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(Circulation. 1996;94:1567-1572.)
© 1996 American Heart Association, Inc.

Articles

Circulatory Status and Response to Cardiac Rehabilitation in Patients With Heart Failure

John R. Wilson, MD; Jay Groves, EdD; Glenn Rayos, MD

the Cardiology Division and the Kim Dayani Rehabilitation Center of the Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to John R. Wilson, MD, Cardiology Division, 315 MRB-2, Vanderbilt University Medical Center, Nashville, TN 37232-6300.

	Abstract

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Background We recently reported that some patients with heart failure and exercise intolerance exhibit severe hemodynamic dysfunction during exercise, whereas others have normal cardiac output responses to exercise. We postulated that patients with preserved cardiac output responses to exercise are limited by deconditioning and would respond to exercise training, whereas patients with reduced cardiac output responses are limited by skeletal muscle underperfusion and would not improve with exercise training. The present study was undertaken to test this hypothesis.

Methods and Results Thirty-two patients with heart failure were studied. Hemodynamic response to maximal treadmill exercise was measured; then patients were enrolled in a standard 3-month cardiac rehabilitation program. Peak exercise VO₂, lactate threshold, and quality-of-life questionnaires were assessed at 1, 2, and 3 months. Twenty-one patients had normal cardiac output responses to exercise. All 21 patients participated in the rehabilitation program without difficulty, and 9 (43%) responded to rehabilitation, defined as a >10% increase in both peak exercise VO₂ and the anaerobic threshold. Of the 11 patients with reduced cardiac output responses to exercise, 3 discontinued rehabilitation because of severe exhaustion, and only 1 qualified as a responder (9%; P<.04 versus preserved cardiac output).

Conclusions Patients with heart failure and normal cardiac output responses to exercise frequently improve with exercise training. Patients with severe hemodynamic dysfunction during exercise usually do not improve with training, which suggests that they are limited primarily by circulatory factors.

Key Words: heart failure • exercise • hemodynamics

	Introduction

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Exercise intolerance is a widespread and serious problem in patients with heart failure.^{1 2 3} In symptomatic patients with heart failure, maximal exercise capacity is often <50% of normal.^{1 2 3} In apparently asymptomatic patients, maximal exercise capacity averages 60% to 70% of normal.⁴

In the past, this exercise intolerance has been attributed primarily to circulatory dysfunction and, in particular, to inadequate skeletal muscle flow. This presumption was based on two observations. First, it was observed that lactate levels increased earlier than normal in patients with heart failure.^{1 2 3} Early lactate release was assumed to reflect muscle ischemia. Second, it was noted that on average both cardiac output and leg blood flow were reduced during exercise in patients with heart failure.^{1 2 5}

Recently, however, we reported that >50% of patients with exercise intolerance and heart failure have normal cardiac output responses to exercise.^{6 7} Despite the presence of preserved flow responses, these patients exhibit early lactate release from skeletal muscle, suggesting that exercise is limited by skeletal muscle changes. These observations led us to speculate that patients with heart failure fall into two general groups: patients limited by circulatory dysfunction and low muscle flow and patients limited by skeletal muscle dysfunction, probably caused by deconditioning. This presumption, in turn, led us to hypothesize that patients with normal flow responses would likely respond to cardiac rehabilitation, whereas patients with reduced flow responses would not benefit from an exercise program.

The present study was undertaken to test this hypothesis. Accordingly, we used Swan-Ganz catheters to measure hemodynamic responses to treadmill exercise in a group of patients with heart failure and exercise limitation. Patients were then enrolled in a standard cardiac rehabilitation program. We then compared the effect of training in patients with normal cardiac output responses to exercise versus patients with impaired flow responses.

