Clinical Investigation

Transcription

1 Clinical Investigation 1351 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<0.001), whereas in normal subjects, maximal Vo2 was similar during the two tests, i.e., 26.7 versus 26.2 ml * kg' * min` (NS). The increase in peak Vo2 during combined LL+UL exercise relative to LL exercise alone was almost exclusively observed in patients with peak Vo2 <15 ml * kg`. min' (mean increase, %). Peak Vo0 during combined LL and UL exercise did not increase relative to LL exercise alone in patients with peak Vo2 >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: ) KEY WoRDs * peak V02 * congestive heart failure * muscle mass M aximaloxygen uptake (Vo2) isan 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, 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 Received February 24, 1992; revision accepted July 17, 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

2 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, 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, 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 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 15- second 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 tests with LL alone and LL+UL were performed on separate days in random order. 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 p<0.05 was considered statistically significant. Results Patients With CHF The rest and peak exercise hemodynamic and metabolic parameters are detailed in Table 1 for the 24 patients with CHF. At peak exercise, heart rate was significantly greater during exercise with LL+UL than with LL exercise alone (147.0±3.5 versus 139.2±4.3 beats per minute, p<0.01), whereas systolic blood pressure was similar (170.8±5.7 versus 173.8±6.1 mm Hg, NS). Peak Vo0 was significantly greater during exercise with LL+UL than that observed with LL alone (15.8+±0.8 versus 14.2±0.9 ml* kg`1 min-1, p<0.001). RER at peak exercise was similar during LL+UL exercise and LL alone (1.17±0.03 versus 1.16±0.03, NS). Normal Subjects The rest and peak exercise hemodynamic parameters are detailed in Table 2 for the seven normal subjects. At peak exercise, heart rate and systolic blood pressure were similar in normal subjects during exercise with LL+UL and LL alone (150.1±7.2 versus 152.7±4.7 beats per minute and 184.9±6.4 versus 181.4±5.1 mm Hg, both NS). In contrast to patients with CHF, peak Vo2 was similar in normal subjects during exercise with LL+UL and LL alone (26.7±1.3 versus 26.2±1.1 ml 1. kg- min-1, NS). RER at peak exercise with LL+UL and with LL alone were similar (1.17±0.05 versus 1.18±0.03, NS). Patients With CHF Versus Normal Subjects Overall, peak Vo2 increased significantly more during exercise with LL+UL relative to LL alone in patients with CHF when compared with normal subjects (14.5±3.7% versus 2.0±2.3%, respectively, p<0.05). However, the increase in peak Vo2 attained during exercise with LL+UL relative to LL alone was predominantly observed in patients with more severe impairment in peak aerobic capacity (Figure 1). Peak Vo2 during LL+UL exercise increased more than 10% relative to LL exercise alone in 12 of 16 patients with peak Vo2 less than 15 ml * kg`-l min` during LL exercise alone. For these 16 patients, the mean increase was 21.7±4.1%. In contrast, peak Vo0 during LL+UL exercise increased more than 10% relative to LL exercise alone in only one of eight patients with peak Vo2 >15 ml* kg` min-1 during LL exercise alone. The absolute changes in peak Vo2 between combined LL and UL exercise and LL exercise alone as a function of initial exercise, whereas ECG was monitored continuously. peak V02 are illustrated in Figure 2. In patients with

3 Jondeau et al Skeletal Muscle Mass, Peak V02, and Heart Failure 1353 TABLE 1. Patients With Congestive Heart Failure: Hemodynamic and Metabolic Parameters V02 RER H] R SBP Patient No. Exercise Rest Peak Rest Peak Rest Peak Rest Peak 1 LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL Mean+SEM LL+UL LL 3.4± ± ± ±6.1 LL+UL 3.8± ±0.8 ± ± ±5.7 Vo2, oxygen consumption (ml* kg- min-'); RER, respiratory exchange ratio; HR, heart rate (beats per minute); SBP, systolic blood pressure (mm Hg); LL, exercise with lower limbs alone; LL+UL, exercise with combined upper limbs and lower limbs.

