1351
Clinical Investigation Active Skeletal Muscle Mass and Cardiopulmonary Reserve Failure to Attain Peak Aerobic Capacity During Maximal Bicycle Exercise in Patients With Severe Congestive Heart Failure Guillaume Jondeau, MD; Stuart D. Katz, MD; Lenore Zohman, MD; Mark Goldberger, MD; Margaret McCarthy, RN; Jean-Pierre Bourdarias, MD; and Thierry H. LeJemtel, MD Background. In addition to depressed cardiac reserve, peripheral factors may contribute to limit maximal exercise capacity in patients with congestive heart failure (CHF). To investigate the role of reduced active skeletal muscle mass, peak oxygen uptake (Vo2, milligrams per kilogram per minute) was determined during maximal symptom-limited exercise involving the lower limbs (LL) alone and the lower limbs and upper limbs (LL+UL) combined in patients with CHF and in normal subjects of similar age and sex. Methods and Results. LL bicycle exercise was performed upright with a ramp protocol and continuous expired gas analysis. When respiratory exchange ratio (RER) reached 1.0, UL exercise was initiated at constant load with the use of a cranking device positioned at shoulder level. LL exercise alone and combined LL+UL exercise were performed on separate days in randomized order by 24 patients with CHF and seven normal subjects. In patients with CHF, peak Vo2 was greater during combined LL+UL exercise than during LL exercise alone, i.e., 15.8±0.8 versus 14.2±0.9 ml * kg-' min` (p 15
ml
kg'
min`
and in normal
subjects
of similar age and sex,
i.e., 0.1 ±4.0%o and 2.0±2.3%
respectively. Conclusions. In contrast to normal subjects and patients with moderate CHF, patients with severe CHF do not exhaust their cardiopulmonary reserve during symptom-limited maximal LL exercise on a bicycle. (Circulation 1992;86:1351-1356) KEY WoRDs * peak V02 * congestive heart failure * muscle mass
aximal oxygen uptake (Vo2) is an objective index of cardiopulmonary reserve in normal peak subjects.'-4 In contrast to normal subjects, peak Vo2 rather than maximal Vo2 is measured in patients with congestive heart failure (CHF) who most often do not reach a plateau in Vo2 during symptomlimited maximal exercise testing.5-7 During graded maximal exercise with the lower limbs (LL) such as running uphill or bicycling, normal subjects recruit at least 50% of the total skeletal muscle mass and thereby exhaust the cardiopulmonary reserve.8-11 When compared with normal subjects of similar age, M
From the Department of Medicine (G.J., T.H.L.), Division of Cardiology, The Albert Einstein College of Medicine, Bronx, N.Y.; the Department of Medicine (S.D.K., L.Z., M.G., M.M.), Division of Cardiology, Montefiore Medical Center, Bronx, N.Y.; and the Department of Cardiology (J.-P.B.), Hopital Ambroise Pare, Boulogne, France. Address for correspondence: Thierry H. LeJemtel, MD, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Received February 24, 1992; revision accepted July 17, 1992.
patients with CHF have a reduced skeletal muscle mass in the LL that correlates with the degree of exercise
intolerance.'2-14 In addition to muscle atrophy, an impaired vasodilatory response to exercise in patients with CHF may reduce oxygen availability and therefore further decrease the amount of active skeletal muscle mass in the LL during bicycling or running uphill. Whether maximal bicycle exercise with the LL involves enough active skeletal muscle mass in these patients to attain the limit of the cardiopulmonary system is unclear. Accordingly, the present study was undertaken to determine peak Vo2 attained during LL bicycling alone and during LL bicycling combined with upper limb (UL) cranking in patients with CHF of variable severity and in normal subjects of matched age and sex.