	Methods

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Patient Population
Studies were performed on 32 ambulatory patients recruited from the Heart Failure and Heart Transplantation Program of Vanderbilt University Medical Center (Nashville, Tenn). Twenty-three patients were men; 9 were women. Their average age was 51±9 (mean±SD) years. Their left ventricular ejection fraction averaged 23±8%. On the basis of the results of cardiac catheterization, heart failure was attributed to coronary artery disease in 22 patients and to idiopathic cardiomyopathy in 10 patients. All patients had histories of congestive heart failure for at least 6 months before enrollment; all had been on stable medications for at least 6 weeks; and all were receiving digoxin, an ACE inhibitor, and diuretics. Patients were excluded if they had severe lung disease, exertional angina, symptomatic peripheral vascular disease, diabetes with severe end-organ damage, significant cerebrovascular disease, or malignancies.

The protocol was approved by the Vanderbilt Institution Review Board, and written informed consent was obtained from all patients.

Protocol
After enrollment in the study, an exercise hemodynamic study was performed. For this study, patients continued their routine medications, except they did not take their diuretic doses the morning of the study. After a 3-hour fast, the patient presented to a special procedure room and underwent insertion of a 7F Swan-Ganz catheter through the right internal jugular vein. The patient was allowed to recover for 20 to 30 minutes; then resting hemodynamic measurements, including pulmonary artery, pulmonary wedge, and right atrial pressure, were made. Thermodilution cardiac outputs were measured in triplicate by use of injection of 10-mL boluses of iced saline and an Edwards thermodilution computer. Arterial blood pressure was measured by cuff sphygmomanometry. Pulmonary artery blood samples were obtained for lactate and hemoglobin O₂ saturation.

The patient then stood on a Marquette treadmill and was connected to a MedGraphics CardioO₂ System with a disposable pneumotach. The patient also was attached to a pulse oximeter through a finger probe. Hemodynamic measurements and blood sampling were repeated. After 3 minutes of resting-data acquisition, maximal symptom-limited exercise testing was performed by use of a 3-minute Naughton protocol. At the end of each exercise stage and at peak exercise, hemodynamic measurements and blood sampling were repeated. Arterial hemoglobin O₂ saturation was monitored continuously with the pulse oximeter. After exercise, the Swan-Ganz catheter was removed, and the patient was discharged.

Cardiac output responses to exercise were defined as normal or reduced. The lower limit of normal was defined as a cardiac output (liters per minute) below 5xVO₂ (L/min)+3 L/min. This lower limit was based on the studies of Higginbotham et al.⁸ These investigators measured the cardiac output responses to upright exercise in normal subjects and calculated a regression curve and 95% confidence limits for the relationship between cardiac index and oxygen consumption. We converted this regression curve to cardiac output by multiplying the cardiac index by 1.8 m², an average body surface area.

To test this definition of the lower limits of the normal cardiac output, studies by Damato et al,⁹ Becklake et al,¹⁰ and Julius et al¹¹ were examined. These investigators studied 172 normal subjects, of whom 65 were women. Damato et al⁹ provided individual data points for oxygen consumption and cardiac output. The linear regression line noted above fell just below the normal data points. The regression line fell below all the normal regression lines described by Becklake et al.¹⁰ Julius et al¹¹ reported mean cardiac output levels±SE versus oxygen consumption for their normal population. The linear regression line noted above was located two or three standard errors below the normal mean values. These observations suggest that the equation 5xVO₂ (L/min)+3 L/min provides a valid reflection of the lower limits of normal cardiac output during exercise.

Within 1 week of the hemodynamic study, patients underwent a second baseline cardiopulmonary exercise test. For the purposes of analysis, the two baseline peak exercise VO₂ and anaerobic threshold values were averaged. At this visit, patients also completed two quality-of-life questionnaires: the Minnesota Living With Heart Failure Questionnaire^{12 13} and the Yale Dyspnea-Fatigue Index.¹⁴ The 21 questions on the Minnesota Living With Heart Failure Questionnaire assess the patient's perception of how his or her emotional and physical states are impaired by heart failure. The answer to each question ranges from a score of 0 (no impairment) to 5 (very much impaired), so the total score can range from 0 to 105. The higher the score is, the more severe the impairment is.

