <0.01. Maximal skeletal muscle isotonic voluntary contractile strength was increased by 17.9% (P <0.001) in the trained muscle groups. Parallel Group Trials of Training In Chronic Heart Failure
Jette in 19913, studied a group of patients with left ventricular ejection fraction <30% (n=8) and a control group of 10 subjects. Using a supervised in-hospital program lasting 4 weeks and a cycle 15 minutes three times per week at 70% to 80% maximum heart rate as well as 30 minutes of callisthenics, they demonstrated a peak oxygen consumption increase of 221 mL per minute (P <0.05) along with an increase in peak work load of 13 W (P <0.05). Koch 199237studied 12 severe heart failure patients and 13 controls using a program of 40 sessions over 90 days. They used a graded program of singlelimb training with little hemodynamic effect. Quality-of-life scores in the trained group increased 52% (P <0.0001) with no change in the control group. Belardinelli in 19925randomized 20 stable moderate heart failure subjects to train (n = 10) or control (n = 10) for a supervised 8week program of cycling at 60% of peak Oz consumption three times per week. Exercise tolerance increased 45% (P <0.005), and peak 0, uptake increased by 20% (P <0.001). The same group reported improved indices of left ventricular diastolic function along with a 12% increase in peak oxygen uptake (P <0.001) in 19953 on 36 trained patients with heart failure. A more complex design was used by Kostis,38 comparing placebo (n = 6), Digoxin (n = 7) and comprehensive cognitive therapy, with dietetic advice and exercise training (walking/rowing/cycling/stair climbing 60 minutes X 3 to 5/week at 50% to 60% max, n = 7) in stable mild heart failure, all for 12 weeks. Exercise tolerance increased by 182 seconds ( P <0.05) in the exercising group, significantly more than the other groups. Kiil a ~ u o r showed i~~ in 8 training heart failure patients compared to 12 control patients that 3 months supervised training using a cycle
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for 30 minutes 3 times per week at 50% to 60% maximal 0, consumption that exercise tolerance increased 71% at submaximal workload (P = 0.01). In addition, they showed that the high-frequency component of RR interval variability (a marker of vagal tone) increased by 22% to 55% in the training group during the day (P = 0.0001). Hambrecht in 199530trained 12 patients in a supervised setting for 3 weeks (60 min/d at 70% maximal Oz consumption) followed by home-based training (cycling 40 m i d d a y at 70% maximum with walking/callisthenics/ ball games 60 minutes twice per week) for a total of 6 months. Compared to 10 untrained control patients, peak 0, consumption increased in the trained patients by 31% (P <0.01). The biopsy-derived skeletal muscle mitochondria1 volume density increased significantly, a finding later shown to correlate well with the training-induced improvement in exercise capacity. In a second study in 1997, the same authors, using a similar trained 9 patients versus 9 controls and demonstrated enhanced skeletal muscle oxidative enzyme activity and improved mitochondria in skeletal muscle biopsies. Finally, in 2000, they showedz9in 36 trained subjects compared to 37 controls that New York Heart Association (NYHA) class improved, exercise time increased and LVEF increased from 0.30 to 0.35 (P = 0.003). In addition, peak exercise total peripheral resistance was decreased, P = 0.003. DubachZ3trained 12 patients (13 controls) for 8 weeks walking 60 minutes twice per day, cycling 40 minutes 4 times per week at 80% capacity and confirmed an increased exercise capacity in his trained group. Similar changes were reported by Reinhart in 199852 for 25 trained heart failure patients in an 8week residential program of cycle exercise for 40 minutes at 70% to 80% capacity 4 times per week and with walking 2 hours per day. They showed an increased maximal cardiac output and peak 0, consumption. Wielanger in 199962* 63 compared 41 trained and 39 control patients. Training was supervised for 12 weeks. They showed that “feelings of being disabled decreased and ”selfassessment of general well-being” along with exercise time being increased ( + 21.4%, P
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peak oxygen consumption by 30.9% and demonstrated a decreased urinary nitrate elimination in the control group (n=8) compared to an unchanged nitrate elimination in the exercise-trained group (n = 9). In 1998, Willenheimer" trained 22 CHF patients (supervised interval cycling training with 60 seconds work at 80% maximum and 30 seconds rest for 15 minutes twice per week for weeks 0 to 7 and 45 minutes 3 times a week for weeks 7 to 16). Compared to 27 control patients, peak exercise work load increased 7 W, P <0.01. Similar beneficial effects on exercise capacity (peak O2 uptake increased by 23.3% (P = 0.001) and peak work load increased by 26% (P = 0001) were seen in controlled trials of training by S t ~ r mstudying ~~ 26 patients for 12 weeks at 50% capacity training progressing to 100 