Exercise intolerance is a hallmark of chronic congestive heart failure (CHF). In recent years, the physiologic mechanisms underlying reduced exercise capacity in this condition have been the source of a great deal of investigation (19,31,46) (22,24,53) (44,52) (4) (26) (3) (10,11,16,17) (10,11) (21,41) (16,17)
A pathophysiologic feature of CHF that has gained particular interest in recent years is abnormal ventilatory responses to exercise. These ventilatory abnormalities contribute to dyspnea in CHF and are a major cause of exercise intolerance (26,32,47) (14,20,35) (32,40,47,50) (8,51) (33,34,37) (20,32,40,51) (26) (6,45)
In the present study, we sought to further elucidate the mechanisms underlying abnormal ventilatory responses to exercise in patients with reduced ventricular function and to study the effects a program of exercise training would have on them. Accurate evaluation of these mechanisms, including ventilation/perfusion matching, ventilatory control, metabolic acidosis, and breathing patterns, requires the simultaneous measurement of ventilatory gas exchange, intrapulmonary pressures, cardiac output, and arterial blood gases. These variables were acquired simultaneously during upright exercise before and after a 2-month high-intensity residential training program among patients with reduced ventricular function after a myocardial infarction.
METHODS
Patients. Twelve male patients (mean age 56 ± 5 yr) participated in the exercise group, and 13 male patients (mean age 55 ± 7 yr) participated in the control group. Clinical characteristics of the two groups are outlined in Table 1 . All had sustained a myocardial infarction, and some had undergone bypass surgery. The hospital course in all patients included the diagnosis of heart failure. Before their hospitalization, none of the patients had a previous history of heart failure. Patients exhibiting angina or ECG signs of ischemia during exercise were excluded from the study. The presence of reduced ventricular function was documented by signs, symptoms, and an angiographically determined ejection fraction < 40%. All were limited by fatigue or dyspnea on baseline exercise testing, and none had clinical evidence of pulmonary disease. All patients were New York Heart Association Functional Class II or III. Six patients in the exercise group and five in the control group had mild to moderate mitral regurgitation. The study was approved by the Investigational Review Board at the Kantonsspital, Chur. Written informed consent was obtained, and all patients had stable symptoms for at least 1 month before randomization.
TABLE 1: Patient characteristics.
Study design. After myocardial infarction or bypass surgery, patients were stabilized for approximately 1 month. At the time of randomization, patients in both groups underwent initial testing (maximal exercise testing with gas exchange, lactate, and hemodynamic measurements). These tests were repeated after 2 months. Randomization was performed using a list of random numbers. After stabilization, each patient's pharmacologic regimen remained constant throughout the study period.
Exercise training. After stabilization and initial testing, patients in the exercise group resided in a rehabilitation center in Seewis, Switzerland for a period of 8 wk. Seewis is a small village in the mountains with an elevation of 3500 feet. The center has its own staff of physicians, consisting of a medical director and three interns/residents. Program components included education, exercise, and low-fat meals prepared three times daily by the center's cook. Two outdoor walking sessions daily for a duration of approximately 1 h were performed, once in the morning and once in the afternoon. Walking intensity was stratified into four levels based on clinical status, exercise capacity, and performance on a 500-m walking test (50-m increase in altitude) on a nearby hill. The patients were accompanied by a physician during these walking sessions. Exercise leaders carried two-way radios for communication with the center in case of emergency. A van equipped with emergency equipment remained in close proximity to the group.
In addition to these walking periods, the patients performed four 45-min periods of monitored stationary cycling per week. The cycling sessions were designed to elicit an intensity equal to roughly 60-80% of the patient's heart rate reserve and were increased progressively over the 2 months as tolerated. Control patients remained at home to convalesce, received usual clinical follow-up, and were encouraged not to exercise beyond a level associated with normal activities of daily living.