The Dyspnea-Fatigue Index uses a scale of 0 to 4 to assess the magnitude of task that produces dyspnea and/or fatigue (0=symptomatic at rest; 4=symptomatic only with extraordinary activity), the pace of task that produces dyspnea and/or fatigue (0=symptomatic at rest; 4=all activities performed at normal pace), and the level of functional impairment (0=very severe; 4=none). Therefore, the composite index can range from 0 (severely limited) to 12 (no limitation).

At this visit, patients also underwent measurement of body composition with dual-energy x-ray absorptiometry and a total body scanner (model DPX, Lunar Corp).^{15 16 17 18} This scanner uses a constant potential x-ray source and a cerium filter to produce two stable radiation beams at 6.4 and 11.2 fJ. A series of transverse scans are made from head to toe at 1-cm intervals for a total scan time of 20 minutes. When the two beams pass through the body, attenuation depends on the tissue mass and type. Based on regional attenuation, the fat mass, lean mass, and mineral content of the region are calculated.

After these baseline studies, patients were enrolled in a standard cardiac rehabilitation program in either the Vanderbilt Dionyi Rehabilitation Center or a rehabilitation program close to home. All centers followed the same exercise training regimen, including a 15-minute warm-up period followed by 45 minutes of exercise on a treadmill, a stair machine, and a bicycle at 60% to 70% of maximal heart rate. Compliance was monitored. Cardiopulmonary exercise tests and quality-of-life questionnaires were repeated monthly, and the exercise prescription was adjusted if maximal exercise capacity improved. Exercise was performed three times per week for a total of 12 weeks. At the end of the 12 weeks, maximal exercise capacity, body composition, anthropometric measurements, and quality-of-life questionnaires were repeated. Patients also were asked whether they felt that the rehabilitation program had improved their overall sense of well-being.

All patients in the study were receiving diuretics, digoxin, and an ACE inhibitor. Doses of these drugs were kept constant during the study, although two patients developed mild fluid retention during the study and transiently received an increase in diuretic dose to return body weight to baseline levels.

Derived Variables
Mean arterial blood pressure was calculated as the diastolic pressure plus one third the pulse pressure. The AV O₂ difference was calculated as hemoglobin concentration times the arterial minus the pulmonary venous hemoglobin O₂ saturation. The Fick cardiac output was calculated as the oxygen consumption divided by the AV O₂ difference.

The ventilatory lactate threshold was defined with three criteria: the point after which the respiratory gas exchange ratio (VCO₂/VO₂) consistently exceeded the resting ratio, the point at which the ventilatory equivalent for oxygen (VE/VO₂) was minimal followed by a progressive increase in VE/VO₂, and the VO₂ after which a nonlinear rise in VE occurred relative to VO₂.^{2 19 20}

The ventilatory response to exercise was evaluated by correlating minute ventilation with carbon dioxide production with the use of linear regression analysis. The slope of this equation was used as an index of ventilatory response to exercise.²¹

Measured Variables
Hemoglobin O₂ saturation was measured with a Ciba-Corning 2500 Co-Oximeter. Blood for lactate determination was deproteinized with cold perchloric acid and assayed with a spectrophotometric technique. Normal values at rest for this technique are 3 to 12 mg/dL.

Data Analysis
All data are expressed as mean±SD. Differences between groups were evaluated with ANOVA, including repeated measures ANOVA when sequential measurements were made. Multiple comparisons were performed with the Bonferroni method. Correlations between variables were assessed by use of least-squares regression analysis. A value of P<.05 was considered statistically significant.

	Results

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Thirty-two patients with an average peak exercise VO₂ of 12.9+2.3 mL·min^-1·kg^-1 were enrolled in the study. Twenty-seven of these patients completed the 3-month cardiac rehabilitation program. All patients attended 80% of the sessions and achieved their target heart rates during the sessions.