minutes of step aerobics and 50 minutes of cycling per week. K e t e ~ i a nshowed ~~ in 21 trained patients (33 minutes x 3/wk at 60% to 80% maximum heart rate using cycling, rowing, arm, treadmill for 24 weeks) compared to 22 controls an increase in peak Ozuptake (P <0.05), and an improved chronotropic response to exercise. Quittan in 199950employed aerobics 3 hours per week in 25 CHF patients and showed improved quality of life assessments (P = O.OOOl), increased physical role fulfillment scores ( P = 0.001) and improved scores for physical ( P = 0.02) and social (P = 0.0002) functioning. Peak Ozuptake and exercise time were also increased, P <0.01. Finally and perhaps most significantly of all the trials published to date, Belardinelli in 19994showed in a study with 50 trained and 49 control heart failure patients that a supervised 8-week training program of cycling at 60% peak capacity 3 times per week followed by a supervised 12-month maintenance program of 2 sessions per week (including 20 minutes of stretching exercises and 40 minutes of cycle exercise) that peak oxygen consumption was increased 18% at 2 months (P <0.001) and that this was associated with a lower mortality (n = 9 versus n = 20, relative risk = 0.37; 95% confidence interval, 0.17 to 0.84; P = 0.01). There were also fewer hospital readmissions for heart failure (5 versus 14; RR=O.29; 95% C1, 0.11 to 0.88; P = 0.02). It is too early to stay that this is the proof we need to recommend training as a disease modifying intervention, but clearly it encourages further ~tUdy.4~ A summary of trials performed by one collaborative European groupz4and an overview
of all trials published to 19984s have both demonstrated a consistent increase in exercise capacity across a broad range of heart failure patients of approximately 15% to 20%. Beneficial changes produced by training have included improvements in hemodynamic responses, myocardial perfusion, diastolic function, skeletal muscle function and histological and biochemical responses, ventilatory control, peripheral vascular and endothelial function and neurohormonal and autonomic improvements. UNANSWERED QUESTIONS
Although there have been many reports of training, few report prospective comparisons of the elements of the training program. Important questions, such as the optimal frequency and intensity of training, the necessary duration for training effects and how long after cessation of a formal program they last, remain unanswered. Beyond this, details of the most appropriate selection of patients, the elements of the training program and any possible interaction with modern heart failure medications remain valid questions for fu.ture controlled trials. Although cardiovascular medicine has made many strides in the last decade in randomized controlled trials of effective treatments, this oldest of physical therapies remains enormously difficult to evaluate, at least in part, because our modern system of funding trials remains firmly in favor of commercial patentable treatments. An adequate program of government support for randomized noncommercializable treatment trials will be needed if these important questions are to receive a timely answer. References Adamopoulos S, Coats AJ, Brunotte F, et al: Physical training improves skeletal muscle metabolism in patients with chronic heart failure. J Am Coll Cardiol 21:llOl-1106, 1993 Anker SD, Volterrani M, Swan J, et al: Hormonal changes in cardiac cachexia. Circ 92:I-206-1-207, 1995 Belardinelli R, Georgiou D, Cianci G, et al: Exercise training improves left ventricular diastolic filling in patients with dilated cardiomyopathy. Clinical and prognostic implications. Circulation 91:2775434, 1995 Belardinelli R, Georgiou D, Cianci G, et al: Randomized, controlled trial of long-term moderate exercise training in chronic heart failure: Effects on functional capacity, quality of life, and clinical outcome. Circulation 99A173-82, 1999
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40. Letac B, Cribier A, Desplanches J F A study of left ventricular function in coronary patients before and after physical training. Circulation 56375-378, 1977 41. Lipchenko AA, Fomin IL: Ispol'zovanie fizicheskikh trenirovok dlia reabilitatsii bol'nykh s postinfarktonoi serdechnoi nedostatochnost'iu. [Use of physical training in the rehabilitation of patients with post-infarct heart failure] Kardiologiia 2748-52, 1987 42. Maiorana A, ODriscoll G, Cheetham C, et a1 Combined aerobic and resistance exercise training improves functional capacity and strength in CHF. J Appl Physiol88:1565-70, 2000 43. Mancini DM, Henson D, LaManca J, et al: Evidence of reduced respiratory muscle endurance in patients with heart failure. J Am Coll Cardiol24972-981,1994 44. Massie BM, Conway M, Rajagopalan B, et al: Skeletal muscle metaboiism during exercise under ischemic conditions in congestive heart failure. Evidence for abnormalities unrelated to blood flow. Circulation 78:32&326,1988 45. Ohtsubo M, Yonezawa K, Nishijima H, et al: Metabolic abnormality of calf skeletal muscle is