Exercise testing. Before randomization, each patient performed a preliminary exercise test to help ascertain clinical stability and to habituate the patients to the testing procedure, apparatus, etc. The data from this preliminary test was not used in the study analysis. On the day of testing, patients were requested to abstain from food, coffee, and cigarettes for 3 h before the test. Standard pulmonary function tests were performed. Maximal exercise testing was performed on an electrically braked cycle ergometer using an individualized ramp protocol. Briefly, this test entailed choosing an individualized ramp rate to yield a test duration of approximately 10 min (30) −1 . A 12-lead electrocardiogram was monitored continuously, and blood pressure was measured manually every minute during exercise and throughout the recovery period. The patient's subjective level of exertion was quantified every minute by using the Borg 6-20 scale (2)
Respiratory gas exchange variables were acquired continuously throughout exercise using the Schiller CS-100 metabolic system. Gas exchange variables analyzed were oxygen uptake, carbon dioxide production, minute ventilation, respiratory rate, tidal volume, oxygen pulse, respiratory exchange ratio, and the ventilatory equivalents for oxygen (V̇E/O2 ) and carbon dioxide (E/CO2 ). The gas exchange data were obtained breath-by-breath and expressed as rolling 30-s averages printed every 10 s. The lactate threshold was determined visually by consensus among two experienced reviewers (blind to group and pre/post test identity) using a computerized plot of the oxygen uptake versus lactate relationship.
Resting and peak exercise cardiac output and pulmonary pressures were determined in the catheterization laboratory. These procedures in our laboratory have been described in detail previously (11) (28) (Equation 1) where PaCO2 is the arterial carbon dioxide tension, and PeCO2 is the mixed expired carbon dioxide tension. Arterial blood lactate samples were drawn every minute throughout the test, and whole blood was analyzed after the test using an enzymatic colorimetric method (Roche Laboratories).
Statistics. Statistical Graphics Corporation Software (Bethesda, MD) was used to perform multivariate analysis of variance procedures comparing gas exchange responses between groups. This procedure considered both inter- and intra-group comparisons, and interactions among the factors (group and test) for each dependent variable. Post hoc multiple comparison procedures were performed using the Scheffe method. Clinical and demographic data were compared using unpaired t -tests and chi-square analysis. Relationships between gas exchange variables and hemodynamic responses to exercise were assessed by simple linear regression. Data are expressed as mean ± SD.
RESULTS
No differences were observed between groups initially in clinical or demographic data, including age, height, weight, resting blood pressure, pulmonary function, ejection fraction, or maximal oxygen uptake (Table 1) . No untoward events occurred during any of the exercise testing or training procedures. During monitored cycling sessions over the 2 months, the mean percentage of maximal heart rate maintained was 83 ± 6%, the mean percentage of maximal workload was 78 ± 7%, and perceived exertion averaged 15.2 ± 2. Two patients in the exercise group and one in the control group did not undergo invasive hemodynamic exercise testing during either the initial or follow-up test due to either clinical reasons or technical difficulties. Thus, pulmonary capillary wedge pressure, pulmonary artery pressure, cardiac output, a-O2 difference, and Vd/Vt are presented for 10 patients in the exercise group and 12 patients in the control group; for all other gas exchange and hemodynamic data, the numbers were 12 and 13 for exercise and control groups, respectively.
Maximal exercise testing. Both groups achieved maximal respiratory exchange ratios greater than 1.20 and perceived exertion levels of roughly 19 on both tests, suggesting maximal efforts were generally achieved (Table 2) . No patient in either group was limited by angina, and none exhibited ECG evidence of ischemia during baseline exercise testing. Arterial oxygen saturation remained above 90% at peak exercise during both tests in all but one patient, who exhibited small decreases to 87 and 89% on pre- and post-testing, respectively. No differences were observed within or between groups in maximal heart rate or blood pressure. The exercise group demonstrated a 29% increase in maximal oxygen uptake (19.4 ± 3.0 to 25.1 ± 4.8 mL·kg−1 ·min−1 , P < 0.01) (Fig. 1) . Concomitant increases in maximal minute ventilation, CO2 production, exercise time, and Watts achieved were observed in the exercise group. No differences between tests were observed among control patients in maximal oxygen uptake, exercise time, or Watts achieved.
TABLE 2: Exercise and gas exchange data.
Figure 1: Study design.
Oxygen uptake at the lactate threshold increased significantly (39%, P < 0.01) in the exercise group, whereas a small decrease was observed among controls. Similar increases in exercise time and Watts achieved at the lactate threshold were observed among patients in the exercise group, whereas the control group demonstrated small decreases in these variables. No differences were observed within or between groups for heart rate, systolic or diastolic blood pressure, respiratory exchange ratio, lactate, or perceived exertion at this point.