Five patients did not complete the 3-month program. Two patients underwent elective heart transplantation after completing 2 months of rehabilitation. Three patients discontinued the rehabilitation program owing to extreme exhaustion caused by exercise training. These 3 patients were willing to continue the program but reported being exhausted for 1 to 2 days after each rehabilitation session. During the sessions, they also reported severe exhaustion. After discussions with these patients, rehabilitation was terminated.

Table 1 summarizes the effect of rehabilitation in the 27 patients who completed the entire program. There was no significant change in exercise time, peak exercise VO₂, lactate threshold, results of quality-of-life questionnaires, anthropometric measurements, or body composition. However, all but 2 patients indicated that the rehabilitation program had improved their overall sense of well-being.

View this table: [in this window] [in a new window]   Table 1. Effect of Cardiac Rehabilitation in 27 Patients Who Completed 3 Months of Training

Although there was no overall change in maximal exercise performance in the population, 9 of the 27 patients who completed 3 months of rehabilitation exhibited >10% increase in both peak exercise VO₂ and the lactate threshold and therefore were considered responders to cardiac rehabilitation. Table 2 summarizes the changes in this subgroup. Peak exercise VO₂ increased significantly by 2 months and thereafter showed no further increase. At 3 months, the increase in peak exercise VO₂ averaged 23%. The lactate threshold did not increase significantly until 3 months, at which point a 28% increase was noted. The slope of the relationship between ventilation and carbon dioxide production decreased. The slope of the relationship between heart rate to VO₂ also decreased. Although all 9 patients reported overall improvement, there was no significant change in the quality-of-life questionnaires. Anthropometric measurements and body composition were also unchanged.

View this table: [in this window] [in a new window]   Table 2. Effect of Cardiac Rehabilitation in Nine Patients Who Responded to Cardiac Rehabilitation

Hemodynamic Status and Response to Rehabilitation
Eleven of the 32 patients (34%) had reduced cardiac output responses to exercise; 21 had normal responses. Table 3 and Fig 2 summarize the exercise responses in these two groups. Patients in the reduced cardiac output group had higher resting heart rates and pulmonary wedge pressures and lower peak exercise cardiac output levels than the patients with normal output responses. However, peak exercise VO₂ and peak exercise lactate levels were not significantly different between the two groups.

View this table: [in this window] [in a new window]   Table 3. Resting Hemodynamic Measurements in the Patient Population

View larger version (24K): [in this window] [in a new window]   Figure 2. Response to cardiac rehabilitation in patients with normal cardiac output responses to exercise vs patients with reduced cardiac output responses.

Fig 2 summarizes the responses to rehabilitation in the two hemodynamic subgroups. Peak exercise VO₂ tended to increase more in patients with normal cardiac outputs (124±209 mL/min) than in patients with reduced cardiac outputs (44±198 mL/min). This difference did not reach statistical significance (P=.34).

All 21 patients with normal cardiac output responses to exercise were able to participate in the rehabilitation program without difficulty, although 2 underwent elective transplantation before completing the program. Eight of the 19 patients who completed the rehabilitation program and 1 of the 2 patients who underwent transplantation responded to rehabilitation, defined by >10% increase in both peak exercise VO₂ and the lactate threshold (43% response rate). All 21 patients reported an overall improvement in their sense of well-being as a result of rehabilitation.

Of the 11 patients with low cardiac output responses to exercise, 3 discontinued the rehabilitation program because of severe exhaustion both during and after each exercise session (3, 4, and 8 weeks, respectively). None of these 3 patients qualified as a responder at the time of program termination. Only 1 of the 8 patients who completed the rehabilitation program was a responder (9% response rate; P<.04 versus normal cardiac output response). There also was no significant change in the quality-of-life questionnaires in this group.