improved by localised muscle training without changes in blood flow in chronic heart failure. Heart 7843743, 1997 46. Owen A, Croucher L: Effect of an exercise programme for elderly patients with heart failure. Eur J Heart Fail 1:65-70, 2000 47. Piepoli M, Clark AL, Volterrani M, et al: Contribution of muscle afferents to the hemodynamic, autonomic, and ventilatory responses to exercise in patients with chronic heart failure: Effects of physical training. Circulation 93:940-952, 1996 48. Piepoli MF, Flather M, Coats AJ: Overview of studies of exercise training in chronic heart failure: The need for a prospective randomized multicentre European trial. Eur Heart J 19:830-841, 1998 49. Piepoli MF, Capucci A Exercise training in heart failure: Effect on morbidity and mortality. Int J Cardiol Mar 31, 2000;73(1):3-6 50. Quittan M, Sturm B, Wiesinger GF, et al: Quality of life in patients with chronic heart failure: A randomized controlled trial of changes induced by a regular exercise program. Scand J Rehabil Med 31223-8,1999 51. Radaelli A, Coats AJ, Leuzzi S, et al: Physical training enhances sympathetic and parasympathetic control of heart rate and peripheral vessels in chronic heart failure. Clin Sci (Colch) 9k92-4, 1996 52. Reinhart WH, Dziekan G, Goebbels U, et a1 Influence of exercise training on blood viscosity in patients with coronary artery disease and impaired left ventricular function. Am Heart J 135379432,1998 53. Sturm B, Quittan M, Wiesinger GF, et al: Moderateintensity exercise training with elements of step aerobics in patients with severe chronic heart failure. Arch Phys Med Rehabil80:74&50,1999 54. Sullivan MJ, Green HJ, Cobb FR Skeletal muscle
biochemistry and histology in ambulatory patients with long-term heart failure. Circ 1:518-527, 1990 55. Sullivan MJ, Higginbotham MB, Cobb FR Exercise training in patients with severe left ventricular dysfunction: Hemodynamic and metabolic effects. Circulation 78:506-516, 1988 56. Sullivan MJ, Higginbotham MB, Cobb FR Exercise training in patients with chronic heart failure delays ventilatory anaerobic threshold and improves submaximal exercise performance. Circulation, 79324329,1989 57. Sullivan MJ, Higginbotham MB, Cobb FR Increased exercise ventilation in patients with chronic heart failure: Intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circ 77:552559,1988 Walton C, Godsland IF, et al: Insulin resis58. Swan JW, tance in chronic heart failure. Eur Heart, 15:15281532, 1994 59. Taylor A Physiological response to a short period of exercise training in patients with chronic heart failure. Physiother Res Int, 493749, 1999 60. Tpi-Lenne R, Gordon A, Jansson E, et al: Skeletal muscle endurance training improves peripheral oxidative capacity, exercise tolerance, and health-related quality of life in women with chronic congestive heart failure secondary to either ischemic cardiomyopathy or idiopathic dilated cardiomyopathy. Am J Cardiol 80:1025-9, 1997 61. Volterrani M, Clark AL, Ludman PF, et al: Determinants of exercise capacity in chronic heart failure. Eur Heart J, 15:8014309, 1994 62. Wielenga RP, Erdman RA, Huisveld IA, et al: Effect of exercise training on quality of life in patients with chronic heart failure. J Psychosom Res 45:459-64, 1998 63. Wielenga RP, Huisveld IA, Bol E, et al: Safety and effects of physical training in chronic heart failure. Results of the Chronic Heart Failure and Graded Exercise study (CHANGE) Eur Heart J 20:872-9,1999 64. Willenheimer R, Erhardt L, Cline C, et al: Exercise training in heart failure improves quality of life and exercise capacity. Eur. Heart J. 19776781,1998 65. Williams R S Exercise training of patients with ventricular dysfunction and heart failure. Cardiovasc Clin 15:218-231, 1985 66. Wilson JR, Mancini DM, Dunkman WB Exertional fatigue due to skeletal muscle dysfunction in patients with heart failure. Circulation 87470-475, 1993 67. Wilson JR, Martin JL, Ferraro N: Impaired skeletal muscle nutritive flow during exercise in patients with congestive heart failure: Role of cardiac pump dysfunction as determined by the effect of dobutamine. Am J Cardiol53:1308-1315, 1984 68. Zelis R, News SH, Longhurst J, Lee G, Mason DT Abnormalities in the regional circulations accompanying congestive heart failure. Progress in Cardiovascular Diseases 18181-199, 1975
Address reprint requests to Andrew J. S. Coats, MA, DM National Heart and Lung Institute Imperial College of Science, Technology and Medicine Royal Brompton Hospital London, SW3 6NP, UK e-mail: a.coatsOic.ac.uk
0733-8651/01 $15.00
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EXERCISE AND HEART FAILURE Andrew J. S. Coats, MA, DM, FRACP, FRCP
Chronic heart failure (CHF) is a common condition with a poor prognosis. It is associated with debilitating limiting symptoms even with optimal modern medical management. Foremost among these symptoms is severe exercise intolerance with marked fatigue and dyspnea at low exercise work loads. The severity of symptomatic exercise limitation varies between patients, and this appears to bear little relationship with the extent of the left ventricular systolic dysfunction measured at rest, or to markers of hemodynamic disturbance. In studying factors limiting exercise capacity in heart failure patients, it is necessary to compare their situation to factors limiting exercise in normal subjects. EXERCISE CAPACITY IN NORMAL SUBJECTS