Maximal cardiac output increased in the exercise group from 12.0 L·min−1 before training to 13.7 L·min−1 after training (P < 0.05). This was accompanied by a widening of the maximal arteriovenous oxygen difference from 13.1 ± 1.3 to 14.8 ± 1.6 mL O2 ·100 mL−1 (P < 0.05). These variables did not differ among controls. No differences were observed within either group before or after the study period in resting ejection fraction or resting or maximal exercise mean arterial, wedge, right atrial, or pulmonary artery pressures, stroke volume, pulmonary vascular resistance, or systemic vascular resistance.
Relationships between hemodynamic responses, gas exchange variables, and work rate. By ANOVA, significant main effects were observed in the exercise group for reductions in E/O2 (P < 0.01), perceived exertion (P < 0.001), heart rate (P < 0.001), and lactate (P < 0.01) at matched time points (work rates) throughout exercise (Figs. 2 and 3) . Trends were also observed for reductions in E/CO2 and the oxygen uptake/work rate relationship (P = 0.06 for both). Among controls, none of these relationships differed significantly with the exception of a reduction in heart rate (P < 0.05). The slope of the relationship between E and CO2 was reduced after training among patients in the exercise group (0.33 pre vs 0.27 post, P < 0.01, Fig. 4 ), whereas control patients did not differ. The ratio of maximal tidal volume to respiratory rate (Vt/RR) improved slightly after training in the exercise group (0.053 ± 0.02 to 0.049 ± 0.02 L/breath·min−1 ), whereas control patients increased slightly (0.053 ± 0.02 to 0.054 ± 0.02 L/breath·min−1 ); these differences were not significant between groups (P = 0.65). A similar response in Vt/RR was observed in each group throughout submaximal exercise. The reduction in minute ventilation during exercise in the trained group was mediated primarily by a reduction in respiratory rate (Fig. 3) .
Figure 2: Influence of exercise training on oxygen uptake, perceived exertion, heart rate, and lactate at matched ramp work rates during exercise. Open squares indicate baseline values; closed circles indicate posttraining. A main effect (P < 0.01) was observed for all except oxygen uptake.
Figure 3: Influence of training on ventilatory responses to exercise at matched ramp work rates during exercise.
Open squares indicate baseline values,
closed squares indicate posttraining. A significant reduction was observed for
/
O
2 (
P < 0.01).
Figure 4: The slope of the relationship between minute ventilation and
CO
2 before (
open circles ) and after (
closed circles ) training in the exercise group. (0.33 pre vs 0.27 post,
P < 0.01).
Figure 5 illustrates the relationships between resting and peak exercise pulmonary wedge pressures and peak O2 among patients in both groups before randomization. Modest but significant inverse correlations were observed both at rest (r = −0.56, P < 0.01) and peak exercise (r = −0.43, P < 0.05). Maximal minute ventilation was correlated with CO2 on both the pre (r = 0.71, P < 0.001) and post (r = 0.85, P < 0.001) tests. Maximal ventilation was not significantly related to pulmonary wedge pressure at rest (r = −0.17) or peak exercise (r = −0.30). The relationships between maximal E/CO2 and maximal cardiac output, Vd/Vt, pulmonary wedge pressure and pulmonary artery pressure are illustrated in Figure 6 . Maximal E/CO2 was strongly inversely related to maximal cardiac output (r = −0.72, P < 0.001) and modestly related to mean maximal pulmonary capillary wedge pressure (r = 0.53, P < 0.05) and maximal Vd/Vt (r = 0.54, P < 0.05), but was unrelated to maximal pulmonary artery pressure (r = 0.09). Maximal E/CO2 was also inversely related to peak O2 (r = 0.47, P < 0.05). When these relationships were reassessed after the training or control periods, no appreciable differences were observed.
Figure 5: The relationships between resting and maximal exercise pulmonary wedge pressures and peak oxygen uptake among patients in both groups before randomization.
Figure 6: The relationships between maximal exercise
E/
CO
2 and maximal cardiac output, maximal pulmonary capillary wedge pressure (PCW), maximal Vd/Vt, and maximal mean pulmonary artery pressure (PA) in both groups at baseline.