	Discussion

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Traditionally, patients with heart failure have been viewed as a homogeneous group limited primarily by inadequate skeletal muscle flow.^{1 2 3} Recently, however, our group and a number of other investigators have reported that patients with heart failure develop skeletal muscle changes consistent with muscle deconditioning, including decreased mitochondrial size, reduced oxidative enzymes, type II fiber atrophy, and altered muscle metabolic responses to small-muscle exercise.^{22 23 24 25 26} It also has been noted that exercise training improves metabolic responses to exercise and peak exercise VO₂ in some patients.^{27 28 29 30 31 32} These observations have led to a growing assumption that muscle deconditioning is a pervasive problem in patients with heart failure and that all patients with heart failure and exercise limitation should be enrolled in some type of exercise program.

Previous studies of exercise training in patients with heart failure, however, have not consistently shown positive effects. Some studies have demonstrated minimal or no significant increase in peak exercise VO₂.^{30 32} Other studies have demonstrated a significant increase in peak exercise VO₂ for the entire study population but no significant response in most of the patients.^{27 28 29 31}

The present study was undertaken to test the hypothesis that response to exercise training is influenced by the level of circulatory dysfunction. On the basis of the demonstration that some patients with heart failure exhibit relatively normal circulatory responses to exercise whereas other exhibit severely impaired flow responses to exercise,^{6 7} we postulated that the patients most likely to respond to exercise training are those with normal flow responses to exercise. This proposal does not exclude the possibility that muscle deconditioning occurs in patients with severe circulatory dysfunction. However, we speculated that patients with reduced cardiac output responses to exercise are limited primarily by inadequate skeletal muscle blood flow and therefore are unlikely to respond to exercise training.

Thirty-two patients were initially enrolled in the trial, many of whom were awaiting heart transplantation. All these patients had reduced peak exercise VO₂ levels and early lactate release, suggesting skeletal muscle dysfunction. However, fewer than half the patients exhibited cardiac output responses to exercise below normal, consistent with prior observations from our laboratory.^{6 7}

Twenty-seven patients were able to complete the entire 3-month rehabilitation program. In this group, we found no significant change in any measure of body composition or exercise performance. Peak exercise VO₂, lactate threshold, exercise time, lean body mass, leg mass, and quality-of-life questionnaire results were all not significantly altered by rehabilitation. However, 9 patients did have classic responses to exercise training, including an increase in peak exercise VO₂ and lactate threshold, coupled with a reduced heart rate and ventilatory response to exercise.

The failure of peak exercise VO₂ to increase significantly in the entire group may appear somewhat surprising, given prior reports that exercise training improves peak exercise VO₂ in patients with heart failure.^{27 28 29 31 32} However, Barlow et al³⁰ also found no significant increase in peak exercise VO₂ in their study of rehabilitation. Belardinelli et al³² enrolled 36 patients in a cardiac rehabilitation program and noted a 12% overall significant increase in peak exercise VO₂. They observed, however, that most patients exhibited no improvement in peak exercise VO₂. Coats et al²⁸ enrolled 17 patients in a home exercise program and noted a 19% to 20% increase in peak exercise VO₂ in the entire group, but that increase was caused primarily by improvements in approximately one third of the patients.

In the nine patients who exhibited substantial increases in peak exercise VO₂ with rehabilitation, no change in either body composition or the quality-of-life questionnaires was noted. The present study is the first to examine changes in body composition. The fact that leg lean mass and lean body mass did not increase suggests that intrinsic muscle changes, such as increased mitochondrial density, rather than increased muscle mass are responsible for the improved exercise capacity.

The absence of change in the quality-of-life questionnaires is more surprising given the improvements in exercise capacity. We suspect that this discrepancy reflects problems with the questionnaire approach; all patients who were responders reported overall improvement when asked to rate their overall responses to rehabilitation.

When we examined the relationship between hemodynamic status and response to training, there was a clear difference in the effects of rehabilitation in patients with low cardiac output responses to exercise versus patients with preserved flow responses. Three of the patients with low flow responses had to discontinue exercise because of extreme fatigue. All three patients reported severe exertional fatigue before enrolling in the study but consented to try rehabilitation with the thought that the fatigue would improve. Of the eight patients who completed 3 months of rehabilitation, only one exhibited improvements.