In normal subjects, exercise is usually possible until maximal cardiac output is achieved, at which time a further increase in work load will produce extra CO, but with no increase in 0, uptake.14 This is termed maximal oxygen uptake (Vo,max). At between 85% and 95% of Vo,max, a point in Professor Coats is supported by the Viscount Royston Trust, the British Heart Foundation, the Clinical Research Committee of the Royal Brompton Hospital and the Asmarley Trust.
exercise is reached where there is an excessive release of CO, for the rate of 0, uptake due to a limitation in the rate of delivery of 0, leading to the onset of anaerobic muscular metabolism with lactate production. This produces arterial acidosis and directly stimulates the chemoreceptors to produce relative hyperventilation. This point is called the anerobic threshold, although whether it truly represents a distinct transition point is highly debatable." In most normal subjects, exercise is limited by cardiac reserve, with lung function rarely being the limiting factor. Training status and genetic factors determine the overall fitness to exercise, and in some people the limitation may be peripheral with impaired peripheral muscle function, and evidence that exercise is terminated before maximal 0, extraction is achieved by exercising muscle. There have been numerous studies of normal subjects undergoing training or detraining to show that exercise capacity can be increased 25% to 50% by training. Major training effects can be seen in the heart; control of ventilation; blood O2carrying capacity; peripheral blood vessels; endothelial function; and skeletal muscle bulk, function and fatigability. EXERCISE CAPACITY IN CHRONIC HEART FAILURE
In nonedematous stable and optimally treated patients with CHF, submaximal exer-
From the National Heart and Lung Institute, Imperial College of Science, Technology, and Medicine, Royal Brompton Hospital, London, United Kingdom CARDIOLOGY CLINICS VOLUME 19 NUMBER 3 * AUGUST 2001
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cise and the hemodynamic response accompanying it may be remarkably normal, with only an increase in nonessential vascular bed vasoconstrictor drive being evidence of a limited cardiac reserve. There is, however, despite preservation of arterial gas concentrations, an exaggerated ventilatory response even at low-level exercise. Most patients with CHF fail to achieve their Vo2max, and it has been shown that in contrast to normal subjects, the addition of arm exercise for a patient already performing maximal leg exercise leads to a further increase in the rate of O2 uptake.33This shows that O2delivery, and by extrapolation, cardiac output, was not maximal during the maximal leg exercise test in the CHF patients. The true limiting factor to exercise appears to reside in the periphery; either the peripheral vasculature or the skeletal muscle is failing, ie either an inability of the muscle to accept adequate blood flow or to efficiently metabolize oxygen delivered to it. A subset of CHF patients has been described in whom exercise is clearly limited by skeletal muscle metabolic inefficiency despite nonlimiting cardiac output and normal leg blood flow responses.66In others, blood flow to the muscle is limited and limiting due to the combined effects of vascular rarefaction and endothelial dysfunction. Features of the Chronic Heart Failure Syndrome
The hemodynamic profile of patients limited by fatigue differs in no substantial measure from those patients limited predominantly by dyspnea.12Ambulatory pulmonary arterial pressure monitoring has shown virtually no correlation between the hemodynamic disturbances and the symptoms noted by the patients at the time of the disturbance.26No measure of hemodynamics (with the possible exception of measures of right ventricular performance) has demonstrated a convincing capacity to predict variations in exercise capacity between patients as well as do measures of peripheral function, such as skeletal muscle strength, endothelial function or ventilatory abnormalities. Whatever treatments are used (with a few exceptions in selected patients), there is a delay between hemodynamic effect and any objective change in exercise tolerance.20Treatments such as angiotensin-converting enzyme (ACE) inhibitors and cardiac transplantation require weeks or
months to improve exercise tolerance. The delay may be due to the need to reverse some of the peripheral pathophysiological changes that have become the weakest link in the chain of oxygen delivery and utilization necessary for muscular exercise. Correlates of Exercise Capacity in Chronic Heart Failure