DISCUSSION
Although excessive ventilatory responses to exercise in patients with reduced ventricular function have been the subject of a great deal of study in recent years, an understanding of the mechanisms and their treatment remains incomplete. Pharmacologic intervention with inotropic therapy or vasodilators has been shown in some studies (7,43) (12,38) (25) (1,6,10,11,16,17,45) (1)
The mechanisms underlying the abnormal ventilatory response to exercise in heart failure have generally been thought to include heightened pulmonary pressures, ventilation/perfusion mismatching, early metabolic acidosis, abnormal ventilatory control, deconditioning, and abnormal breathing patterns (5,26,32,46) (6,45)
Response to exercise training. The high-intensity training stimulus employed in the present study yielded considerable increases in peak V̇O2 (29%) and concomitant increases in V̇O2 at the lactate threshold (39%), Watts achieved, and exercise time (Table 2) . These increases in peak V̇O2 and other variables are substantially larger than those in the aforementioned trials (6,19,45) −1 in the trained group, which contrasts with several studies in CHF showing either no change (17,21,41) −1 (6,45)
Ventilatory response to exercise. The ventilatory requirement for exercise is defined by three factors according to the alveolar gas equation: 1) metabolic CO2 production (expressed as V̇E/V̇CO2 ); 2) the PaCO2 set point; and 3) the fraction of dead space ventilation (expressed as Vd/Vt). As other investigators have observed in patients with CHF (47,51) 2 remained normal throughout exercise in the present study (falling from 34.0 ± 3.8 to 30.9 ± 4.2 mm Hg), and V̇E and V̇CO2 were tightly coupled, suggesting that neural and chemoreceptor control of ventilation were normal. Exercise training reduced the slope of the relationship between V̇E and V̇E/V̇CO2 (Fig. 4) . V̇E/V̇CO2 was characteristically shifted upward (Table 2 and Figure 3 ), which reflects a heightened Vd/Vt (50) 2 , particularly on the initial test (Fig. 3) .
Ventilation/perfusion mismatching. Ventilation/perfusion mismatching has been identified as a major factor contributing to an increase in physiologic dead space (Vd/Vt) in CHF (26,31,46,47) (47) 2 ) and maximal cardiac output in the present study (Fig. 6) suggests that decreased pulmonary perfusion did in fact underlie an increased physiologic dead space by increasing ventilation/perfusion mismatching. A better matching of ventilation to perfusion, and thus a reduction in Vd/Vt, could in theory be accomplished by either an improvement in cardiac output or a reduction in physiologic dead space. We hypothesized that an increase in maximal cardiac output with training observed in some previous studies (10,11,17)
Efficiency of ventilation. The significant reductions in V̇E/V̇O2 (Fig. 3) and the reduction in the slope of the relation between V̇E and V̇CO2 (Fig. 4) clearly confirm a beneficial effect of exercise training on the ventilatory response to exercise. These measures are well-recognized indices of ventilatory efficiency and have been used as markers of the severity of CHF (32,50)
Breathing pattern. The alveolar gas equation also defines a condition in which a reduction in tidal volume would raise the V̇E/V̇CO2 [V̇E/V̇CO2 = 863/(PaCO2 × (1 − Vd/Vt] and contribute to hyperventilation. Rapid, shallow respiration is characteristic of the response to exercise in patients with CHF (20,31,32,40,51) (20) (5) anatomic dead space per se in patients with CHF, but rather due to an altered ventilatory pattern (ratio of tidal volume to breathing rate). Initially, our patients demonstrated a ratio of tidal volume to breathing rate which was similar to that observed in previous studies among patients with CHF (5,32) 2 ) we observed after training was attributable mainly to a lower respiratory rate, whereas tidal volume remained relatively unchanged (Fig. 3) . Training had only minimal effects on the breathing pattern.
Metabolic acidosis. Numerous investigators have associated early lactate accumulation in the blood with metabolic acidosis, hyperventilation, and exercise intolerance in patients with CHF (8,31,47,51) 2 , which stimulates ventilation. Previous studies have demonstrated that exercise training causes a delay in the ventilatory threshold in normal subjects (9,36) (18,42) (23) (29) (6,42) (Table 2) and an overall reduction in the slope of the relationship between blood lactate and work rate throughout exercise (Fig. 2) . Because ventilation is an important component of perceived effort (39) (Fig. 2) .