Methods Patient Population Twenty-one men and three women with stable CHF and symptoms compatible with functional class I-IV
Downloaded from http://circ.ahajournals.org/ at University of GA on May 25, 2015
1352
Circulation Vol 86, No 5 November 1992
according to the criteria of the New York Heart Association (NYHA) were studied. Their age averaged 58.6 years (range, 37-72 years), and mean left ventricular ejection fraction obtained by nuclear cardiac imaging was 25.7% (range, 10-40%). The etiology of CHF was coronary artery disease in nine patients who had previous myocardial infarction or >75% coronary artery stenoses and idiopathic in 16 patients without significant coronary artery disease. Medical therapy for CHF that included loop diuretics (n=24), angiotensin converting enzyme inhibitors (n= 18), digoxin (n = 17), and nitrates (n=7) was withheld at least 12 hours before the exercise testing. Exercise was limited by general fatigue and/or leg discomfort in all patients. None had symptoms compatible with angina or peripheral vascular disease or overt evidence of fluid retention at the time of the study. All patients were familiar with bicycle exercise testing and had undergone several previous tests with continuous expired gas analysis and consistent peak Vo, determinations. Four men and three women leading a sedentary lifestyle who had a normal examination and ECG and were not taking any medication served as untrained controls. Their age averaged 61.7 years (range, 58-77 years). They were all familiarized with bicycle exercise testing and continuous measurement of expired gas before the study. The protocol was approved by the Ethical Review Board of the Albert Einstein College of Medicine, and all patients gave written informed consent.
Exercise Protocol Lower limbs exercise. Exercise was conducted in a temperature-controlled room at 22°C. Exercise testing was performed in the upright position on a mechanically braked bicycle ergometer (Monark, Sweden) with both feet secured to the pedals. Patients with CHF warmed up at 0 work load for 1 minute. Work rate increased by 25 kpm/min for the next 2 minutes and thereafter by 50 kpm/min until exhaustion. Normal subjects warmed up at 25 kpm for 1 minute. The work rate was then increased by a mean of 90 kpm/min until exhaustion. Expired gases were collected continuously during exercise through a low-resistance three-way valve (Hans Rudolph). Oxygen uptake and carbon dioxide production were determined in milliliters per minute at 15second intervals (Sensor Medics). Respiratory exchange ratio (RER) was calculated as oxygen uptake/ carbon dioxide production. Blood pressure obtained by standard cuff technique and ECG were monitored continuously during the exercise and recovery periods. Upper limbs and lower limbs exercise. UL exercise was performed with a specially-built arm ergometer (Monark) positioned at shoulder level when patients or normal subjects were sitting upright on the ergometer. Patients or normal subjects began exercise with the lower limbs alone as described above. When RER reached 1, arm cranking was added to LL bicycle exercise. Arm work load was constant during the test, chosen as minimal for patients with CHF (free wheeling) and about 20% of maximal work load obtained during the previous test in normal subjects.15 Blood pressure was measured before and immediately after exercise, whereas ECG was monitored continuously.
Exercise tests with LL alone and LL+UL performed on separate days in random order.
were
Statistical Analysis All results are expressed as mean±SEM. Paired Student's t tests were used to compare the values measured for the same subjects during the two exercise tests, and unpaired Student's t tests were used for intergroup comparisons. Comparison of patients with severe and moderate CHF and normal subjects was performed by ANOVA with Fisher post hoc test when applicable. A value of p50% of the total skeletal mass is actively involved in exercise, maximum Vo2 is limited by the output of the heart and is not affected by increasing the active muscle mass.8 Our findings in patients with severe CHF, who clearly behave differently from normal subjects and patients with moderate CHF, argues for the potential role of reduced skeletal muscle mass in determining exercise intolerance.14"18"19 Alternatively, inadequate vasodilatory response to exercise resulting in impaired oxygen delivery may explain our findings in patients with severe CHF. Mancini et al demonstrated that muscle atrophy, which they found to be unduly prevalent in patients with CHF, did correlate with the severity of exercise intolerance.14 The ability of our patients with severe CHF to substantially increase peak Vo2 during exercise with LL+UL over that attained during exercise with LL alone strongly suggests that insufficient active muscle mass and not the heart was the predominant limiting factor for maximal exercise capacity. Similarly, reduced skeletal muscle mass has been demonstrated to play an important role on the age-related decline in maximum Vo2.20 Fifty percent or more of the age-related decline in maximum Vo2 can be accounted for by selective loss