Much work has recently concentrated on abnormalities in peripheral blood flow, endothelial function, skeletal muscle and lung function in CHF.", 8, 15,25 These changes acting alone or in combination may lead to early muscle fatigue and dyspnea. Better correlations with exercise tolerance are seen with these peripheral abnormalities than for hemodynamic measurements.61 These limiting changes are only slowly corrected by heart failure treatments and only by treatments with an effect on the disordered periphery, either directly31or via the effects of increased physical activity producing secondary training effects. It is easy to see how major alterations in skeletal muscle and endothelial function could contribute to fatigue, and with the major abnormalities described within the lung and in two major ventilatory control reflexes (the muscle ergo or metaboreflexes and the arterial chemoreflexes),it is now also easy to understand how exercise dyspnea can be exaggerated in CHF even when hemodynamics are relatively well controlled)P, lo,27 These may also be important pathophysiological mechanisms, as abnormalities of ventilatory control have consistently been shown to accurately predict a poor prognosis in CHE6 These may be more important in predicting symptomatic limitation than even the underlying cause of the heart fail~re.3~ Patients with heart failure exhibit a subnormal peripheral blood flow response to both exercise and pharmacological vasodilatation,68 due to a combination of persistent vasoconstrictor drive, a relative paucity of peripheral blood vessels, a deficient nitric oxide vasodilator system and an enhancement of the vasoconstrictor endothelin system.21CHF patients can demonstrate evidence of early muscular lactate release despite normal skeletal muscle blood flow. An inherent defect in skeletal muscle metabolism independent of blood flow has been described in this condition.& There are abnormalities in histology, mitochondria1 structure and function, oxida-
EXERCISE AND HEART FAILURE
tive enzymes and a shift in fiber-type distributions with a predominance of type IIb over IIa fibers and many of reduced fiber dimension.% Metabolic abnormalities have also been described, including early dependence on anaerobic metabolism, excessive early depletion of high-energy phosphate bonds, and excessive early intramuscular acidification. Biopsy studies have confirmed defects in oxidative and lipolytic enzymes, succinate dehydrogenase and citrate synthetase, and p hydroxyacyl dehydrogenase. Muscle is also abnormal in gross function, showing early fatigability and reduced maximal strength in particular.8 The cause, progress and best management of these abnormalities in muscle structure and function remain unknown. Physical inactivity is likely to play a role in some cases, along with activation of catabolic processes and loss of normal anabolic function, such as insulin resistance,58elevated levels of tumor necrosis factor-a, and excessive norepinephrine levels., Anorexia and intestinal malabsorption may also play a role in some patients. We have demonstrated in the rat coronary artery ligation model of heart failure that the classical magnetic resonance spectroscopy abnormalities of muscle of heart failure (early high-energy phosphate bond depletion and early acidification) can be completely avoided by regular exercise training commencing 6 weeks after the index infarction.6 In human CHF patients, we have also demonstrated a partial correction of these muscle abnormalities by exercise training.' Respiratory muscle is also abnormal in CHF. Early muscle deoxygenation, respiratory muscle fatigue and histological changes have all been de~cribed.4~ These may contribute to the sensation of dyspnea. Whether these abnormalities can explain the excessive ventilatory response to exercise seen frequently in CHF remains unknown. The relationship between minute ventilation (VE) and CO, production (Vco,) during progressive exercise, the VE/VCO, slope, is approximately linear for most subjects at least until near maximal exercise. There are deviations from linearity in more severe heart failure cases.13 This slope is increased in heart failure. Possible causes include ventilation-perfusion mismatch within the lung, causing excessive but noncontributory ~entilation:~along with enhanced sensitivity of ventilatory control mechanisms described above. The ergoreflex system senses the metabolic state of exercis-
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ing skeletal muscle and reflexively increases ventilation. It is sensed by small work-sensitive afferents and carried by small myelinated or unmyelinated nerve fibres. Overactivity of these fibers and the resultant reflex responses have recently been described in CHF47;interestingly, it was also shown that the overactivity could be partially reduced by localized muscle training, highlighting the possible importance of muscle deconditioning in this abnormal response. The second overactive ventilatory control system in CHF is the chemoreceptor system. We have recently described augmentation of peripheral hypoxic and central CO, sensitivity in CHF patients.'O These alterations could explain the heightened ventilatory responses and also lead to excessive sympathoexcitation. The cause of the heightened chemosensitivity itself remains undetermined, but it is possible that there is a direct interaction between the ergoreflex and chemoreflex systems. EXERCISE TRAINING IN CHRONIC HEART FAILURE