Pulmonary pressure. Historically, the predominant explanation for exertional dyspnea in patients with CHF has been higher than normal pulmonary wedge pressures, causing reflex hyperventilation (14,20,26,35) (9,12,31,46) 2 (Fig. 5) and the ventilatory response to exercise (Fig. 6) . As reported by others (12,13) 2 (Fig. 5) . Unlike previous studies, however, we observed a significant inverse relationship between peak V̇O2 and pulmonary wedge pressure during exercise, though the relationship was weak (r = −0.43, P < 0.05).
These data confirm the relatively weak relations between intrapulmonary pressures, peak V̇O2 , and the ventilatory requirement for exercise (12,31,46) (21,41) (41,49) (11,21,48)
Limitations. The present population differed somewhat from other recent studies in that the patients had newly diagnosed ventricular dysfunction after a myocardial infarction. The findings may have been different had the disease been more chronic or had the ventricular dysfunction been more severe. Our observations cannot be attributed entirely to exercise training because there is some spontaneous improvement in exercise tolerance during the 1-2 months after a myocardial event (15) 2 ; this measurement is influenced by the variability of the blood gas sample and how the increments in gas exchange data are averaged. Recent studies have demonstrated that inspiratory muscle strength is a determinant of peak V̇O2 in CHF, and that these muscles can be trained (27) rehabilitation or home programs would be as effective in improving ventilatory and gas exchange responses to exercise. Although the patients in the present study were consecutive, it is likely that some patients exposed to such a high intensity regimen would drop out, become injured, or be unable to complete the program for safety reasons.
SUMMARY
The present data demonstrate that exercise training among patients with reduced left ventricular function after a myocardial infarction or surgery results in a systematic improvement in the ventilatory response to exercise. Training increased peak V̇O2 , increased maximal cardiac output, tended to lower Vd/Vt, and markedly improved the efficiency of ventilation. Training reduced lactate levels in the blood throughout exercise and delayed the lactate threshold, and these responses largely explained the reduced ventilatory response to exercise after training. Peak V̇O2 and ventilatory responses to exercise were only modestly related to pulmonary vascular pressures, and training had no effect on the relationships between exercise capacity, ventilatory responses, and pulmonary pressures. The favorable influence of exercise training on ventilatory responses to exercise in the present study provides further support for the use of this modality in patients with reduced ventricular function.
REFERENCES
1. Agency for Health Care Policy and Research.
Clinical Practice Guidelines for Cardiac Rehabilitation , 1995.
2. Borg, G. A. V. Psychophysical bases of perceived exertion.
Med. Sci. Sports Exerc. 14:377-381, 1982.
3. Bristow, M. R., R. Ginsburg, W. Minobe, et al. Decreased catecholamine sensitivity and B-adrenergic-receptor density in failing human hearts.
N Engl. J. Med. 307:205-211, 1982.
4. Chati, Z., F. Zannad, C. Jeandel, et al. Physical deconditioning may be a mechanism for the skeletal muscle energy phosphate metabolism abnormalities in chronic heart failure.
Am. Heart J. 131:560-566, 1996.
5. Clark, A. L., T. P. Chua, and A. J. S. Coats. Anatomical dead space, ventilatory pattern, and exercise capacity in chronic heart failure.
Br. Heart J. 74:377-380, 1995.
6. Coats, A. J..S., S. Adanopoulos, A. Radaelli, et al. Controlled trial of physical training in chronic heart failure.
Circulation 85:2119-2131, 1992.
7. Cowley, A. J., J. M. Rowley, K. Stainer, and J. R. Hampton. The effect of the angiotensin converting enzyme inhibitor, enalapril, on exercise tolerance and abnormalities of limb blood flow and respiratory function in patients with severe heart failure.
Eur. Heart J. 14:964-968, 1993.
8. Cowley, A. J., K. Stainer, J. M. Rowley, and J. R. Hampton. Abnormalities of the peripheral circulation and respiratory function in patients with severe heart failure.
Br. Heart J. 55:75-80, 1986.
9. Davis, J. A., M. H. Frank, B. J. Whipp, and K. Wasserman. Anaerobic threshold alterations caused by endurance training in middle-aged men.
J. Appl. Physiol. 46:1039, 1979.
10. Dubach, P., J. Myers, G. Dziekan, et al. Effect of exercise training on myocardial remodeling in patients with reduced ventricular function following myocardial infarction: application of magnetic resonance imaging (MRI).
Circulation 95:2060-2067, 1997.
11. Dubach, P., J. Myers, G. Dziekan, et al. Effect of high intensity exercise training on central hemodynamic responses to exercise in men with reduced left ventricular function.