of skeletal muscle mass that accompanies aging.20 In addition to atrophy, intrinsic skeletal muscle abnormalities have been documented in patients with CHF.21-27 They include fiber atrophy, reduction in lipolytic and oxidative enzymes, and altered metabolic responses to exercise. The extent to which these abnormalities may have compounded the effects of muscle atrophy and prevented our most severely symptomatic patients from reaching true peak aerobic capacity during maximum LL bicycling remains to be determined. Of interest, these intrinsic skeletal muscle abnormalities could result from inactivity and, thus, may be more prominent in the LL than the UL. The capacity of the skeletal muscle vasculature to dilate in response to exercise is impaired in patients with CHF.28 When patients with CHF are in functional class III-IV, the response of the skeletal muscle vasculature to pharmacological stimuli and arterial occlusion is substantially reduced when compared with that of normal subjects.29 At that stage, the vasodilatory response to exercise is fixed and independent of global pump performance, thereby limiting exercise capacity.30-32Notwithstanding muscle atrophy, peripheral vascular abnormalities may reduce the amount of muscle mass directly involved in exercise when patients with severe CHF bicycle with LL alone. Recruitment of the UL skeletal muscle vasculature by arm cranking can, in this situation, increase the amount of active muscle mass and thereby allow patients to exhaust cardiopulmonary reserve.33 Vascular abnormalities may also con-
1355
tribute to age-related decline in maximum Vo2 since limb blood flow attained during exercise has been shown to steadily decrease with age in normal subjects.34 Attenuation of the metaboreceptor system in CHF may result in a less effective distribution of cardiac output during exercise.35-37 Whether this phenomena is directly responsible for decreased exercise tolerance in CHF or whether exercise intolerance may result from an increased stimulation of central command is unclear. The higher heart rate attained during exercise with LL+UL when compared with LL alone argues in favor of the latter explanation.
Study Limitations There are several potential limitations of the study. Skeletal muscle mass was not measured in the LL of patients or normal subjects. Moreover, skeletal muscle metabolism was not assessed during exercise with LL+UL and with LL alone. Although the increase in peak Vo2 observed during exercise with LL+UL when compared with exercise with LL alone could have resulted from a wider (A-V) 02 difference, this is unlikely because skeletal muscle oxygen extraction is already maximum during LL bicycling in patients with severe CHF.38 Because skeletal muscle mass, metabolism, and regional blood flow were not measured, the relative contribution of muscle atrophy, abnormal muscle metabolism, and impaired vasodilatory response to exercise to explain the difference in peak Vo2 between combined LL bicycling and UL cranking and LL bicycling alone in patients with severe CHF cannot be determined. Nevertheless, our data point out that besides the cardiopulmonary system, the amount of active skeletal mass is an important determinant of peak Vo2 in patients with severe CHF.
References
1. Astrand P-O: Quantification of exercise capability and evaluation of physical capacity in man. Prog Cardiovasc Dis 1976;19:51-67 2. Mitchell JH, Sproule BJ, Chapman CB: The physiological meaning of the maximal oxygen intake test. J Clin Invest 1958;37:538-547 3. Mitchell JH, Blomqvist G: Maximal oxygen uptake. N Engl J Med 1971;284:1018-1022 4. Wasserman K, Whipp BJ: Exercise physiology in health and disease. Am Rev Respir Dis 1975;112:219-249 5. Wilson JR, Fink LI, Ferraro N, Dunkman WB, Jones RA: Use of maximal bicycle exercise testing with respiratory gas analysis to assess exercise performance in patients with congestive heart failure secondary to coronary artery disease or to idiopathic dilated cardiomyopathy. Am J Cardiol 1986;58:601-606 6. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR: Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991;83:778-786 7. LeJemtel TH, Mancini D, Gumbardo D, Chadwick B: Pitfalls and limitations of maximal oxygen uptake as an index of cardiovascular functional capacity in patients with chronic heart failure. Heart Failure 1985;1:112-124 8. Rowell LB: Human cardiovascular adjustments to exercise and thermal stress. Physiol Rev 1974;54:75-159 9. Taylor LH, Buskirk E, Henschel A: Maximal oxygen uptake as an objective measurement of cardio-respiratory performance. JAppl Physiol 1955;8:83-90 10. Astrand PO: Aerobic work capacity during maximal performance under various conditions. Circ Res 1967;20:202-210 11. Hermanssen L, Saltin B: Oxygen uptake during maximal treadmill and bicycle exercise. JAppl Physiol 1969;26:31-37 12. Pittman JG, Cohen P: The pathogenesis of cardiac cachexia. N Engl J Med 1964;271:453-461 13. Carr J, Stevenson L, Walden J, Heber D: Prevalence and hemodynamic correlates of malnutrition in severe congestive heart failDownloaded from http://circ.ahajournals.org/ at University of GA on May 25, 2015
1356
14.