Exercise training in carefully selected patients with stable mild to moderate CHF can increase exercise capacity and lessen dyspnea and fatigue.ls Early suggestions of this effect came from studies of cardiac rehabilitation in In patients with left ventricular dy~function.6~ mild to moderate CHF exercise tolerance, leg blood flow and ventilatory control was improved.56,55 In a prospective, controlled comparison of training versus restI6 in class 11-111 patients, we showed that 8 weeks of training, exercising at 60% to 80% of peak heart rate for 20 to 60 minutes 3 to 5 days per week leads to significant increases in exercise tolerance and a reduction in the symptoms during daily life. These improvements have been seen with no consistent effect on left ventricular ejection fraction, either beneficial or detrimental. Most of the beneficial effects seem to depend on training-induced adaptations in the periphery, such as are described below. History of Exercise Training in Chronic Heart Failure
Participation in an exercise program was considered an absolute contraindication in patients with significant left ventricular im-
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pairment until the 1980s. Until then, avoidance of physical exercise was the standard recommendation for all patients suffering from heart failure. This was initially challenged by uncontrolled studies that showed that selected patients with significantly impaired left ventricular function could increase their exercise tolerance after a period of exercise training.40,39, l9 In these studies, there was no detectable deterioration in left ventricular function. The earliest reports of training patients with significant left ventricular impairment were case reports or small series. The prize for the report of the first training of a heart failure patient goes to Russian investigators,4I who in 1987 reported the effects of exercise training in 15 post-myocardial infarction (MI) patients showing clinical signs of heart failure with 17 patients taken as controls. The drills continued for 11 months and included exercise therapy, bicycle ergometry and walks. In addition to a considerable increase in physical working capacity, the patients doing exercise showed a more favorable hemodynamic response to stress with a higher stroke index, a reduced heart rate increment and a greater fall in systemic peripheral resistance. Sullivan and colleagues5, 56 found that patients with severe left ventricular dysfunction, some of whom had previously suffered heart failure, improved their maximal exercise performance after a prolonged regime of physical training. They demonstrated both an increased blood flow to exercising muscle and an increased ability of skeletal muscle to extract oxygen from the nutritive blood flow. Ventilatory function was also improved, with a reduction in the respiratory exchange ratio at submaximal exercise and a delay in the anaerobic threshold. The first controlled study was published soon after. It was controlled cross-over trial in 11 subjects with stable class 11-111 CHF.16 These were carefully selected patients with CHF who could exercise without serious ventricular arrhythmias and in whom there were no other medical conditions limiting exercise tolerance. After baseline evaluation and familiarization with laboratory procedures, all patients performed 8 weeks of exercise training and 8 weeks of exercise avoidance in a randomized cross-over study. The training regime lead to approximately a 20% to 25% increase in exercise tolerance and peak oxygen consumption. There was also a significant reduction in questionnaire-rated symptoms attributable to heart failure and a coincident increase in both the extent and ease of per-
forming daily activities. In a later report on 17 subjects, it was reported17 that there was an improvement in sympatho-vagal balance, and an increase in submaximal and peak cardiac output and a reduction in the ventilatory response to exercise. Published Cross-Over Trials of Training in Chronic Heart Failure
In addition to the two reports by Coats and colleagues referred to in the paragraph above, other cross-over studies explored the physiological effects of training in patients with stable mild to moderate CHF. Adamopoulos' trained 12 patients with a homebased 8-week program of cycling at 60% to 80% maximum heart rate three times per week and showed improvements in muscle metabolism by magnetic resonance spectroscopy, including a reduced intramuscular phosphocreatine (PC) depletion and adenosine diphosphate (ADP) accumulation, P <0.003. Radaelli?' using a similar program in six patients 5 days per week for 5 weeks, showed a 15% increase in peak oxygen consumption, P <0.05, and an improved autonomic control of both heart rate and the peripheral circulation. Tyni-Lenne,'jO in 16 female heart failure patients, showed that 8 weeks of knee extensor endurance training could increase skeletal muscle citrate synthase activity by 44%, P <0.0001 and lactate dehydrogenase activity by 23%, P <0.002. There was an increase in oxidative capacity in relation to the glycolytic capacity of 23% ( P <0.002), showing plasticity of the skeletal muscle abnormalities described as accompanying CHF. In addition, peak oxygen uptake was increased 14% ( P <0.0005), and peak work rate increased 43% ( P