J. Am. Coll. Cardiol. 29:1591-1598, 1997.
12. Fink, L., J. Wilson, and N. Ferraro. Exercise ventilation and pulmonary artery wedge pressure in chronic stable congestive heart failure.
Am. J. Cardiol. 57:249-253, 1986.
13. Franciosa, J. A., J. B. Baker, and L. Seth. Pulmonary versus systemic hemodynamics in determining exercise capacity of patients with chronic left ventricular failure.
Am. Heart J. 110:807-813, 1985.
14. Gazetopolous, N., H. Davies, C. Oliver, and D. Deuchan. Ventilation and hemodynamics in heart disease.
Br. Heart J. 28:11-16, 1966.
15. Goebbels, U., J. Myers, G. Dziekan, et al. A randomized comparison of exercise trading in patients with normal versus reduced ventricular function.
Chest 113:1387-1393, 1998.
16. Hambrecht, R., E. Fiehn, J. Yu, et al. Effects of endurance training on mitochondrial ultrastructure and fiber type distribution in skeletal muscle of patients with stable chronic heart failure.
J. Am. Coll. Cardiol. 29:1067-1073, 1997.
17. Hambrecht, R., J. Niebauer, E. Fiehn, et al. Physical training in patients with stable chronic heart failure: effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscles.
J. Am. Coll. Cardiol. 25:1239-1249, 1995.
18. Hambrecht, R., J. Niebauer, C. Marburger, et al. Various intensities of leisure time physical activity in patients with coronary artery disease: effects on cardiorespiratory fitness and progression of coronary atherosclerotic lesions.
J. Am. Coll. Cardiol. 22:468-477, 1993.
19. Hanson, P. Exercise testing and training in patients with chronic heart failure.
Med. Sci. Sports Exerc. 26:527-537, 1994.
20. Ingram, R. H., and E. R. McFadden. Respiratory changes during exercise in patients with pulmonary venous hypertension.
Prog. Cardiovasc. Dis. 19:109-115, 1976.
21. Jette, M., R. Heller, F. Landry, and G. Blumchen. Randomized 4-week exercise program in patients with impaired left ventricular function.
Circulation 84:1561-1567, 1991.
22. Jondeau, G., S. D. Katz, J-F. Toussaint, et al. Regional specificity of peak hyperemic response in patients with congestive heart failure: correlation with peak aerobic capacity.
J. Am. Coll. Cardiol. 22:1399-1402, 1993.
23. Kiilavuori, K., A. Sovijarvi, H. Naveri, T. Ikonen, and H. Leinonen. Effect of physical training on exercise capacity and gas exchange in patients with chronic heart failure.
Chest 110:985-991, 1996.
24. Kraemer, M. D., S. H. Kubo, T. S. Rector, N. Brusnvold, and A. J. Bank. Pulmonary and peripheral vascular factors are important determinants of peak exercise oxygen uptake in patient with heart failure.
J. Am. Coll. Cardiol. 21:641-648, 1993.
25. Marzo, K. P., J. R. Wilson, and D. M. Mancini. Effects of cardiac transplantation on ventilatory response to exercise.
Am. J. Cardiol. 69:547-553, 1992.
26. Mancini, D. M. Pulmonary abnormalities limiting exercise capacity in patients with heart failure.
Prog. Cardiovasc. Dis. 37:347-370, 1995.
27. Mancini, D. M. Pulmonary factors limiting exercise capacity in patients with heart failure.
Prog. Cardiovasc. Dis. 37:347-370, 1995.
28. Myers, J. N.
Essentials of Cardiopulmonary Exercise Testing. Champaign, IL: Human Kinetics Publishers, 1996.
29. Myers, J., and E. Ashley. Dangerous curves: a perspective on exercise, lactate, and the anaerobic threshold.
Chest 111:787-95, 1997.
30. Myers, J., N. Buchanan, D. Walsh, et al. Comparison of the ramp versus standard exercise protocols.
J. Am. Coll. Cardiol. 17:1334-1342, 1991.
31. Myers, J., and V. F. Froelicher. Hemodynamic determinants of exercise capacity in chronic heart failure.
Ann. Int. Med. 115:377-386, 1991.
32. Myers, J., A. Salleh, N. Buchanan, et al. Ventilatory mechanisms of exercise intolerance in chronic heart failure.
Am. Heart J. 124:7-10, 1992.