15. 16. 17.
Circulation Vol 86, No 5 November 1992
ure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1989;63:709-713 Mancini DM, Walter G, Reichek N, Lenkinski R, McCully KK, Mullen JL, Wilson JR: Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation 1992;85:1364-1373 Bergh U, Kanstrup L-L, Ekblom B: Maximal oxygen uptake during exercise with various combinations of arm and leg work. J Appl Physiol 1976;41:191-196 Astrand PO, Saltin B: Maximal oxygen uptake and heart rate in various types of muscular activity. JAppi Physiol 1961;16:977-981 Stenberg J, Astrand P-0, Ekblom B, Royce J, Saltin B: Hemodynamic response to work with different muscle groups, sitting and
27.
28.
29.
supine. JAppl Physiol 1967;22:61-70 18. Minotti JR, Christoph I, Oka R, Weiner MW, Wells L, Massie BM: Impaired skeletal muscle function in patients with congestive heart failure: Relationship to systemic exercise performance. J Clin Invest 1991;88:2077-2082 19. Frontera WR, Meredith CN, O'Reilly KP, Knuttgen HG, Evans WJ: Strength conditioning in older men: Skeletal muscle hypertrophy and improved function. JAppl Physiol 1988;64:1038-1044 20. Fleg JL, Lakatta EG: Role of muscle loss in the age-associated reduction in Vo2max. JAppi Physiol 1988;65:1147-1151 21. Shafiq SA, Sande MA, Carruthers RR, Killip T, Milhorat AT: Skeletal muscle in idiopathic cardiomyopathy. J Neurol Sci 1972; 15:303-320 22. Lipkin DP, Jones DA, Round JM, Poole-Wilson PA: Abnormalities of skeletal muscle in patients with chronic heart failure. Int J Cardiol 1988;18:187-195 23. Massie B, Conway M, Yonge R, Frostick S, Ledingham J, Sleight P, Radda G, Rajagopalan B: Skeletal muscle metabolism in patients with congestive heart failure: Relation to clinical severity and blood flow. Circulation 1987;76:1009-1019 24. Massie BM, Conway M, Rajagopalan B, Yonge R, Frostick S, Ledingham J, Sleight P, Radda G: Skeletal muscle metabolism during exercise under ischemic conditions in congestive heart failure: Evidence for abnormalities unrelated to blood flow. Circulation 1988;78:320-326 25. Caforio ALP, Rossi B, Risaliti R, Siciliano G, Marchetti A, Angelini C, Crea F, Mariani M, Muratorio A: Type 1 fiber abnormalities in skeletal muscle of patients with hypertrophic and dilated cardiomyopathy: Evidence of subclinical myogenic myopathy. J Am Coil Cardiol 1989;14:1464-1473 26. Mancini DM, Coyle E, Coggan A, Beltz J, Ferraro N, Montain S, Wilson JR: Contribution of intrinsic skeletal muscle changes to 3P
30. 31.
32.
33.
34.
35.
36.
37. 38.