EXERCISE AND HEART FAILURE
weeks and showed that 6-minute walk distances increased 2070, P <0.012. Finally, Maiorana” showed in 13 patients that a circuit weight training program for 8 weeks increased peak oxygen uptake 11.8% (P <0.01) and exercise time by 18.4%, P <0.01. Maximal skeletal muscle isotonic voluntary contractile strength was increased by 17.9% (P <0.001) in the trained muscle groups. Parallel Group Trials of Training In Chronic Heart Failure
Jette in 19913, studied a group of patients with left ventricular ejection fraction <30% (n=8) and a control group of 10 subjects. Using a supervised in-hospital program lasting 4 weeks and a cycle 15 minutes three times per week at 70% to 80% maximum heart rate as well as 30 minutes of callisthenics, they demonstrated a peak oxygen consumption increase of 221 mL per minute (P <0.05) along with an increase in peak work load of 13 W (P <0.05). Koch 199237studied 12 severe heart failure patients and 13 controls using a program of 40 sessions over 90 days. They used a graded program of singlelimb training with little hemodynamic effect. Quality-of-life scores in the trained group increased 52% (P <0.0001) with no change in the control group. Belardinelli in 19925randomized 20 stable moderate heart failure subjects to train (n = 10) or control (n = 10) for a supervised 8week program of cycling at 60% of peak Oz consumption three times per week. Exercise tolerance increased 45% (P <0.005), and peak 0, uptake increased by 20% (P <0.001). The same group reported improved indices of left ventricular diastolic function along with a 12% increase in peak oxygen uptake (P <0.001) in 19953 on 36 trained patients with heart failure. A more complex design was used by Kostis,38 comparing placebo (n = 6), Digoxin (n = 7) and comprehensive cognitive therapy, with dietetic advice and exercise training (walking/rowing/cycling/stair climbing 60 minutes X 3 to 5/week at 50% to 60% max, n = 7) in stable mild heart failure, all for 12 weeks. Exercise tolerance increased by 182 seconds ( P <0.05) in the exercising group, significantly more than the other groups. Kiil a ~ u o r showed i~~ in 8 training heart failure patients compared to 12 control patients that 3 months supervised training using a cycle
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for 30 minutes 3 times per week at 50% to 60% maximal 0, consumption that exercise tolerance increased 71% at submaximal workload (P = 0.01). In addition, they showed that the high-frequency component of RR interval variability (a marker of vagal tone) increased by 22% to 55% in the training group during the day (P = 0.0001). Hambrecht in 199530trained 12 patients in a supervised setting for 3 weeks (60 min/d at 70% maximal Oz consumption) followed by home-based training (cycling 40 m i d d a y at 70% maximum with walking/callisthenics/ ball games 60 minutes twice per week) for a total of 6 months. Compared to 10 untrained control patients, peak 0, consumption increased in the trained patients by 31% (P <0.01). The biopsy-derived skeletal muscle mitochondria1 volume density increased significantly, a finding later shown to correlate well with the training-induced improvement in exercise capacity. In a second study in 1997, the same authors, using a similar trained 9 patients versus 9 controls and demonstrated enhanced skeletal muscle oxidative enzyme activity and improved mitochondria in skeletal muscle biopsies. Finally, in 2000, they showedz9in 36 trained subjects compared to 37 controls that New York Heart Association (NYHA) class improved, exercise time increased and LVEF increased from 0.30 to 0.35 (P = 0.003). In addition, peak exercise total peripheral resistance was decreased, P = 0.003. DubachZ3trained 12 patients (13 controls) for 8 weeks walking 60 minutes twice per day, cycling 40 minutes 4 times per week at 80% capacity and confirmed an increased exercise capacity in his trained group. Similar changes were reported by Reinhart in 199852 for 25 trained heart failure patients in an 8week residential program of cycle exercise for 40 minutes at 70% to 80% capacity 4 times per week and with walking 2 hours per day. They showed an increased maximal cardiac output and peak 0, consumption. Wielanger in 199962* 63 compared 41 trained and 39 control patients. Training was supervised for 12 weeks. They showed that “feelings of being disabled decreased and ”selfassessment of general well-being” along with exercise time being increased ( + 21.4%, P