In contrast, all patients with normal cardiac output responses to exercise were able to participate in the rehabilitation program without difficulty, and nearly half the patients exhibited substantial increases in peak exercise VO₂ and the lactate threshold. Moreover, all the patients in this group, including patients who exhibited no objective improvement in maximal exercise capacity, reported that their overall sense of well-being was improved by participating in a rehabilitation program.

These findings suggest that hemodynamic responses to exercise can define responders to rehabilitation and therefore support our original hypothesis. We suspect that patients with low cardiac output responses to exercise are limited primarily by circulatory dysfunction and particularly by low skeletal muscle flow. These patients may have muscle changes consistent with muscle deconditioning. However, they are limited primarily by circulatory dysfunction. Consequently, they do not respond to training. In contrast, patients with normal flow responses are limited, at least in part, by deconditioning and therefore respond to training. This phenomenon may explain the fact that different investigators have noted different responses to cardiac rehabilitation in patients with heart failure; response rate would depend on the proportion of patients with normal flow responses.

Why did only a few of the patients with normal flow responses to exercise improve with training? One reason may be that the intensity of training was insufficient for some subjects. For example, two patients with normal flows had respiratory gas exchange ratios during initial exercise testing that never exceeded 0.90, a level that suggests poor motivation. Therefore, training of these patients at 60% to 70% of maximal heart rate may actually represent training at 40% to 50% of maximal exercise capacity, a level unlikely to improve exercise performance. It is also possible that other factors, such as lung dysfunction, limit the exercise performance of patients with normal flow responses.

Study Limitations
All training studies to date have used exercise protocols developed in normal subjects. It is possible that more aggressive and prolonged training protocols might have had more effect on the patients. It is also possible that different training approaches, such as strength training, may be more effective.

The definition of normal cardiac output response to exercise used in this study also has limitations. We used observations by Higginbotham et al⁸ to define a reduced cardiac output response to exercise and found that this definition was consistent with several other prior studies.^{9 10 11} Nevertheless, it is important to emphasize that the cardiac output response to exercise is influenced by sex and age.¹⁰ In addition, the definition of normal flow is to some extent arbitrary because it depends on the confidence limit range used. We defined a reduced flow response as a flow response below the 95% confidence limits reported by Higginbotham et al.⁸ This very strict definition ensures that all flow responses defined as reduced are clearly reduced. However, this approach also is likely to classify borderline flow responses or even mildly abnormal flow responses as within the normal range. Consequently, the flow responses classified as normal in this study population may actually fall into the borderline normal or mild abnormal range.

Clinical Implications
Our results suggest that patients with heart failure and exercise intolerance fall into two general groups. Most patients exhibit normal or nearly normal cardiac output levels during exercise and have high response rates to cardiac rehabilitation, suggesting that skeletal muscle deconditioning is a major contributor to their exercise intolerance. A smaller proportion of patients exhibit reduced cardiac output responses to exercise. These patients usually do not improve with cardiac rehabilitation and may actually find the training program exceedingly exhausting. Although the skeletal muscle of these patients may exhibit changes consistent with muscle deconditioning, it is likely that their exercise intolerance is due primarily to circulatory dysfunction.

These findings, in turn, suggest that direct measurement of hemodynamic response to exercise may help to clarify the basis of exercise limitation in patients with heart failure and identify those patients who should be referred for cardiac rehabilitation. Such an approach might result in substantial cost and time savings and therefore probably should be tested in future outcome studies.

View larger version (26K): [in this window] [in a new window]   Figure 1. Comparison of hemodynamic responses to exercise in patients with normal vs reduced cardiac output (CO) responses to exercise. Statistical comparisons were not performed at 6 and 9 minutes because many patients terminated exercise at 4 to 9 minutes. PWP indicates pulmonary wedge pressure.

	Acknowledgments

 
This work was supported by a Grant-in-Aid from the American Heart Association. We thank Jane Smith, RN, and Patricia Gothard, RN, for their technical assistance.

Received November 15, 1995; revision received March 28, 1996; accepted April 11, 1996.

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