NMR skeletal muscle metabolic abnormalities in patients with chronic heart failure. Circulation 1989;80:1338-1346 Minotti JR, Johnson EC, Hudson TL, Zuroske G, Murata G, Fukushima E, Cagle TG, Chick TW, Massie BM, Icenogle MV: Skeletal muscle response to exercise training in congestive heart failure. J Clin Invest 1990;86:751-758 Zelis R, Longhurst J, Capone RJ, Mason DT: A comparison of regional blood flow and oxygen utilization during dynamic forearm exercise in normal subjects and patients with congestive heart failure. Circulation 1974;50:137-143 Zelis R, Mason DT, Braunwald E: A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure. J Clin Invest 1968;47:960-970 Sullivan MJ, Green HJ, Cobb FR: Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 1990;81:518-527 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 Cardiol 1984;53:1308-1315 LeJemtel TH, Maskin CS, Lucido D, Chadwick BJ: Failure to augment maximal limb blood flow in response to one-leg versus two-leg exercise in patients with severe heart failure. Circulation 1986;74:245-251 Martin WH, Berman WI, Buckey JC, Snell PG, Blomqvist CG: Effects of active muscle mass size on cardiopulmonary responses to exercise in congestive heart failure. J Am Coll Cardiol 1989;14: 683-694 Jordfeldt L, Wahren J: Leg blood flow during exercise in man. Clin Sci 1971;41:459-473 Sterns DA, Ettinger SM, Gray KS, Whisler SK, Mosher TJ, Smith MB, Sinoway LI: Skeletal muscle metaboreceptor exercise responses are attenuated in heart failure. Circulation 1991;84: 2034-2039 Rowell LB, O'Leary DS: Reflex control of the circulation during exercise: Chemoreflexes and mechanoreflexes. JAppl Physiol 1990; 69:407-418 Mitchell JH: Cardiovascular control during exercise: Central and reflex neural mechanisms. Am J Cardiol 1985;55:34D-41D LeJemtel TH, Maskin CS, Chadwick B, Sinoway L: Near maximal oxygen extraction by exercising muscles in patients with severe heart failure: A limitation to benefits of physical training. (abstract) J Am Coil Cardiol 1983;1:662
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Active skeletal muscle mass and cardiopulmonary reserve. Failure to attain peak aerobic capacity during maximal bicycle exercise in patients with severe congestive heart failure. G Jondeau, S D Katz, L Zohman, M Goldberger, M McCarthy, J P Bourdarias and T H LeJemtel Circulation. 1992;86:1351-1356 doi: 10.1161/01.CIR.86.5.1351 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1992 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/86/5/1351
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Clinical Investigation Active Skeletal Muscle Mass and Cardiopulmonary Reserve Failure to Attain Peak Aerobic Capacity During Maximal Bicycle Exercise in Patients With Severe Congestive Heart Failure Guillaume Jondeau, MD; Stuart D. Katz, MD; Lenore Zohman, MD; Mark Goldberger, MD; Margaret McCarthy, RN; Jean-Pierre Bourdarias, MD; and Thierry H. LeJemtel, MD Background. In addition to depressed cardiac reserve, peripheral factors may contribute to limit maximal exercise capacity in patients with congestive heart failure (CHF). To investigate the role of reduced active skeletal muscle mass, peak oxygen uptake (Vo2, milligrams per kilogram per minute) was determined during maximal symptom-limited exercise involving the lower limbs (LL) alone and the lower limbs and upper limbs (LL+UL) combined in patients with CHF and in normal subjects of similar age and sex. Methods and Results. LL bicycle exercise was performed upright with a ramp protocol and continuous expired gas analysis. When respiratory exchange ratio (RER) reached 1.0, UL exercise was initiated at constant load with the use of a cranking device positioned at shoulder level. LL exercise alone and combined LL+UL exercise were performed on separate days in randomized order by 24 patients with CHF and seven normal subjects. In patients with CHF, peak Vo2 was greater during combined LL+UL exercise than during LL exercise alone, i.e., 15.8±0.8 versus 14.2±0.9 ml * kg-' min` (p 15
ml
kg'
min`
and in normal
subjects
of similar age and sex,
i.e., 0.1 ±4.0%o and 2.0±2.3%
respectively. Conclusions. In contrast to normal subjects and patients with moderate CHF, patients with severe CHF do not exhaust their cardiopulmonary reserve during symptom-limited maximal LL exercise on a bicycle. (Circulation 1992;86:1351-1356) KEY WoRDs * peak V02 * congestive heart failure * muscle mass
aximal oxygen uptake (Vo2) is an objective index of cardiopulmonary reserve in normal peak subjects.'-4 In contrast to normal subjects, peak Vo2 rather than maximal Vo2 is measured in patients with congestive heart failure (CHF) who most often do not reach a plateau in Vo2 during symptomlimited maximal exercise testing.5-7 During graded maximal exercise with the lower limbs (LL) such as running uphill or bicycling, normal subjects recruit at least 50% of the total skeletal muscle mass and thereby exhaust the cardiopulmonary reserve.8-11 When compared with normal subjects of similar age, M
From the Department of Medicine (G.J., T.H.L.), Division of Cardiology, The Albert Einstein College of Medicine, Bronx, N.Y.; the Department of Medicine (S.D.K., L.Z., M.G., M.M.), Division of Cardiology, Montefiore Medical Center, Bronx, N.Y.; and the Department of Cardiology (J.-P.B.), Hopital Ambroise Pare, Boulogne, France. Address for correspondence: Thierry H. LeJemtel, MD, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Received February 24, 1992; revision accepted July 17, 1992.