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peak oxygen consumption by 30.9% and demonstrated a decreased urinary nitrate elimination in the control group (n=8) compared to an unchanged nitrate elimination in the exercise-trained group (n = 9). In 1998, Willenheimer" trained 22 CHF patients (supervised interval cycling training with 60 seconds work at 80% maximum and 30 seconds rest for 15 minutes twice per week for weeks 0 to 7 and 45 minutes 3 times a week for weeks 7 to 16). Compared to 27 control patients, peak exercise work load increased 7 W, P <0.01. Similar beneficial effects on exercise capacity (peak O2 uptake increased by 23.3% (P = 0.001) and peak work load increased by 26% (P = 0001) were seen in controlled trials of training by S t ~ r mstudying ~~ 26 patients for 12 weeks at 50% capacity training progressing to 100 minutes of step aerobics and 50 minutes of cycling per week. K e t e ~ i a nshowed ~~ in 21 trained patients (33 minutes x 3/wk at 60% to 80% maximum heart rate using cycling, rowing, arm, treadmill for 24 weeks) compared to 22 controls an increase in peak Ozuptake (P <0.05), and an improved chronotropic response to exercise. Quittan in 199950employed aerobics 3 hours per week in 25 CHF patients and showed improved quality of life assessments (P = O.OOOl), increased physical role fulfillment scores ( P = 0.001) and improved scores for physical ( P = 0.02) and social (P = 0.0002) functioning. Peak Ozuptake and exercise time were also increased, P <0.01. Finally and perhaps most significantly of all the trials published to date, Belardinelli in 19994showed in a study with 50 trained and 49 control heart failure patients that a supervised 8-week training program of cycling at 60% peak capacity 3 times per week followed by a supervised 12-month maintenance program of 2 sessions per week (including 20 minutes of stretching exercises and 40 minutes of cycle exercise) that peak oxygen consumption was increased 18% at 2 months (P <0.001) and that this was associated with a lower mortality (n = 9 versus n = 20, relative risk = 0.37; 95% confidence interval, 0.17 to 0.84; P = 0.01). There were also fewer hospital readmissions for heart failure (5 versus 14; RR=O.29; 95% C1, 0.11 to 0.88; P = 0.02). It is too early to stay that this is the proof we need to recommend training as a disease modifying intervention, but clearly it encourages further ~tUdy.4~ A summary of trials performed by one collaborative European groupz4and an overview
of all trials published to 19984s have both demonstrated a consistent increase in exercise capacity across a broad range of heart failure patients of approximately 15% to 20%. Beneficial changes produced by training have included improvements in hemodynamic responses, myocardial perfusion, diastolic function, skeletal muscle function and histological and biochemical responses, ventilatory control, peripheral vascular and endothelial function and neurohormonal and autonomic improvements. UNANSWERED QUESTIONS
Although there have been many reports of training, few report prospective comparisons of the elements of the training program. Important questions, such as the optimal frequency and intensity of training, the necessary duration for training effects and how long after cessation of a formal program they last, remain unanswered. Beyond this, details of the most appropriate selection of patients, the elements of the training program and any possible interaction with modern heart failure medications remain valid questions for fu.ture controlled trials. Although cardiovascular medicine has made many strides in the last decade in randomized controlled trials of effective treatments, this oldest of physical therapies remains enormously difficult to evaluate, at least in part, because our modern system of funding trials remains firmly in favor of commercial patentable treatments. An adequate program of government support for randomized noncommercializable treatment trials will be needed if these important questions are to receive a timely answer. References Adamopoulos S, Coats AJ, Brunotte F, et al: Physical training improves skeletal muscle metabolism in patients with chronic heart failure. J Am Coll Cardiol 21:llOl-1106, 1993 Anker SD, Volterrani M, Swan J, et al: Hormonal changes in cardiac cachexia. Circ 92:I-206-1-207, 1995 Belardinelli R, Georgiou D, Cianci G, et al: Exercise training improves left ventricular diastolic filling in patients with dilated cardiomyopathy. Clinical and prognostic implications. Circulation 91:2775434, 1995 Belardinelli R, Georgiou D, Cianci G, et al: Randomized, controlled trial of long-term moderate exercise training in chronic heart failure: Effects on functional capacity, quality of life, and clinical outcome. Circulation 99A173-82, 1999
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Address reprint requests to Andrew J. S. Coats, MA, DM National Heart and Lung Institute Imperial College of Science, Technology and Medicine Royal Brompton Hospital London, SW3 6NP, UK e-mail: a.coatsOic.ac.uk