33. Nery, L. E., K. Wasserman, W. French, A. Oren, and J. A. Davis. Contrasting cardiovascular and respiratory responses to exercise in mitral valve and chronic obstructive pulmonary disease.
Chest 83:446-451, 1983.
34. Oren, A., K. Wasserman, J. A. Davis, and B. J. Whipp. Effect of CO
2 set point on ventilatory response to exercise.
J. Appl. Physiol. 51:185-189, 1981.
35. Parker, G. W., and R. Gorlin. Immediate post-exercise vital capacity: a measure of increased pulmonary capillary pressure.
Am. J. Med. Sci. 257:365-370, 1969.
36. Ready, A. E., and H. A. Quinney. Alterations in anaerobic threshold as the result of endurance training and detraining.
Med. Sci. Sports Exerc. 14:292, 1982.
37. Reed, J. W., M. Ablett, and J. E. Cotes. Ventilatory responses to exercise and carbon dioxide in mitral stenosis before and after valvulotomy: causes of tachypnoea.
Clin. Sci. Molec. Med. 54:9-16, 1978.
38. Reindl, I., and F. X. Kleber. Exertional hyperpnea in patients with chronic heart failure is a reversible cause of exercise tolerance.
Basic Res. Cardiol. 92(Suppl. 1):37-43, 1996.
39. Robertson, R. J., and B. J. Noble. Perception of physical exertion: methods, mediators, and applications.
Exerc. Sport Sci. Rev. 25:407-452, 1997.
40. Rubin, S. A., and H. V. Brown. Ventilation and gas exchange during exercise in severe chronic heart failure.
Am. Rev. Respir. Dis. 129(Suppl):563-564, 1984.
41. Scalvini, S., S. Marangoni, M. Volterrani, M. Schen, A. Quadri, and G. F. Levi. Physical
rehabilitation in coronary patients who have suffered from episodes of cardiac failure.
Cardiology 80:417-423, 1992.
42. Sullivan, M., S. Ahnve, V. F. Froelicher, and J. Myers. The influence of exercise training on the ventilatory threshold of patients with coronary heart disease.
Am. Heart J. 109:458-463, 1985.
43. Sullivan, M., J. E. Atwood, J. Myers, et al. Increased exercise capacity after digoxin administration in patients with heart failure.
J. Am. Coll. Cardiol. 13:1138-1143, 1989.
44. Sullivan, M. J., H. J. Green, and F. R. Cobb. Altered skeletal muscle metabolic response to exercise in chronic heart failure: relation to skeletal muscle aerobic enzyme activity.
Circulation 84:1597-1607, 1991.
45. Sullivan, M. J., M. B. Higgenbotham, and F. R. Cobb. Exercise training in patients with severe left ventricular dysfunction: hemodynamic and metabolic effects.
Circulation 78:506-515, 1988.
46. Sullivan, M. J., and M. Hawthorne. Exercise intolerance in patients with chronic heart failure.
Prog. Cardiovasc. Dis. 38:1-22, 1995.
47. Sullivan, M. J., M. B. Higginbotham, and F. R. Cobb. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite hemodynamic and pulmonary abnormalities.
Circulation 77:552-559, 1988.
48. Sullivan, M. J., M. B. Higginbotham, and F. R. Cobb. Exercise training in patients with severe left ventricular dysfunction: hemodynamic and metabolic effects.
Circulation 78:506-515, 1988.
49. Tavazzi, L., and G. Ignone. Short-term haemodynamic evolution and late follow-up of post-infarct patients with left ventricular dysfunction undergoing a physical training programme.
Eur. Heart J. 12:657-665, 1991.
50. Wada, O., H. Asanoi, K. Miyagi, et al. Importance of abnormal lung perfusion in excessive exercise ventilation in chronic heart failure.
Am. Heart J. 125:790, 1992.
51. Weber, K. T., G. T. Kinasewitz, J. S. Janicki, and A. P. Fishman. Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure.
Circulation 65:1213-1223, 1982.
52. Wilson, J. R. Exercise intolerance in heart failure: importance of skeletal muscle.
Circulation 91:559-561, 1995.
53. Wilson, J. R., J. L. Martin, D. Schwartz, and N. Ferraro. Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle.
Circulation 69:1079-1987, 1984.