patients with CHF have a reduced skeletal muscle mass in the LL that correlates with the degree of exercise
intolerance.'2-14 In addition to muscle atrophy, an impaired vasodilatory response to exercise in patients with CHF may reduce oxygen availability and therefore further decrease the amount of active skeletal muscle mass in the LL during bicycling or running uphill. Whether maximal bicycle exercise with the LL involves enough active skeletal muscle mass in these patients to attain the limit of the cardiopulmonary system is unclear. Accordingly, the present study was undertaken to determine peak Vo2 attained during LL bicycling alone and during LL bicycling combined with upper limb (UL) cranking in patients with CHF of variable severity and in normal subjects of matched age and sex.
Methods Patient Population Twenty-one men and three women with stable CHF and symptoms compatible with functional class I-IV
Downloaded from http://circ.ahajournals.org/ at University of GA on May 25, 2015
1352
Circulation Vol 86, No 5 November 1992
according to the criteria of the New York Heart Association (NYHA) were studied. Their age averaged 58.6 years (range, 37-72 years), and mean left ventricular ejection fraction obtained by nuclear cardiac imaging was 25.7% (range, 10-40%). The etiology of CHF was coronary artery disease in nine patients who had previous myocardial infarction or >75% coronary artery stenoses and idiopathic in 16 patients without significant coronary artery disease. Medical therapy for CHF that included loop diuretics (n=24), angiotensin converting enzyme inhibitors (n= 18), digoxin (n = 17), and nitrates (n=7) was withheld at least 12 hours before the exercise testing. Exercise was limited by general fatigue and/or leg discomfort in all patients. None had symptoms compatible with angina or peripheral vascular disease or overt evidence of fluid retention at the time of the study. All patients were familiar with bicycle exercise testing and had undergone several previous tests with continuous expired gas analysis and consistent peak Vo, determinations. Four men and three women leading a sedentary lifestyle who had a normal examination and ECG and were not taking any medication served as untrained controls. Their age averaged 61.7 years (range, 58-77 years). They were all familiarized with bicycle exercise testing and continuous measurement of expired gas before the study. The protocol was approved by the Ethical Review Board of the Albert Einstein College of Medicine, and all patients gave written informed consent.