4 1354 Circulation Vol 86, No 5 November 1992 TABLE 2. Normal Subjects: Hemodynamic and Metabolic Parameters Vo2 RER HR SBP Patient No. Exercise Rest Peak Rest Peak Rest Peak Rest Peak 1 LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL LL LL+UL Mean±SEM LL ± ± ± ± ±5.1 LL+UL 4.0± ±1.3 ± ± ± ± ± ±6.4 Vo,2 oxygen consumption (ml* kg`1 min-1); RER, respiratory exchange ratio; HR, heart rate (beats per minute); SBP, systolic blood pressure (mm Hg); LL, exercise with lower limbs alone; LL+UL, exercise with combined upper limbs and lower limbs. peak Vo2 <15 ml. kg1. min-1, the absolute increase was 2.3+±0.4 mg/kg/min, which was significantly greater than that observed in patients with initial peak Vo2 > 15 ml * kg` * min-, i.e., 0.1±0.7 ml *kg.*min-', p<0.05, and normal subjects, i.e., ml- kg- min-1, p< Moreover, in patients with initial peak Vo2 - <15 ml kg1 min- 1, heart rate and ventilation were significantly greater at peak exercise during combined LL and UL exercise than during LL exercise alone, i.e., 144.6±45 versus 134.4±55 beats per minute (p<0.05) and 48.0±3.0 versus 40.3±1.8 1/min (p<0.05), respectively. Peak Vo0 did not increase during LL+UL exer- W LU 0: W < IL _I z z wa wj cn ' m <: gn - v 5 *6 S S S PEAK V02 (ml/kg/min.) FIGURE 1. Scatterplot of relative changes (A, %) in peak Vo2 between exercise with combined lower limb (LL) and upper limb (UL) and exercise with LL alone as a function of absolutepeak VO2 attained during exercise with LL alone in 24 patients with congestive heartfailure (closed circles) and seven normal subjects ofsimilar age and sex (open circles). Patients with peak Vo2 <15 ml] kg1. minm during exercise with LL alone demonstrated a greater increase in peak V02 during exercise with combined LL and UL than patients with peak Vo2 >15 ml* kg-l * mm-l and normal subjects. Hatched area illustrates relative changes in peak Vo2 of +10%. a cise by >10% relative to LL exercise alone in any normal subjects. Discussion The present data demonstrate that patients with severe CHF reach a substantially greater peak Vo2 during exercise with LL+UL than during exercise with LL alone. In contrast, patients with mild-to-moderate CHF, i.e., peak Vo2 > 15 ml * kg.* minm-, behave like normal subjects as they reach similar peak Vo2 during exercise with LL+UL and LL alone. Our findings in normal subjects are in agreement with previously published data.15-17astrand and Saltin16 first reported that six normal men and one woman reached an almost identical maximum Vo0 during exercise with LL+UL and LL alone. They subsequently confirmed their early results in another cohort of 10 normal subjects that included six men and four women. The difference in maximum Vo, between exercise with r. _ j > _ 14 m C: x 1-,:4 FIGURE 2. r--pco.os pco.05 CHF < 15 CHF > 15 NL Bar graph of absolute changes (A) in peak Vo2 between exercise with combined lower limb (LL) and upper limb (UL) and exercise with LL alone in patients with congestive heartfailure (CHF) and initialpeak Vo2 lower and greater than 15 ml * kg-'. minm and in normal subjects (NL).

5 Jondeau et al Skeletal Muscle Mass, Peak Vo2, and Heart Failure 1355 LL+UL and LL alone was 2.6% in the 10 normal subjects.17 Bergh et al15 found that maximum Vo2 increased by 5% when exercise with LL+UL and LL alone was compared in 10 normal men. Moreover, Bergh et al15 demonstrated that this relative increase in maximum Vo, was the greatest when 20% of the total work load was performed with the arms. The inability of combined LL bicycling and UL cranking to increase maximum Vo2 over that attained with LL bicycling alone in normal subjects is consistent with >50% of the total muscle mass being active during LL bicycling. When >50% 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 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 contribute 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 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. 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