Exercise Protocol Lower limbs exercise. Exercise was conducted in a temperature-controlled room at 22°C. Exercise testing was performed in the upright position on a mechanically braked bicycle ergometer (Monark, Sweden) with both feet secured to the pedals. Patients with CHF warmed up at 0 work load for 1 minute. Work rate increased by 25 kpm/min for the next 2 minutes and thereafter by 50 kpm/min until exhaustion. Normal subjects warmed up at 25 kpm for 1 minute. The work rate was then increased by a mean of 90 kpm/min until exhaustion. Expired gases were collected continuously during exercise through a low-resistance three-way valve (Hans Rudolph). Oxygen uptake and carbon dioxide production were determined in milliliters per minute at 15second intervals (Sensor Medics). Respiratory exchange ratio (RER) was calculated as oxygen uptake/ carbon dioxide production. Blood pressure obtained by standard cuff technique and ECG were monitored continuously during the exercise and recovery periods. Upper limbs and lower limbs exercise. UL exercise was performed with a specially-built arm ergometer (Monark) positioned at shoulder level when patients or normal subjects were sitting upright on the ergometer. Patients or normal subjects began exercise with the lower limbs alone as described above. When RER reached 1, arm cranking was added to LL bicycle exercise. Arm work load was constant during the test, chosen as minimal for patients with CHF (free wheeling) and about 20% of maximal work load obtained during the previous test in normal subjects.15 Blood pressure was measured before and immediately after exercise, whereas ECG was monitored continuously.
Exercise tests with LL alone and LL+UL performed on separate days in random order.
were
Statistical Analysis All results are expressed as mean±SEM. Paired Student's t tests were used to compare the values measured for the same subjects during the two exercise tests, and unpaired Student's t tests were used for intergroup comparisons. Comparison of patients with severe and moderate CHF and normal subjects was performed by ANOVA with Fisher post hoc test when applicable. A value of p50% of the total skeletal mass is actively involved in exercise, maximum Vo2 is limited by the output of the heart and is not affected by increasing the active muscle mass.8 Our findings in patients with severe CHF, who clearly behave differently from normal subjects and patients with moderate CHF, argues for the potential role of reduced skeletal muscle mass in determining exercise intolerance.14"18"19 Alternatively, inadequate vasodilatory response to exercise resulting in impaired oxygen delivery may explain our findings in patients with severe CHF. Mancini et al demonstrated that muscle atrophy, which they found to be unduly prevalent in patients with CHF, did correlate with the severity of exercise intolerance.14 The ability of our patients with severe CHF to substantially increase peak Vo2 during exercise with LL+UL over that attained during exercise with LL alone strongly suggests that insufficient active muscle mass and not the heart was the predominant limiting factor for maximal exercise capacity. Similarly, reduced skeletal muscle mass has been demonstrated to play an important role on the age-related decline in maximum Vo2.20 Fifty percent or more of the age-related decline in maximum Vo2 can be accounted for by selective loss of skeletal muscle mass that accompanies aging.20 In addition to atrophy, intrinsic skeletal muscle abnormalities have been documented in patients with CHF.21-27 They include fiber atrophy, reduction in lipolytic and oxidative enzymes, and altered metabolic responses to exercise. The extent to which these abnormalities may have compounded the effects of muscle atrophy and prevented our most severely symptomatic patients from reaching true peak aerobic capacity during maximum LL bicycling remains to be determined. Of interest, these intrinsic skeletal muscle abnormalities could result from inactivity and, thus, may be more prominent in the LL than the UL. The capacity of the skeletal muscle vasculature to dilate in response to exercise is impaired in patients with CHF.28 When patients with CHF are in functional class III-IV, the response of the skeletal muscle vasculature to pharmacological stimuli and arterial occlusion is substantially reduced when compared with that of normal subjects.29 At that stage, the vasodilatory response to exercise is fixed and independent of global pump performance, thereby limiting exercise capacity.30-32Notwithstanding muscle atrophy, peripheral vascular abnormalities may reduce the amount of muscle mass directly involved in exercise when patients with severe CHF bicycle with LL alone. Recruitment of the UL skeletal muscle vasculature by arm cranking can, in this situation, increase the amount of active muscle mass and thereby allow patients to exhaust cardiopulmonary reserve.33 Vascular abnormalities may also con-
1355
tribute to age-related decline in maximum Vo2 since limb blood flow attained during exercise has been shown to steadily decrease with age in normal subjects.34 Attenuation of the metaboreceptor system in CHF may result in a less effective distribution of cardiac output during exercise.35-37 Whether this phenomena is directly responsible for decreased exercise tolerance in CHF or whether exercise intolerance may result from an increased stimulation of central command is unclear. The higher heart rate attained during exercise with LL+UL when compared with LL alone argues in favor of the latter explanation.
Study Limitations There are several potential limitations of the study. Skeletal muscle mass was not measured in the LL of patients or normal subjects. Moreover, skeletal muscle metabolism was not assessed during exercise with LL+UL and with LL alone. Although the increase in peak Vo2 observed during exercise with LL+UL when compared with exercise with LL alone could have resulted from a wider (A-V) 02 difference, this is unlikely because skeletal muscle oxygen extraction is already maximum during LL bicycling in patients with severe CHF.38 Because skeletal muscle mass, metabolism, and regional blood flow were not measured, the relative contribution of muscle atrophy, abnormal muscle metabolism, and impaired vasodilatory response to exercise to explain the difference in peak Vo2 between combined LL bicycling and UL cranking and LL bicycling alone in patients with severe CHF cannot be determined. Nevertheless, our data point out that besides the cardiopulmonary system, the amount of active skeletal mass is an important determinant of peak Vo2 in patients with severe CHF.
References
1. Astrand P-O: Quantification of exercise capability and evaluation of physical capacity in man. Prog Cardiovasc Dis 1976;19:51-67 2. Mitchell JH, Sproule BJ, Chapman CB: The physiological meaning of the maximal oxygen intake test. J Clin Invest 1958;37:538-547 3. Mitchell JH, Blomqvist G: Maximal oxygen uptake. N Engl J Med 1971;284:1018-1022 4. Wasserman K, Whipp BJ: Exercise physiology in health and disease. Am Rev Respir Dis 1975;112:219-249 5. Wilson JR, Fink LI, Ferraro N, Dunkman WB, Jones RA: Use of maximal bicycle exercise testing with respiratory gas analysis to assess exercise performance in patients with congestive heart failure secondary to coronary artery disease or to idiopathic dilated cardiomyopathy. Am J Cardiol 1986;58:601-606 6. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR: Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991;83:778-786 7. LeJemtel TH, Mancini D, Gumbardo D, Chadwick B: Pitfalls and limitations of maximal oxygen uptake as an index of cardiovascular functional capacity in patients with chronic heart failure. Heart Failure 1985;1:112-124 8. Rowell LB: Human cardiovascular adjustments to exercise and thermal stress. Physiol Rev 1974;54:75-159 9. Taylor LH, Buskirk E, Henschel A: Maximal oxygen uptake as an objective measurement of cardio-respiratory performance. JAppl Physiol 1955;8:83-90 10. Astrand PO: Aerobic work capacity during maximal performance under various conditions. Circ Res 1967;20:202-210 11. Hermanssen L, Saltin B: Oxygen uptake during maximal treadmill and bicycle exercise. JAppl Physiol 1969;26:31-37 12. Pittman JG, Cohen P: The pathogenesis of cardiac cachexia. N Engl J Med 1964;271:453-461 13. Carr J, Stevenson L, Walden J, Heber D: Prevalence and hemodynamic correlates of malnutrition in severe congestive heart failDownloaded from http://circ.ahajournals.org/ at University of GA on May 25, 2015
1356
14.
15. 16. 17.
Circulation Vol 86, No 5 November 1992
ure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1989;63:709-713 Mancini DM, Walter G, Reichek N, Lenkinski R, McCully KK, Mullen JL, Wilson JR: Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation 1992;85:1364-1373 Bergh U, Kanstrup L-L, Ekblom B: Maximal oxygen uptake during exercise with various combinations of arm and leg work. J Appl Physiol 1976;41:191-196 Astrand PO, Saltin B: Maximal oxygen uptake and heart rate in various types of muscular activity. JAppi Physiol 1961;16:977-981 Stenberg J, Astrand P-0, Ekblom B, Royce J, Saltin B: Hemodynamic response to work with different muscle groups, sitting and
27.
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Active skeletal muscle mass and cardiopulmonary reserve. Failure to attain peak aerobic capacity during maximal bicycle exercise in patients with severe congestive heart failure. G Jondeau, S D Katz, L Zohman, M Goldberger, M McCarthy, J P Bourdarias and T H LeJemtel Circulation. 1992;86:1351-1356 doi: 10.1161/01.CIR.86.5.1351 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1992 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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